Pain

Question 1

INTRO: what can pain can be broadly categorized into?

Answer 1

nociceptive pain, neuropathic pain and generalized pain

Question 2

INTRO: what is nociceptive pain is caused by?

Answer 2

an inflammatory or non-inflammatory response to a noxious stimulus such as tissue damage

Question 3

INTRO: what is stimulated in nociceptive pain?

Answer 3

Nociceptive pain is caused by stimulation of sensory nerve fibers that respond to stimuli approaching or exceeding harmful intensity (nociceptors)

Question 4

INTRO: how is nociceptive pain classified?

Answer 4

can be classified according to the mode of noxious stimulation. The most common categories are “thermal” (e.g. heat or cold), “mechanical” (e.g. crushing, tearing, shearing, etc.) and “chemical” (e.g. iodine in a cut or chemicals released during inflammation)

Question 5

INTRO: what is neuropathic pain is initiated or caused by?

Answer 5

a primary lesion or disease in the peripheral (PNS) or central nervous system (CNS).

Question 6

INTRO: what is neuropathic pain devided into?

Answer 6

Neuropathic pain may be divided into peripheral, central, or mixed (peripheral and central) neuropathic pain

Question 7

INTRO: what happens after a peripheral nerve lesion?

Answer 7

After a peripheral nerve lesion, aberrant regeneration may occur and there is a local increase in nociceptor excitability. Neurons become unusually sensitive and develop spontaneously pathological activity and abnormal excitability.

Question 8

INTRO: what is the phenomenon when neurons become unusually sensitive and develop spontaneously pathological activity and abnormal excitability called and what can it lead to?

Answer 8

This phenomenon is called “peripheral sensitization” and can lead to local allodynia and hyperalgesia.

Question 9

INTRO: what are the major ascending pain pathways called?

Answer 9

The spinal cord dorsal horn neurons give rise to the spinothalamic tract (STT) and the spinoparabrachial tract, which constitute the major ascending nociceptive pathways

Question 10

INTRO: what happens as a consequence of spontaneous activity arising in the periphery?

Answer 10

a form of learning occurs whereby central neurons are sensitized leading to enlarged receptive fields and exaggerated responses to normal inputs. This phenomenon is called “central sensitization”.

Question 11

INTRO: what is central sensitization?

Answer 11

Central sensitization is an important mechanism of persistent neuropathic pain.

Question 12

INTRO: what is generalized pain defined as?

Answer 12

generalized pain is defined as pain that occurs when there is no tissue damage or nerve damage.

Question 13

INTRO: give an example of nociceptive and neuropathic pain occurring together

Answer 13

Nociceptive and neuropathic pain can occur together as in the case of cancer induced bone pain. As the tumor grows the tissue distends and the bone stretches causing nociceptive pain; when the tumor presses on the nerves innervating the bone neuropathic pain is present as well.

Question 14

INTRO: what are the three types of nerve fibre and how are they classified?

Answer 14

classified by conduction velocity, A beta, A delta and C-fibres; in non-pain states only A delta and C-fibres respond to noxious stimuli.

Question 15

INTRO: what are A beta?

Answer 15

A beta are large myelinated nerves which respond to non-painful tactile stimuli such as vibrations and soft pressure

Question 16

INTRO: what are A delta?

Answer 16

A delta are small myelinated fibres that respond to painful mechanical stimuli such as a pin prick

Question 17

INTRO: what are C?

Answer 17

unmyelinated C fibres respond to thermal stimuli

Question 18

Inflammatory nociceptive pain: When tissue is damaged what inflammatory mediators are released?

Answer 18

ATP, protons and prostaglandins

Question 19

Inflammatory nociceptive pain: what do low and higher levels of these mediators do?

Answer 19

Low levels of these chemicals sensitize the C-fibre, whilst higher levels activate it so you have ongoing pain.

Question 20

Inflammatory nociceptive pain: what are prostaglandins produced by?

Answer 20

Prostaglandins are produced by cyclooxygenase (COX) enzymes present in the damaged tissue.

Question 21

Inflammatory nociceptive pain: two types of COX enzymes?

Answer 21

the constitutive COX1 and COX2 which is induced in response to tissue damage that makes the inflammatory prostaglandins PGE2 and PGD2

Question 22

Inflammatory nociceptive pain: Several classes of drugs act to inhibit COX enzymes to reduce inflammation and thus pain. what are they?

Answer 22

Aspirin, ibuprofen and some steroids inhibit COX and prevent prostaglandin production. These drugs are only targeting the prostaglandins and do not affect the production of other mediators. These drugs are not selective inhibiting COX1 and COX2. COX2 selective (rofecoxib) had an effect on circulation and the heart and thus were eventually withdrawn.

Question 23

Inflammatory nociceptive pain: what are responsible for wiring up the NS?

Answer 23

Neurotrophic factors, such as nerve growth factor (NGF), make nerves grow and are responsible for wiring up PNS and CNS in foetal and neonatal life.

Question 24

Inflammatory nociceptive pain: what happens after the NS is wired up?

Answer 24

Once the nervous system (NS) is wired up, the gene switches off until tissue damage, upon which non-neuronal cells like bone cells release NGF.

Question 25

Inflammatory nociceptive pain: what does NGF work on? and how is this shown?

Answer 25

NGF works on mast cells and autonomic afferents. They also work on the peripheral terminals of pain fibres and sensitize them, this can be shown simply; when NGF is injected into a muscle the patient initially feels nothing until someone touches the area sensitizing peripheral endings.

Question 26

Inflammatory nociceptive pain: what monoclonal AB binds to NGF? what is the problem with its use in OA?

Answer 26

Tanezumab is a Monoclonal Antibody which binds to NGF preventing it from binding to its receptor stopping NGF from working. Tanezumab was tested in patients with osteoarthritis (OA) and was shown to have a remarkable analgesic action which lasted about 6 weeks. However, many of the patients needed new joints much earlier than expected.

Question 27

Neuropathy in the periphery: who cut each others nerves and why?

Answer 27

Henry Head and William Rivers in 1903 took in turns to cut each other’s nerves to see what would happen. They concluded that a small lesion of the nerve could heal, but if it was too big it wouldn’t.

Question 28

Neuropathy in the periphery: what 2 major things happen in neuropathy?

Answer 28

if the nerve is disconnected from the periphery and dead the patient will have no sensation and the affected region goes numb. If the nerve is disconnected but still alive, it can generate activity without any peripheral stimulation; the affected area is numb but also generates pain signals.

Question 29

Neuropathy in the periphery: Nerves contain ion channels, such as.....

Answer 29

sodium channels which drive the action potential (AP), potassium channels which stop the AP and calcium channels which control the release of transmitter.

Question 30

Neuropathy in the periphery: Damage of a peripheral nerve alters the expression of these ion channels.....

Answer 30

there is upregulation of sodium channel function, upregulation of calcium channel function and a loss of potassium channels.

Question 31

Neuropathy in the periphery: The nervous system detects a loss of input from degenerating fibres and tries to compensate by.....

Answer 31

increasing excitation and decreasing inhibition. Thus, instead of restoring normal transmission, a pain syndrome ensues.

Question 32

Neuropathy in the periphery: Abnormal sodium channel function is the pharmacological basis for the use of drugs such as.....

Answer 32

carbamazepine, lamotrigine and local anaesthetics in patients with neuropathic pain.

Question 33

Neuropathy in the periphery: what happens after nerve injury? and what does this contribute to?

Answer 33

demyelination and abnormal trafficking of sodium channels occur along the membrane of injured nerves and may also occur in their uninjured neighbours. This contributes to the development of central sensitization and amplification of peripheral events, possibly leading to allodynia and hyperalgesia seen in patients.

Question 34

Neuropathy in the periphery: how do sodium channel blockers such as carbamazepine stop pain transmission

Answer 34

by blocking the propagation of APs

Question 35

Neuropathy in the periphery: Mutations in sodium channels (particularly Nav 1.7 coded for by SCN9A) have been implicated in.....

Answer 35

many pain disorders such as inherited erythromyalgia, paroxysmal extreme pain disorder and channelopathy associated insensitivity to pain. This highlights how important Nav 1.7 is in the transmission of pain and many companies are looking for sodium channel blockers that only target this channel in an attempt to selectively block pain signaling and thereby avoid unwanted side-effects.

Question 36

Neuropathy in the periphery: Finding a mutation in SCN9A may have implications in treatment and in choosing a drug with activity against voltage-gated sodium channels.....

Answer 36

such as mexiletine, which is not normally recommended in the treatment of neuropathic pain but is used in inherited erythromelalgia. Mexiletine has proven efficacy in normalizing abnormal channel properties in vitro and clinical efficacy in individual cases (Luana et al., 2017).

Question 37

Neuropathy in the periphery: Voltage-gated calcium channels (VGCC) control neurotransmitter release from the.....

Answer 37

central presynaptic terminals of peripheral fibres arriving at the dorsal horn of the spinal cord, and so are crucial for activation of spinal post-synaptic neurons, which promote propagation of the sensory signal to the higher centres of the central nervous system (CNS).

Question 38

Neuropathy in the periphery: where do gabapentin and pregabalin bind?

Answer 38

Drugs such as gabapentin and pregabalin have been found to bind to alpha 2 and delta subunit complex of voltage dependent calcium channel effectively blocking it.

Question 39

Neuropathy in the periphery: what happens in peripheral neuropathy?

Answer 39

The alpha 2 and delta subunits are upregulated in peripheral neuropathy and, therefore, these subunits are attractive drug targets to treat pain associated with peripheral neuropathy. Blocking these receptors prevents the release of transmitter and decreases pain transmission.

Question 40

Neuropathy in the periphery: So far no drugs act on potassium channels in the treatment of pain.....

Answer 40

but opioids indirectly open potassium channels via the βγ subunit of the mu opioid receptor-coupled G-protein.

Question 41

Wind up: what is pain wind up? and what is it caused by?

Answer 41

Pain wind-up is the increase in pain intensity over time, when a given stimulus is delivered repeatedly above a critical rate. It is caused by repeated stimulation of peripheral C nerve fibers, leading to progressively increasing electrical response in the corresponding spinal cord (posterior horn) neurons due to priming of the NMDA receptor (NMDARs) based response. It describes an exponentially progressive increase in firing of wide dynamic range (WDR) neurons with repeated stimulation. Wind up is a form of LTP.

Question 42

Wind up: what receptors are involved in pain?

Answer 42

NMDARs and AMPA receptors (AMPARs) are involved in the transmission of pain, with 90% of C fibre inputs using glutamate.

Question 43

Wind up: what happens after a brief acute stimulus?

Answer 43

pain transmission from C-fibres is largely mediated by the action of glutamate on AMPA receptors. However, when the stimulus is sustained or its intensity is increased the action of substance P, which is co-released with glutamate, helps remove the magnesium-ion block and the NMDA receptor is activated.

Question 44

Wind up: why are AMPARs bad pain targets?

Answer 44

AMPARs are not a good pain target as they are involved in the transmission of touch and pain.

Question 45

Wind up: why are NMDARs good pain targets?

Answer 45

NMDARs are a good target for both inflammation and neuropathic pain as both involve temporal summation and the abnormal enhancement of activity.

Question 46

Wind up: NMDAR antagonists?

Answer 46

NMDARs mediate wind up so antagonists, such as ketamine or MK-801 which block the ion channel, block wind up and each stimulus is reduced back to the original neuronal response. NMDAR antagonists have powerful analgesic effects

Question 47

Wind up: NMDAR antagonists problems?

Answer 47

due to the ubiquitous nature of NMDARs they are associated with profound changes in consciousness and dissociative hallucinations, which limits their use. Nonetheless, ketamine is still used extensively in emergency medicine and pediatrics (Kurdi et al. 2014).

Question 48

Hypersensitivity after tissue and nerve damage: what is hypersensitivity and when does it occur?

Answer 48

Hypersensitivity, which usually occurs after tissue and nerve damage, causes some normally non-noxious stimuli to become painful.

Question 49

Hypersensitivity after tissue and nerve damage: hypersensitivity can.....

Answer 49

amplify pain via wind up, prolong pain and increase the area of pain.

Question 50

Hypersensitivity after tissue and nerve damage: what happens when central neurons have gone into sensitized state?

Answer 50

large A beta fibres now allow non-painful stimuli like brush to access pain pathways

Question 51

Hypersensitivity after tissue and nerve damage: Inflammation and tissue injury in peripheral pain, such as osteoarthritis can lead to.....

Answer 51

peripheral sensitization and local hyperexcitability of nociceptors, which is associated with tissue injury and typically spreads about 5-10mm (Fitzgerald, 1979). If these are left untreated they will eventually become centrally driven.

Question 52

Descending Controls: In the spinal cord lamina 1 and 5 go up to the.....

Answer 52

thalamus and cortex respectively. a=1 e=5

Question 53

Descending Controls: Descending pain controls are from well-defined brain stem nuclei that receive painful inputs; the two transmitters involved in the descending pathway are.....

Answer 53

noradrenaline (NA) and serotonin (5HT)

Question 54

Descending Controls: what drugs target NA and 5HT?

Answer 54

These two transmitters are the targets for a major class of drugs known as antidepressants. They are important in mood but equally critical for descending control pathways in brain.

Question 55

Descending Controls: Painful inputs into limbic brain disrupt function and start to generate comorbidities. .....are a series of interconnected brain stem nuclei that project to spinal cord.

Answer 55

The locus coeruleus and the rostral ventromedial medulla (RVM)

Question 56

Descending Controls: what does the RVM contain?

Answer 56

The RVM contains ON (facilitate pain) and OFF cells (inhibit pain) which use serotonin and noradrenaline (NA), respectively. OFF cells can also respond to opioids.

Question 57

Descending Controls: how does NA inhibit pain? and why is the action of 5HT mixed?

Answer 57

NA inhibits pain via alpha 2 adrenoceptors, whist the effects of serotonin are mixed: 5HT1 and 5HT7 inhibit pain and 5HT2 and 5HT3 facilitate it.

Question 58

Descending Controls: what is fibromyalgia? and what did Staud find?

Answer 58

Fibromyalgia is a disorder associated with dysregulated descending controls. Staud and colleagues (2003) found that immersing one's hand in a hot bath while the other is presented with noxious heat stimuli led to increased pain thresholds in female controls but not females with fibromyalgia, indicating reduced effectiveness of the descending controls in the disorder.

Question 59

Descending Controls: what do SNRIs do?

Answer 59

Serotonin–norepinephrine reuptake inhibitors (SNRIs) antidepressants (such as duloxetine) increase the level of synaptic neurotransmitters which activate and restore descending pathways resulting in reduced pain.

Question 60

Descending Controls: alpha 2 agonists?

Answer 60

Alpha 2 agonists (clonidine) also have analgesic effects but also induce sleep which make them not as useful for treating human patients but very effective in veterinary medicine.

Question 61

Descending Controls: OA pain

Answer 61

Osteoarthritis (OA) pain is typically characterised as nociceptive. However, in some patients, OA pain manifests with neuropathic features. Nerve disruption in conjunction with central sensitisation can result in pain with neuropathic features, such as a decreased pain threshold and an increased vibration detection threshold, in a subset of patients.

Question 62

Descending Controls: how is OA treated?

Answer 62

While OA pain is commonly treated with paracetamol as well as non-steroidal anti-inflammatory drugs (NSAIDs), preliminary studies suggest that a subset of OA patients, which express pain with neuropathic features, may benefit from non-standard analgesics such as tricyclic antidepressants or SNRIs. Recently, duloxetine, an SNRI was approved by the FDA for treatment of osteoarthritis pain (Havelin et al., 2016).

Question 63

Descending Controls: 5HT drugs in pain?

Answer 63

Ondansetron, a 5HT3 receptor antagonist, acts as an antiemetic but has also been shown to be effective in relieving some types of pain. Triptans, such as sumatriptan are 5HT1B/D agonists and are effective in the treatment of migraine. However, they have not been shown to be good at treating any other forms of pain.

Question 64

Descending Controls: what is DNIC?

Answer 64

Diffuse noxious inhibitory controls (DNIC) is where one painful stimulus somewhere in the body would inhibit the other. The human counterpart is called conditioned pain modulation. This inhibition of pain is also controlled by the inhibitory descending controls, which relies on opioid and noradrenergic signalling.

Question 65

Descending Controls: what is tapentadol? and how doe it work?

Answer 65

Tapentadol is an drug that acts as both mu opioid receptor agonist and a noradrenaline reuptake inhibitor (NRI). When you block the uptake of NA, you produce more synaptic NA and thus more alpha 2 receptor activity which reduces pain. When alpha 2 receptors are blocked with atipamezole, tapentadol still exerts an analgesic activity due to its opioid properties and in mu opioid knockout mice the drug remained effective through NA pain control mechanisms.