Pharmacology of Drugs Used for Pain

In this topic, we will look at the pharmacology of non-steroid anti-inflammatory drugs (NSAIDs). We will learn about the two classes of NSAIDs and explore the differences in their pharmacological effects throughout the body. We will also look at the pharmacology of paracetamol, its metabolism and the dangers of overdose.

Intro to Pain and Pain Pathways

We have all experienced pain. Pain serves an important physiological role, it alters us to actual or potential injury however pain can also become disordered.
The International Association for the Study of Pain (IASP) define pain as: “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage”.

In 2020, IASP provided six additional notes regarding pain:

• Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors.
• Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neurons.
• Through their life experiences, individuals learn the concept of pain.
• A person’s report of an experience as pain should be respected.
• Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being.
• Verbal description is only one of several behaviours to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain.

 

 

 

Whilst acute pain can is important to alert us of actual or potential injury, chronic pain (>3months) can lead to significant morbidity and a very high burden on the healthcare system. Chronic pain is responsible for 40% of all early retirements and almost half of chronic pain sufferers also experience depression or anxiety.

Although this module will discuss the pharmacology of analgesics, it is vital to acknowledge that analgesics are associated with very real risk of harm. Pain (especially chronic pain) is best managed by a multidisciplinary team (where available).

Pain Pathways (as they relate to pharmacology)

Before we begin to discuss the pharmacology of analgesics, it is important to understand the generation, transmission, and regulation of nociception (perception of noxious stimuli). You will cover this in greater detail within the NEURO component but there are important concepts that will help you to understand the pharmacology. It is also important to acknowledge that our understanding of the pharmacology of analgesics may at times lean on an incomplete comprehension/application of all elements of nociception.

Watch this YouTube video for a quick reminder of pain transmission and regulation

Please note that the video above does not provide a complete explanation of all anatomical features involved in the pain pathway, nor does is discuss all the chemical mediators involved in pain signalling. More complete information will be provided in NEURO and additional chemical mediators will be introduced in this module.

Ascending pain pathway

The ascending pain pathways are responsible for the detection of noxious stimuli and transmission of these signals to the somatosensory cortex for the perception of pain.

1st Order Nociceptive Neurons

Nociceptors are afferent neurons (1st order neurons) with their sensory region located in peripheral tissues. The presence of various stimuli facilitates depolarisation which triggers an action potential.

The action potential propagates along the neuron ultimately progressing to the dorsal horn of the spine where the neuron ends in a presynaptic terminal that releases the neurotransmitter glutamate (and possibly ATP).

Additional neuropeptides including substance P, calcitonin gene-related peptide (CGRP) and galanin also play important roles in nociception.

Substance P and CGRP act peripherally to promote inflammation (neurogenic inflammation) which leads to the production of additional ‘noxious’ chemical stimulators while galanin produces anti-inflammatory effects. Within the dorsal horn, Substance P is thought to sensitise 2nd order neurons to glutamate (increasing transmission to higher centres) and appears to be most active in regions of the dorsal horn where C fibres terminate.

If we take a deeper look at the chemical mediators, receptors and channels present at the sensory end of the 1st order neuron, we can see the complex interplay of numerous chemical messengers, receptors and ion channels involved in triggering depolarisation and action potential generation within the 1st order neuron.

Non-Steroidal Anti-Inflammatories (NSAIDs) are a classic example of an analgesic that works to reduce chemical stimulation at the sensory end of the 1st order neuron.

Dorsal Horn

The 1st order neuron terminates within the dorsal horn where it synapses with the 2nd order neuron. The 2nd order neuron then proceeds to the thalamus via the contralateral spinothalamic tract.

In terms of pharmacology, the modulation of pain within the dorsal horn is particularly important. Descending neurons and interneurons release inhibitory neurotransmitters (eg enkephalins) that reduce depolarisation of both presynaptic 1st order neurons and post-synaptic 2nd order neurons, reducing the transmission of nociceptive signals to the thalamus. These inhibitory processes are sometimes referred to as the ‘pain gate’.

Let’s take a closer look at some of the neurotransmitters and their receptors within the dorsal horn. In the image below, you can see that endogenous opioids, serotonin and noradrenaline are all potential targets to reduce pain transmission.

2nd order neurons transmit signals up the spinothalamic tract eventually terminating in the thalamus where 3rd order neurons then relay the signals to the somatosensory cortex. It is in the somatosensory cortex that the pain is perceived.

Descending Pain Pathways (Inhibitory)

We’ve briefly discussed the ascending pain pathways, but they are only half the story. It is equally important (or perhaps more important for pharmacology) to understand the descending (modulating/inhibitory) pain pathways.

The descending pathways play an important role in modulating the pain transmission in the ascending pathways. From a pharmacology perspective, we will focus on the inhibitory effects of the descending pathways although the descending pathways are not exclusively inhibitory.

Descending pathways may originate in higher centres however much of our understanding focuses on the actions of inhibitory neurons that originate within regions of the brainstem.

The periaqueductal grey (PAG) is located around the cerebral aqueduct within the midbrain. PAG neurons extend to the locus coeruleus (LC) in the pons and the raphe nuclei within the rostral ventromedial medulla (RVM). Neurons arising in the LC are noradrenergic while those arising in the raphe nuclei are serotonergic.

From here, these neurons descend to the dorsal horn where they have their inhibitory effects on propagation/relay of signals from 1st order to 2nd order neurons. Endogenous opioids (enkephalins) release from inhibitory neurons in the dorsal horn play an important role.

Coming back to the pharmacology, the following diagram begins to pull together various elements. Each of these will be discussed in more detail as we move through the different analgesics in more detail.

🎥 Watch this video

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