9.2 Principles of drug therapy: Focus on opioids

Question 1

What are two predominant differences between acute and chronic pain

Answer 1

Acute pain - series of excitatory events at peripheral and central levels that transmit signals of noxious events that have an overt relationship to identifiable damage

Chronic pain - altered neurophysiological and pharmacological substrates at many levels from periphery to CNS and the relationship between noxious phenomena and level of pain can become altered

Question 2

What are 3 results of nervous plasticity in chronic pain?

Answer 2

expanded receptor fields
increased amplitude of response to a given stimulus (hyperalgesia)
pain elicited by normally innocuous stimuli (allodynia)
Spontaneous pain in absence of any stimuli
sensory deficits
affective and emotional response to pain

Question 3

Name two types of nerves that conduct nociceptive info from the periphery. Where do they terminate in the spinal cord?

Answer 3

Adelta and c fibres

terminate in the superficial laminae of the dorsal horn of the spinal cord

Question 4

List three areas to which the second order neurons from the Lamina 1 project

Answer 4

Periaqueductal grey area (PAG)
lateral parabrachial nucleus
thalamus
nucleus tractus solitarius 
medually reticular formation

Question 5

List 3 ways through which a polymodal nociceptor may be activated. Give two examples of chemicals that activate a nociceptor

Answer 5

voltage changes, chemical mediators of pain, thermal/mechanical

adenosine, bradykinin, prostaglandin, noradrenaline, protons, heat/capsaicin, adenosine triphosphate (ATP), nerve growth factors

Question 6

What is the process through which a peripheral stimulus is converted into an electrical stimulus to transmit a message to the CNS

Answer 6

transduction

Question 7

What is central sensitization? What neurotransmitter receptor mediates the effect of wind up?

Answer 7

Central sensitizaion - The CNS amplifies the inputs it receives from the peripheral nervous system which causes increased perception of pain

NMDA receptors are ligand gated ion channel that are blocked by a Mg ion. After prolonged peripheral c fibre nociceptive drive, increased presynaptic glutamate and substance P cause depolarization and displacement of the Mg ion and calcium ions enter the cell - leads to more post synaptic excitability and potentiates response

Question 8

List two types of bone. Which is more prominent in the skeleton? What are the two main cells involved in bone remodelling? What do they each do?

Answer 8

cortical bone (dense outer layer - 80% of skeleton) and trabecular bone

osteoclasts - bone degradation

osteoblasts - bone formation

Question 9

List four peripheral mechanisms that contribute to cancer induced bone pain

Answer 9

• infiltration of tumor cells and immune mediated response to tumor leads to release of cytokines, interleukins, chemokines, prostanoids, growth factors, endothelins
• As the tumor grows there is progressive innervation of the tissue driven NGF
• ATP is present in all cells and released when there is cell damage. This may increase activation of central terminals of afferents and enhance spinal excitability
• The osteoclast/osteoblast/RANK-L axis disruption - ie. PTHrP release by tumor
• osteoclast induced acidosis - increased osteoclast activation -> decreased cellular pH, increased sensitization by protons
• structural damage to bone and nerves

Question 10

List four treatments for cancer induced bone pain

Answer 10

opioids
gabapentin 
NSAIDs
COX-2 inhibitors
bisphosphonate
steroids

Question 11

Provide 4 causes of nerve damage in people with advanced disease

Answer 11

tumor compressing nerve
surgical resection
radiotherapy
chemotherapy

Question 12

A patient experiences nerve damage. A neuroma forms at the site of damage. What is likely to happen to the neuron sodium channels in the area? What will be two effects of this?

Answer 12

Sodium channel accumulation has been shown to occur around the neuroma

lower the threshold for activation and induce ectopic activity in the peripheral nerve

Question 13

Other than sodium channels, name another ion channel whose dysregulate activity may be involved in the generation of neuropathic pain

Answer 13

voltage gated calcium channels

Question 14

Higher brain centres impact the experience of pain. What neurotransmitter regulates the transmissions from the dorsal horn to the brainstem? What neurotransmitter is responsible for descending facilitation of pain signalling?

Answer 14

substance p - the dorsal horn to the brainstem

serotonin (5HT3) - descending facilitation of pain signalling

Question 15

List 7 functions of Mu Receptors:

Answer 15

Analgesia
Resp depression
Reduced GI motility
Miosis
Euphoria
Physical dependence
Sedation

Question 16

List 3 downstream effects of mu-opioid receptor activation:

Answer 16

Inhibition of adenylyl cyclase
which inhibits cyclic AMP, which is important in transmission of pain signals.

Increased opening of K+ channels
hyperpolarization of post-synaptic neurons causing reduced synaptic transmission.

Inhibition of calcium channels
decreases pre-synaptic neurotransmitter release.

Question 17

List 2 opioid receptor antagonists:

Answer 17

naloxone

naltrexone

Question 18

List 3 opioid receptor mixed agonist/antagonist:

Answer 18

pentazocine
butorphanol
nalbuphine

Question 19

List four central mechanisms that contribute to cancer-induced bone pain:

Answer 19

primary afferent fibres are sensitized following tumour growth in the periphery

central changes to the spinal cord following tumour growth at the periphery

• astrocyte hypertrophy
• increase in pro-hyperalgesic peptide dynorphin
• release of pro-inflammatory cytokines
• substance P internalization
• increased c-Fos expression

Change in ratio of Wide Dynamic Range neurons and Nociceptive Specific Neurons in the superficial laminae of the dorsal horn

Anxiety, fear and other negative emotions from higher level centres can influence perceived pain and impact response at spinal cord level (mediated by periqueductal grey area and rostroventral medial medulla).