Pain

Question 1

What is pain?

Answer 1

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage

Question 2

What is nociceptive pain?

Answer 2

• Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors
• First Pain
• Second Pain
• Visceral Pain (Referred Pain)

Question 3

What is Acute pain?

Answer 3

Acute pain (short duration) is often nociceptive and can be associated with a cause

Question 4

What is neuropathic pain?

Answer 4

Neuropathic Pain
• Pain caused by a lesion or disease of the somatosensory nervous
system, either located in the CNS or in the PNS

• Chronic pain (long duration, months or more) is often neuropathic

Question 5

Contrast comduction velocity in A-delta fibers and C fibers?

Answer 5

Conduction velocity of A-delta fibers is higher than of C fibers, which means the pain signals reach consciousness at different times, depending on the type of fibers that carry them.

Question 6

Where does pain perception take place?

Answer 6

Cerebral cortex

Question 7

Describe visceral pain (referred pain)

Answer 7

• Visceral pain is carried in visceral afferent C-fibers, running alongside autonomic (mostly sympathetic) efferent fibers.
• Visceral pain is often colicky or cramping, and poorly localized.
• The phenomenon of feeling visceral pain in certain dermatomal areas is called “referred pain”.
• Example: A reduction of blood flow to the heart (coronary heart disease), causes chest pain (angina pectoris), and may include dermatomal areas from C7 to T4

Question 8

Explain the convergence of reffered pain

Answer 8

Convergence kv afferent fibers from viscera skin

Visceral afferent fiver from heart

Cutaneous afferent fiber from dermatome

To brain —> conscious perception

No distinction between cutaneous and visceral pain because of convergence

Question 9

What are the spinal pain and temperature pathway generalization?

Answer 9

1. Primary sensory neuron: axon in peripheral nerve; cell body in peripheral ganglion
2. Secondary sensory neuron: cell body in CNS; axon crossing midline; ascending to thalamus
3. Tertiary sensory neuron: cell body in thalamus; axon through internal capsule and corona radiata; ending in primary somatosensory cortex

Question 10

Explain the anterolateral system/spinothalmkc tract as s spinal pain pathway

Answer 10

• The primary afferent fibers start in the dermatomes of the skin, run through peripheral nerves, are bundled in spinal nerves and synapse in the dorsal horn of the grey matter of the spinal cord, where they form synapses on second order neurons.
• Axons of the second order neurons immediately cross over to the contralateral side, where they ascend in the anterolateral system (ALS) fiber tract (or spinothalamic tract) up to the ventral posterior lateral (VPL) nucleus of the thalamus, where they form synapses on third order neurons. As in previous lectures, we focus on major pathways which allow us to explain most clinical scenarios. There are, however, additional fiber connections, such as fibers terminating in other posterior thalamic nuclei, as mentioned in your Siegel and Sapru textbook.
• The axons of third order neurons run through the posterior limb of the internal capsule and the corona radiata. They synapse in the primary somatosensory cortex (S1).

Question 11

Explain the. Trigeminal pain pathway

Answer 11

• The pathway for pain originating in the face travels through a trigeminal pathway.
• Primary afferent fibers carrying pain and temperature sensations enter the brainstem at the pons. Instead of synapsing in the principal (chief) sensory nucleus of CN V, the fibers descend (!) ipsilaterally in the spinal trigeminal tract, to synapse in the lower third of the spinal nucleus of CN V, located in the lower medulla.
• Fibers of second order neurons immediately cross the body’s midline in the lower medulla and then ascend in the ventral trigeminothalamic tract until they reach the ventral posterior medial nucleus of the thalamus.
• Axons of the third order neurons ascend through the posterior limb, close to the genu of the internal capsule, run through the corona radiata, and synapse again in the primary somatosensory cortex (S1).
• Please note: Fibers carrying sensory information of pain or temperature, originating in one side of the face, descend in the brainstem (pons and medulla) on the ipsilateral side of stimulation, and ascend on the contralateral side. Knowledge of the location of these different fibers in cross sections of the brainstem is crucial for the interpretation of clinical scenarios (and for answering vignette-based questions

Question 12

Highlight the generalizations of the trigeminal pain and temperature pathway

Answer 12

1. Primary sensory neuron: axon in peripheral nerve; cell body in peripheral ganglion
2. Secondary sensory neuron: cell body in CNS; axon crossing midline; ascending to thalamus
3. Tertiary sensory neuron: cell body in thalamus; axon through internal capsule and corona radiata; ending in primary somatosensory cortex

Question 13

Explain the activation of Nociceptors

Answer 13

Some types of nociceptors are activated by mechanical (with a much higher threshold than touch receptors) or thermal noxious stimuli.

In addition, tissue damage leads to release of a number of chemicals, which in turn activate chemosensitive nociceptors.

One of the substances released from damaged cells is potassium, which can activate nociceptors.

You have learned about the intracellular and extracellular potassium concentrations during the cellular neuroscience lectures. Under normal conditions, potassium is high inside neurons (and other cells) and low in the extracellular space. Increasing extracellular potassium, by breaking the cell membrane of cells and releasing potassium into the extracellular space, reduces the electrochemical potassium gradient between the inside and the outside of cells, causing depolarization of nociceptors in the vicinity of the damage.

Other substances released at the site of damage are bradykinin from blood and histamine from mast cells, which also activate nociceptors

Question 14

How are mechanosensitive nociceptors activated?

Answer 14

Mechanosensitive
High threshold receptors, respond to intense
mechanical stimuli

Question 15

How are thermosensitive nociceptors activated?

Answer 15

Thermosensitive
High threshold receptors, respond to intense
heat or cold stimuli

Question 16

How are chemosensitive nociceptors activated?

Answer 16

Chemosensitive

Respond to chemical stimuli

Histamine from mast cells
Bradykinin from damaged blood vessels
Potassium from damaged cells

Question 17

How are polymodal nociceptors activated?

Answer 17

• Respond to multiple stimulus modalities

Question 18

What is sensitization?

Answer 18

• Increased responsiveness of nociceptive neurons to their normal input, and/or recruitment of a response to normally subthreshold inputs.
• Note: Sensitization can include a drop in threshold and an increase in suprathreshold response. Spontaneous discharges and increases in receptive field size may also occur. This is a neurophysiological term that can only be applied when both input and output of the neural system under study are known, e.g., by controlling the stimulus and measuring the neural event.
• Clinically, sensitization may only be inferred indirectly from phenomena such as hyperalgesia or allodynia

Question 19

How do NSAIDs reduce pain?

Answer 19

Note: Prostaglandins are enzymatically synthesized from arachidonic acid by cyclooxygenases (COX-1 and COX-2). Non- Steroidal Anti-Inflammatory drugs (NSAIDs) inhibit cyclooxygenase, which reduces pain.

Question 20

How does substance P influence pain?

Answer 20

Note: Substance P, the neuropeptide of nociceptors, is released at the site of injury, increasing pain sensitivity.

Question 21

What are the pain response before and after injury?

Answer 21

The consequences of this sensitization of nociceptors after injury is shown on the figure on the right. The response curve showing the level of pain sensation in relation to stimulus intensity is shifted to the left, compared to a normal condition prior to the injury.

Based on this, previously painless stimuli become painful (allodynia) and the intensity of sensations already painful under normal circumstances is increased (hyperalgesia).

Question 22

What is Allodynia?

Answer 22

Change in pain perception-Pain due to a stimulus that does not normally provoke pain

Sensitization mechanism- Lowering of pain threshold of nociceptors

Question 23

What is Hyperphagia?

Answer 23

Change in pain peception- Increased pain from a stimulus that normally provokes pain

Sensitization mechanism- Increase of supra- threshold response of nociceptors

Question 24

Explain afferent regulation of pain

Answer 24

We know from experience that pain often can be relieved by gently stimulating the skin around an injured area, such as light brushing, massage, or tickling. It seems as if touch can inhibit the pain pathway. Based on the experience described above, Melzack and Wall (1965) suggested a gate control theory, which suggested a neuronal circuitry responsible for this phenomenon.
The gate control circuitry in the dorsal horn of the spinal cord is well established now.

Medium sized myelinated A-beta fibers carrying touch sensations activate inhibitory interneurons within the dorsal horn of the spinal cord, which then reduce the flow of nociceptive information through the “gate” between primary nociceptors and secondary neurons along the pain pathway.
Enkephalin, one of the endogenous opioid peptides, has been identified as neurotransmitter of these inhibitory interneurons, acting on opioid receptors, which can be found on the cell bodies of the primary afferent neurons, on their presynaptic ending and also on the postsynaptic membrane of the second order neurons.

When opioids bind to these opioid receptors, they decrease the duration of action potentials generated in the primary afferent neurons, decrease the amplitude of the excitatory postsynaptic potentials, and they hyperpolarize the second order neurons along the pain pathway.

Question 25

Explain descending pain control

Answer 25

Apart from the thick and medium myelinated fibers of the somatosensory receptor neurons, descending serotonergic (from periaqueductal grey, nucleus raphe magnus) or noradrenergic (from locus ceruleus) fibers originating in the brainstem participate in the physiological modulation of pain.
These descending monoaminergic fibers run in the lateral and anterior funiculi of the spinal cord and terminate on the opioidergic interneurons in the dorsal horn, where they control the transmission of pain.

The nuclei where the descending pain control fibers originate, receive input from ascending ALS fibers carrying nociceptive information.

Some of the ALS fibers synapse in specific brainstem areas, such as the periaqueductal grey of the midbrain (spino-mesencephalic fibers) and the reticular formation of pons and medulla (spino-reticular fibers).

Question 26

How can pain be examined?

Answer 26

Pain can be examined together with touch, using either side of a safety pin (or more sophisticated devices with dull and sharp ends). With the patient’s eyes closed, the examiner touches different areas of the body’s surface with one end of the safety pin or the other, asking the patient “Is this sharp, or is this dull?”

As part of your practical clinical skills training, you will be performing these tests in small group practical sessions. To familiarize yourself with these examinations, you may watch the hyperlinked YouTube video: neurological examination of pain (0:15 to 0:50).

A lack of any response to either touch or pain stimuli in a small area may be due to a peripheral nerve lesion, or a central lesion in the primary somatosensory cortex.
When pain sensations are lost in a larger area, such as one side of the body, but touch sensations are still intact, lesions along the pain pathway are considered where touch and pain fibers run distant to each other, and/or receive blood supply through different arteries that might have been affected.
A review of brainstem sections with regards to pathway localization and blood supply (Haines Atlas, 10th edition (2019), Figures 6-16, 6-23 and 6-30) is highly recommended

Question 27

Summarize neurological examination of pain

Answer 27

• Usually done by randomly alternating with touch stimulation
• Explain the procedure with the patient’s eyes open
• Ask the patient to close eyes
• Test different dermatomes
• Randomly alternate between sharp and dull stimuli
• Compare proximal vs distal / left vs right touch or pain perception
• Forced choice: “Is it sharp or is it dull?”

Question 28

Assess pain intensity

Answer 28

There is no objective measurement of pain intensity, so the physician has to rely on patient self-reporting of the intensity of pain. To be able to compare pain intensity before and after an intervention (pharmacological, surgery, etc.), it is necessary to use the same tools before and after to quantify the pain.

There are multiple pain assessment tools available, including verbal rating scales, questionnaires, etc. Two of the key assessment tools are described below.

For adults, a Visual Analogue Scale can be used, where the patient has to mark the perceived intensity of pain on a line that ranges from “No pain” on one end to “Pain as bad as it could be” on the other end. The location can be easily translated into equivalent numbers, usually ranging from “0” for no pain to “10” for pain as bad as it could be.

For children, a Faces Pain Scale has been developed, where a child can describe the intensity of pain felt, by choosing a face that best describes how much it hurt

Question 29

What is a headache?

Answer 29

Headache is a pain sensation caused by the stimulation of pain-sensitive structures within the head, such as the wall of blood vessels, the dura mater, or the periost. Note: there are no nociceptors in the brain parenchyma

Question 30

What is the effect of aspirin?

Answer 30

The effect of aspirin and other non-steroidal anti-inflammatory analgesics in controlling pain is due to its ability to inhibit the enzyme cyclo-oxygenase. This enzyme is responsible for the synthesis of prostaglandins, agents which sensitize sensory afferent fibers.

Question 31

What is Acupuncture

Answer 31

One of the most recent and most thoroughly conducted systematic reviews by Ernst et al 2011 (Ernst E, Myeong Soo Lee and Tae-Young Choi, Acupuncture: Does it alleviate pain and are there serious risks?). In this review of reviews, published in Pain 152 (2011), and using reviews from Medline, Embase, AMED, CINHAL, the Cochrane Library, and 6 Korean and Chinese databases without language restrictions, the authors concluded that “numerous systematic reviews have generated little truly convincing evidence that acupuncture is effective in reducing pain. Serious adverse effects continue to be reported.

Question 32

How do NSAIDs manage pain?

Answer 32

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Inhibit cyclo- oxygenases (COX-1 and COX-2), the enzymes responsible for prostaglandin synthesis from arachidonic acid.

• Example: Aspirin

Question 33

What are Opioids?

Answer 33

Opioid substances, such as morphine, are very strong pain killers, but also have strong aversive effects, including the addiction potential. They are used for serious pain conditions. By binding to opioid receptors, they activate the physiological pain control circuitry.

Question 34

How can pain be managed surgically?

Answer 34

After all non-surgical measures have been exhausted, surgical treatment of pain may be considered. The underlying rationale is that a surgical interruption of the pain pathway prevents pain signals from reaching consciousness. Multiple procedures are described in the literature and are used in clinical practice

Question 35

What is phantom limb pain?

Answer 35

After amputation of a limb, some patients suffer from pain seemingly still originating from the amputated limb. These pain sensations can range from rarely occurring, short episodes, to constant, long lasting and excruciating pain. Phantom limb pain is a form of neuropathic pain (deafferentation pain). Most of the pathophysiological mechanisms associated with this pain syndrome are likely to happen within the central nervous system. The cerebral cortex is one of the prime candidates where the pathological mechanism is most likely located.

Question 36

How can opioids be used to treat pain?

Answer 36

• Opioids bind to presynaptic and postsynaptic sites on the synapses between primary and secondary pain neurons, where they mimic the effect of endogenous opioids (enkephalin), closing the gate.
• Opioid use needs to be considered carefully (see IASP Statement on Opioids)

Question 37

How can SNRIs be used for pain?

Answer 37

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) are antidepressants, which can also alleviate pain. They increase the availability of serotonin and norepinephrine in the synaptic cleft between descending pain control fibers and inhibitory enkephalinergic interneurons. The subsequent increase of enkephalin release closes the gate between first and second order pain neurons.

Question 38

How can we surgically interupt pain pathways?

Answer 38

• Surgical interruptions of pain pathways prevent pain signals from reaching the brain, preventing pain perception.
• These are very rare procedures, applied in extreme cases of terminally ill persons, after other ways of intervention have been exhausted.