Pharma

Question 1

What is the definition of pain and who defined it?

Answer 1

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage (Mersky, 1979)

Question 2

How is chronic pain currently classified?

Answer 2

Chronic pain is currently classified by etiology; nociceptive pain is caused by tissue injury. neuropathic pain is caused by peripheral nerve lesion and generalized pain is idiopathic.

Question 3

Outline the processes that lead to inflammation

Answer 3

Tissue damage leads to the release of cytokines such as tumor necrosis factor alpha and interleukin-3 which increases levels of inflammatory mediator production in surrounding cells including prostaglandins (PG) and nerve growth factor (NGF). These inflammatory mediators will both directly and indirectly lead to local sensitization of nociceptors (peripheral sensitization)

Question 4

How do we reduce prostaglandin levels?

Answer 4

Reduce the production of PG by cyclooxygenase (COX) enzymes 1 and 2. Classical non-selective COX inhibitors (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen and diclofenac block both COX 1 and 2

Question 5

What are the limitations of NSAIDS (who)?

Answer 5

Inhibition of COX1 leads to deficits in gastric mucosal defence causing gastric ulcer formation and thereby limiting the tolerability of these drugs (Peskar, 2001)

Question 6

What kind of drugs were created to mitigate against classic NSAID side effects?

Answer 6

COX2 selective inhibitors such as Celecoxib

Question 7

Why were COX2 inhibitors discontinued (who)?

Answer 7

Dose-dependently increase the risk of serious cardiovascular events including myocardial infarction (Solomon et al., 2005) which eventually led to discontinuation of use

Question 8

What type of studies suggested anti-NGF’s may be a useful alternative to COX inhibitors?

Answer 8

Reducing levels of NGF markedly reduced hyperalgesia and inflammatory pain in animal models of different pain states (Zahn et al., 2004; Ma and Woolf, 1997)

Question 9

In what recent pain conditions has Tanuzemab been found effective ( and who)?

Answer 9

Chronic lower back pain- Webb et al.,2018

Chronic knee osteoarthritis - Walicke et al., 2018

Hip osteoarthritis have demonstrated efficacy - Birbara et al.,2018).

Question 10

What causes spontaneous and persistent pain?

Answer 10

Alterations in gene expression that lead to abhorrent expression of ion and cation channels in nociceptors; this leads to enhancement of action potential (AP) generation and nociceptor sensitivity

Question 11

What subunits of calcium channels are upregulated in chronic pain conditions?

Answer 11

Upregulation of alpha-2 and delta subunits of voltage-gated calcium channels seen in conditions such as peripheral neuropathy

Question 12

What drugs target calcium channels?

Answer 12

1. gabapentin and pregabalin, which bind to these subunits prevent calcium influx and subsequent neurotransmitter release.
2. opiates have been found to indirectly inhibit calcium channels by beta-gamma dissociation following mu opioid receptor activation.

Question 13

How do opiates act on K+ channels?

Answer 13

Beta-gamma subunits open potassium channels to induce hyperpolarization and reduce nociceptor excitability

Question 14

How can we target TRPV1 (who)?

Answer 14

60-90-minute application of an 8% capsaicin patch following the application of a local anesthetic has been found to desensitize TRPV1 by means of ubiquitin-mediated degradation in the local area of dermatome where the patch is applied (Jones et al., 2011)

Question 15

Which receptor-coupled cation channels are upregulated in pain?

Answer 15

TRPV1 + NMDAR

Question 16

How can we target NMDAR’s?

Answer 16

Antagonists such as ketamine and MK-801

Question 17

How is NMDAR block limited?

Answer 17

Widespread distribution of this receptor and its importance in vital functions such as cognition, these drugs are only used for short durations in emergency medicine and pediatrics (Kurdi et al, 2014)

Question 18

How do we know that chronic pain patients have ON/OFF cell imbalances (who)?

Answer 18

Patients with extensive spreading hyperalgesia, such as those with fibromyalgia, have an imbalance of ON/OFF cell activity whereby there is more ON than OFF cell activity as evidenced by lack of conditioned pain modulation (CPM) (Staud et al., 2003; Tuveson et al., 2007; Roosnik et al., 2011)

Question 19

How do we know that 5-HT3 is important in regulating RVM activity on pain (who)?

Answer 19

5-HT3 receptor knockout mice demonstrate an inability to experience persistent but not acute pain (Zeitz et al., 2002)

Question 20

How can we target 5-HT3?

Answer 20

Ondanserton, a highly selective 5-HT3 receptor antagonist is used as an antiemetic but has been found to have pain attenuating effects

Question 21

How can we target NA?

Answer 21

Serotonin-noradrenaline reuptake inhibitors such as duloxetine have also been effective in the treatment of pain; the efficacy of which can be predicted by CPM (Yarnitsky et al., 2012) - likely produced through NA since SSRI’s useless

Question 22

How do opiates act on OFF cells?

Answer 22

Opiates exert their effects through OFF cell enhancement by activation mu opioid receptors in such descending projections which produces profound analgesia

Question 23

What are the limitations of opiates?

Answer 23

Dependency, tolerance and opiate-induced hyperalgesia, thus lacking tolerability

Question 24

What could be a better option than opiates (who)?

Answer 24

Tapentadol which acts both on mu opioid receptors and as a NA reuptake inhibitor; efficacy of this treatment can be predicted by CPM (Niesters, 2014)

Question 25

What is a more precise way to categorize pain conditions (who)?

Answer 25

Sensory profiling through electrophysiological measures of brush, punctuate mechanical, cooling and heat induced pain (Dickenson and Patel, 2018; Patel et al., 2018)

Question 26

How else can pain be categorized (who)?

Answer 26

Psychosocial factors, sleep patterns and other measures have also been suggested (Edwards et al., 2016)