Pain

Question 1

What is pain?

Answer 1

Pain is an, unpleasant sensory and emotional experience associated with actual or potential tissue damage.

Noci - prefix denoting pain or injury.

Nociceptive - describing nerve fibres, or pathways concerned with pain.

Nociceptor - receptor responding to pain (interceptors, exteroceptors).

Question 2

What is transduction?

Answer 2

Conversion of noxious thermal, mechanical, or chemical stimulus into electrical activity in the peripheral terminals.

Question 3

What is conduction?

Answer 3

Passage of action potentials from the peripheral terminal along axons to central terminal in the CNS.

Question 4

What is transmission?

Answer 4

Synaptic transfer and modulation of input from one neuron to another.

Question 5

What is perception?

Answer 5

Appreciation of signals arriving in higher structures and pain.

Question 6

What is modulation?

Answer 6

Inhibitory and facilitatory input from the brain that modulates nociceptive transmission at the spinal cord.

Question 7

How is pain modulated?

Answer 7

Periaqueductal grey (PAG):

Role in mediation of analgesia.

Electrical stimulation of the PAG mediates analgesia and release of endogenous opioids.

Question 8

How does pain inhibition work?

Answer 8

Inhibition of spinal pain transmission by defending pathways:

Electrical stimulation of the midbrain periaqueductal grey (PAG), causes analgesia.

Neurons in the PAG project to the rostral ventral medulla (RVM) (i.e. descending pathways).

RVM contain “on cells” which can cause hyperalgesia or “off cells” which can case analgesia.

Question 9

What are the different types of analgesic drugs?

Answer 9

Nonopioids:

Acetaminophen.
NSAIDs.
COX-2 inhibitors.

Morphine-like drugs (opioids).

Adjuvant analgesics:

Antiepileptics.
Topical agents/local anaesthetics.

Question 10

What are the clinical indications for nanopioids?

Answer 10

Variety of acute and chronic pain types:

Trauma, post-op, cancer, arthritis.

Somatic pain:

Muscle and joint pain, bone/dental pain, inflammatory pain, post-op pain.

Question 11

How is pain transmitted to the spinal cord?

Answer 11

DRG are a specialised sensory neurons (bipolar), which mean that it extends and goes into the surface tissue. You can have two different types:

Non myelinated , c fibres - transmit slower information, low conduction velocities (> 1 m/s), dull burning pain.
Myelinated Aẟ and Aβ fibres, higher conductance, sharp, localised pain.

Once these fibres are activated, they will send a signal to dorsal root ganglion cell bodies.

The cell bodies will be activated and fire an action potential , which is carried down the axon, into the spinal cord (the dorsal horn).

The neurons within the dorsal horn are involved in pain transmission, so the DH will fire an action potential, cause a release of exitatory transmittors which will be able to activate the dorsal horn neurons and then fire an action potential and extend ascending fibres to the brain to transmit information.

Through the medulla and pons into the thalamus.

Question 12

What are antiepileptics?

Answer 12

Examples:

Gabapentin, pregabalin, carbamazepine, phenytoin, levetiracetam, lamotrigine.

Mechanism of action:

Suppress neuronal hyperexcitability via:

Reducing neuronal influx of Na+ and Ca2+.

Direct/indirect enhancement of GABA inhibitory effects.

Reduce activity of glutamate and/or blocking NMDA receptors.

Adverse events:

Mental clouding, dizziness, nausea, unsteadiness, fatigue, GI upset, hematologic abnormalities, liver dysfunction, hypersensitivity reactions, rash.

Question 13

What are topical analgesics?

Answer 13

Examples:

Lidocaine, LidoDerm 5% patch®, EMLA®,Capsaicin cream.

Mechanism of action:

Block sodium channels and inhibit generation of abnormal impulses by damaged nerves.

Depletion of substance P in sensory nerve endings.

Adverse events:

Local allergic reactions, systemic reactions (rare); localized burning sensation.

Question 14

What are the different types of pain?

Answer 14

Cutaneous pain - sharp, bright, burning; can have a fast or slow onset.

Somatic pain - activated by pain receptors in cutaneous or deep tissues.

Visceral pain - originates from internal organs; diffused 1st & later may be localized (i.e. appendicitis).

Neuropathic pain - pain initiated or caused by a 1º lesion or dysfunction in the nervous system; stabbing pain, continuous burning.

Question 15

What is the role of neuronal plasticity in chronic pain?

Answer 15

Causes nervous system changes in:

Neuronal structure.
Connections between neurons.
Quantity/properties of neurotransmitters, receptors, ion channels.

Decreases body’s pain inhibitory systems —> Increased pain.

Injury, inflammation, and disease are culprits.
Produces short-term and permanent changes.
Pivotal to the development of hypersensitivity of inflammatory pain.
Enables NS to modify its function according to different conditions.

Question 16

How is pain transduced?​

Answer 16

Pain transduction is accomplished via specialized ion channels including those noted in the figure (TRP, ASIC, and voltage-gated sodium channels).

Simultaneously, the brain can alter the transmission of a pain signal via descending pain modulatory tracts.

Question 17

How is pain transmitted to the brain?

Answer 17

A pain message is transmitted to the brain by specialized nerve cells known as nociceptors, or pain receptors.

When pain receptors are stimulated by temperature, pressure or chemicals, they release neurotransmitters within the cells.

The stimulus directly or indirectly acts on sensory nerve fibres, generating an action potential that is used to transmit the pain signal to the dorsal horn of the spinal cord.

The signal crosses the spinal cord and eventually reaches the brain, which is when we become aware or conscious of the pain.

Question 18

How does acute pain become chronic​?

Answer 18

Peripheral sensitization:​

Tissue damage releases sensitizing “soup” of cytokines & neurotransmitters.​

​Tissue injury —> release of bradykinin and the activation of cyclooxygenases —> generation of prostaglandins and other mediators, such as K+ and H+. ​
​Bradykinins and prostaglandins activate and sensitize neurons. ​

​Sensitized nociceptors exhibit a decreased threshold for activation & increased rate of firing.​

Plays an important role in central sensitization, hyperalgesia, & allodynia​.

Central sensitization​:

​Activation: sensitization of dorsal horn nociceptors ​

​Neuronal plasticity: ​

Modulation - changes in neurotransmitter systems and ions channel function.​

Modification - new pain-sensing fibres form. ​

​Decreased central inhibition of pain transmission. ​

​Prime role in chronic pain, particularly neuropathic pain.​

Question 19

How does central sensitization leads to secondary hyperalgesia​?

Answer 19

Repeated impulse activity in C nociceptive neurons. ​

Produces sensitization of spinothalamic tract neurons over time. ​

​Previously subthreshold inputs reach threshold: ​

Initiate action potential.​
Increases in spontaneous activity. ​

​Enlargement of area in periphery where stimulus will activate neurons. ​

​N-methyl-D-aspartate (NMDA) receptor and substance P mechanisms​.

Question 20

What are nonopioids?

Answer 20

Like acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) control mild to moderate pain.

Some can be bought without a prescription (over-the-counter).

These medicines are stronger pain relievers than most people realize.

Mechanism of action:

Inhibits COX, a key enzyme responsible for the biosynthesis of prostanoids, including prostaglandins. Nonselective NSAIDs inhibit both COX-1 and COX-2.

Question 21

What are opioids?

Answer 21

Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia.

Mechanism of action:

The actions of opioids are primarily inhibitory. Opioids close N-type voltage-operated calcium channels and open calcium-dependent inwardly-rectifying potassium channels.

This results in hyperpolarization and a reduction in neuronal excitability. Kappa receptors may act only on calcium channels.