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General Analgesic Pharmacology / Location of action

Updated: Jan 27, 2021



- Initial overstimulation of nociceptors leading to a period of insensitivity

- Agonist at TRPV1 receptors

- Depletion of substance P (excitatory neurotransmitter that coexists with glutamate) from nerve endings leading to refractory period

Primary use: Diabetic neuropathy and post-herpetic neuropathy


- Reduce inflammation through inhibition of COX leading to reduction in prostaglandins


- Minimise local inflammation through inhibition of arachidonic acid from phospholipids


- Small effect at the periphery through local mu-opioid receptors seen after injury (Transported there in response to inflammation. Opioid agonists can attenuate the excitability of nociceptive neurons and the release of the pronociceptive neuropeptides substance P and calcitonin gene-related peptide (CGRP) from central and peripheral neuron terminals. Particularly within injured tissue, these events lead to antinociceptive and anti-inflammatory effects)

Stein, C., & Lang, L. J. (2009). Peripheral mechanisms of opioid analgesia. Current opinion in pharmacology, 9(1), 3-8.

Peripherally along the nerve:

Local anaesthetics

- Blocks Na channels along nerve fibres preventing conduction of nerve impulses

Dorsal Horn: (Summary diagram below)

Alpha-2-delta receptor blockers (gabapentin/pregabalin)

- Modulate voltage gated calcium channels limiting calcium influx from presynaptic terminals of afferent neurones

- Reduced intracellular calcium --> reduced release of excitatory neurotransmitters such as glutamate and substance P


- Bind to MOR (Mu opiate receptors). Large amount at the dorsal horn ++.


- Increase inhibitory pathways by inhibiting uptake of monoamines (serotonin, noradrenaline) into the nerve terminals of the dorsal horn

NMDA antagonists (Ketamine)

- Bind to NMDA receptors postsynaptically preventing their activation by excitatory neurotransmitters such as glutamate

Central Actions


- Multiple mechanisms (which are possibly interlinked) may be involved in its analgesic activity, including serotonergic descending inhibitory pathways, opioidergic systems, eicosanoid systems, nitric oxide containing pathways and endocannabinoid signalling

- Its effect in combination with NSAIDs or opioids is synergistic and provides better pain relief than either drug alone BUT it is not as good as NSAIDs

- In a recent meta-analysis undertaken by Australian authors, paracetamol alone was found to be ineffective in reducing pain and disability or in improving quality of life in patients with low back pain. Also it had only limited benefit in reducing pain and disability in patients with hip or knee osteoarthritis. In addition, there was evidence of an increased risk of mild elevations in liver function tests

Opioids - Central actions

- interact with opioid receptors throughout the brain modifying the affective and somatosensory aspects of pain perception

SNRIs and TCAs

- have effects on mood that influence the perception of pain (How??)

Pregabalin and Gabapentin

- Reduce anxiety (How??)

Descending inhibitory pathways

(Cortex & Thalamus --> RVM and medullary nucleai --> spinal dorsal horn. Utilises serotonin, noradrenaline and endogenous opioids)


- Bind to mu opioid receptors in medbrain and medulla activating inhibitory neurons (thought to be opiates strongest effects)


- Increased endogenous monoamines (e.g. serotonin and noradrenaline) by preventing reuptake


2-1-21 to 25 - Routes of administration of drugs

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