Pain and Nociception

Defining Pain and Nociception

• Pain is an unpleasant sensory and emotional experience tied to actual or potential tissue damage, subjective in nature.
• Pain is a combination of sensory i.e discriminative, and affective i.e emotional components.
• Nociception is the sensory component of pain alone and involved in mechanical AP i.e action potential.
• Activity in nociceptors and nociceptive pathways by itself is not pain.

Types of Pain

• Pain is broadly classified into nociceptive and non-nociceptive pain.

Nociceptive vs. Non-Nociceptive Pain

• Nociceptive pain arises from the stimulation of specific pain receptors at the distal end of sensory neurons and it can respond to heat, cold, vibration, stretch, and chemical stimuli from damaged cells.
• Non-nociceptive pain originates within the peripheral and central nervous system, with nerve cell dysfunction and less involvement of specific nociceptors.

Pain as a Public Health Issue

• 1 in 5 adult Europeans experience chronic pain.
• A significant percentage of chronic pain sufferers are diagnosed with depression.
• Some chronic pain sufferers have considered suicide due to the severity of their pain.
• Chronic pain leads to substantial economic losses, i.e 500 million working days lost worldwide each year, and it has a $23 million hit to the European economy.

Acute versus Chronic Pain

• Acute pain is predictable and associated with tissue damage with well-defined circuitry and useful as a warning function.
• Chronic pain is unpredictable, its relationship to tissue damage is unclear, its circuitry is less known, and it has no useful warning function.
• Chronic pain is defined as pain lasting longer than 12 weeks or persisting beyond the normal tissue healing time.

Acute Pain Signalling

• Acute pain signalling involves: periphery to spinal cord, primary afferent fibres to dorsal horn neurons, neurotransmission at the primary afferent synapse and Spinal Gate Theory of Pain.

Types of Pain Categorization

• Pain is further categorized into somatic, visceral, neuropathic (central, peripheral), and mixed pain types, including CPRS i.e complex regional pain syndrome.

Somatic Pain

• Somatic pain originates from tissues like skin, muscle, joints, bones, and ligaments.
• Somatic pain is activated by specific receptors (nociceptors) responding to heat, cold, vibration, stretch, inflammation, tissue disruption or oxygen starvation.
• Somatic pain is often sharp, well localized, reproducible by touching or moving the affected area.
• Medications for somatic pain may include combinations of paracetamol, weak opioids, strong opioids, or NSAIDs.

Visceral Pain

• Visceral pain arises from internal organs within the thorax, abdomen, and pelvis.
• Visceral pain is activated by specific receptors (nociceptors) responding to stretch, inflammation, and oxygen starvation.
• Visceral pain is poorly localized, and may feel like a vague, deep ache, cramping, colicky, and frequently produces referred pain to the back and usually responsive to weak and strong opioids.

Two Kinds of Nociceptors

• Mechanical nociceptors are activated by strong shearing forces in the skin and it is associated with sharp pain from e.g cut or strong blow.
• Polymodal nociceptors respond to multiple stimuli, i.e sharp blow, damaging heat (>46°C), and chemicals from damaged tissue like K+, H+, histamine, prostaglandins, bradykinin and associated with dull burning pain.

Primary Sensory Neurons

• Mechanical nociceptors have Aδ (delta) fibres.
• Polymodal nociceptors have C fibres.
• Primary afferent fibres have mechanical and polymodal nociceptors.

Classification of Primary Afferent Fibres

• Aβ fibres are very fast, heavily myelinated, and transmit innocuous touch pressure or vibration.
• Aδ fibres is fast, and transmit noxious innocuous inputs.
• C fibres are slow, unmyelinated, transmit noxious inputs and reflexes.

Noxious Information Transmission

• Low-threshold and fast transmission are associated with sharp pain and high-threshold, slower transmission are associated with dull, burning pain.

Primary Afferent Fibres Entry into the CNS

• Primary afferent fibres enter the CNS and contains a Substantia gelatinosa, and (C fiber) non-myelinated nociceptor.

Pain Processing and Modulation

• Nociceptive inputs to the dorsal horn exhibit laminar organization.
• Somatotopic organization involves arranging and organizing signals from each body region and relayed to the spinal cord to be sent to the brain.
• Synapses with second-order neurons relay signals up the spinal cord to the brain.
• Interneurons facilitate direct or indirect contact with projection neurons to amplify or dampen signals.
• Substantia gelatinosa is part of lamina II and bring thin signals to modulate pain and opioid site of action.

Gate Theory of Pain

• The Gate Theory of Pain was proposed by Melzack and Wall in 1965.
• The yellow box represents the spinal cord dorsal horn, the T represents the transmission neuron to the brain, and SG – inhibitory intrinsic interneuron (GABAergic neuron within substantia gelatinosa) and CIAS fibres.

Neurotransmission at the Primary Afferent Synapse

• Neurotransmission involves primary afferent, second order neuron and release of Substance P, NK-1 receptor, AMPA receptor, NMDA receptor, and Glutamate.
• Acute pain signaling involves substance P, glutamate neurotransmitters, high commitment to accurately and efficiently transmit signals, and ascending to 'pain' signal receptors.

Ascending Spinothalamic Pathway

• Perceived at the subcortical level and localized localized at cortical level.
• Connects to the limbic system for the affective component (feelings).

Plasticity of Pain

• Pain sensation can change.

Descending Pathways

• Descending pathways have feedback control and include brain stem nuclei (rich in opioids).
• Descending pathways release 5-HT noradrenaline and enkephalin, closing the spinal gate.

Pain Following Injury

• This a clinical pain and normal acute pain where sensation of pain = afferent input, duration and intensity physiological.
• Persistent/chronic pain states leads to the increase sensitivity to pain which modifies peripheral and central signalling plasticity.

Changes in Pain Sensation Induced by Injury

• Injury affect pain sensation from innocuous to noxious.
• Hyperalgesia is an exaggerated, enhanced pain response to a normally painful stimulus.
• Allodynia is a painful response to a normally non-painful stimulus.

Sensitization of Peripheral Nociceptors by Inflammatory Mediators

• Inflammatory mediators like histamine+, prostaglandins, and bradykinin are released as inflammatory 'soup'.
• Peripheral sensitization is induced by inflammatory mediators.
• Central mechanisms in persistent pain involve SP, NK-1, AMPA, + NMDA and glutamate.
• Enhanced neurotransmitter release relief of voltage-dependant block by Mg2+.
• Persistent pain results in facilitated transmission, which winds up with increasing pain.

Persistent Pain Perspective

• Persistent pain is a physiological process and still useful.
• It provides a protective function and allows for healing.

OTC / POM Analgesics

• There is no strict distinction with analgesic drug classes like Aspirin derived from willow tree or opioids from opium poppy.
• Analgesics contain a mechanism of action and side effects.

Inflammatory Process & NSAIDs

• NSAIDs inhibit cyclooxygenase, reducing AA metabolites and PGD.
• Prostaglandins sensitize peripheral nerve endings and the inflammatory process causes pain.

Eicosanoids, Prostaglandins, and Pain

• Eicosanoids is a family of inflammatory mediators, subdivided into prostaglandins, thromboxane, and leukotrienes, exhibiting varied effects.
• Main pain-producing prostaglandins include PGE2 (vasodilator, hyperalgesic) and PGI2 (vasodilator, Hyperalgesic, stops platelet aggregation).

Arachidonic Acid Metabolites and Inflammation

• Arachidonic acid is a result when steroid inhibits Phospholipases.

Inflammatory Effects of Prostenoids

• PGE2 and PGI2 predominate and are generated by local tissues and blood vessels, PGD2 is released from mast cells.
• Prostenoids are potent vasodilators, synergize with histamine and bradykinin.
• They do not cause pain directly, but potentiate the effect of bradykinin by sensitizing afferent C-fibres.
• They do not increase vascular permeability directly, but potentiate the effects of histamine and bradykinin.

COX-2 "Inducible"

• NSAIDs act by inhibiting cyclooxygenase which reduces the synthesis of prostaglandins that is associated with pain.

Types of NSAIDs - COX-1 and COX-2

• Diverse drug class that inhibits COX for inflammatory purposes and they have >50 different drugs of various chemical classes.

• 70000000 people take NSAID’s per day, and 230000000 take NSAIDS OTC.

• COX-1 "Constitutive and protects gastric mucosa, and responsible for Hemostasis.
• COX-2 is "Inducible" and is responsible for prostaglandins and inflammation, so it will decrease mediate pain, inflammation, and fever.

Gastric Cytoprotection by COX-1

• COX-1 mediated, and made of PGE and PGI.
• It inhibits gastric acid secretion, stimulates gastric mucus secretion, are vasodilators and promotes water and electrolyte passage into the intestinal lumen.
• It is key to promote ulcer healing.

NSAIDs Side Effects

• Side effects from NSAIDs include: GI problems, PGs is involved in body function, and side effect such as high profile.
• Adverse GIT effects hospitilise 100000 / year in USA.
• 34-46% of NSAID users will sustain some GIT damage, that while asymptomatic carries increased risk of haemorrhage.
• 20000 associated deaths annually.

Specific Side Effects of NSAIDs

• Gastrointestinal disturbances (Discomfort, dyspepsia, nausea, vomiting, bleeding, ulceration).
• Blockage of platelet aggregation (Haemorrhage risk/prolonged bleeding).
• Inhibition of Prostaglandin mediated renal function if underlying circulatory problem
• Inhibition of uterine motility (prolong gestation) and it is contraindicated.
• Hypersensitivity reactions.

Gastrointestinal Risks with NSAIDs

• Fenoprofen has highest risk of GIT, and Ketoprofen and Azapropazone have high risk as well.
• Relative risk if ibuprofen is 1.
• Ibuprofen itself at 1200mg/day has risk 2x that of placebo.

How to Reduce Side Effects of NSAIDs?

• To reduce the side effects of GIT issues while taking GI prescriptions, it is only recommended when GIT risks high and CVS risk low.
• Be sure to consider Cox levels and drug class like COX-1.selective.

Paracetamol

• Paracetamol an analgesic and anti-pyretic but no anti-inflammatory activity.
• Well absorbed in tablet form with peak concentration seen within 30-60 minutes.

Paracetamol Mechanism of Action

• Inhibits PGHS Prostaglandin H⑪ synthesis ->Peroxides, and a bifunctional COX and POX. Activated by glutamine.
• Links to the endocannabinoid system, 5-HT system, and it reduces Nitro Related Pain Signaling.

Adverse Effects of Paracetamol

• There are remarkably few and uncommon side effect, such as allergic skin rashes and kidney damage for prolonged use.
• In OD (10-15 g) causes acute Hepatotoxicity and Glutathione induction (acetylcysteine or methionine) within 12hrs can prevent liver damage, however don't see hepatox until 24-48 hrs, but will be fatally.

Opioids Overview

• Made of a diverse drug class of >50 different drugs of various chemical classes like Morphine.
• Has similar mechanisms.

Definition of Opioids

• Derived from Morphine from the CNS and produce morphine and effects.

Use of Opioids

• Opium have been know/used in use for thousands of years like Tincture of laudenum (~1600), morphine isolated (~1800) and Diamorphine (~1900).
• However wasn't until early 1970s that endogenous opioids and specific receptors were discovered, and 3 receptors of mu, delta and and 3 peptides Dynorphin, endorphin, and enkephalin.
• All GPCR negatively linked to action adenylate cyclase and cellular inhibition.

Selectivity of Opioid Receptor Agonists

• mu, delta, agonist show selectivity and have different pain control.

Opioids Pharmacology

• Opioids differ in receptor specificity and at one receptor may be partial, or agonist.

Functional Effects of Opioid Receptor Activation

• Functional effects and level of effect depends on type of pain.

Analgesic Effects

• Generally effective in acute and chronic pain and tissue injury, inflammation, and tumour growth.

Opioid Analgesic Overview

• Opioids indirectly excite brain regions that target the brain stem which descendin fibres (5- HT, enkephalin, NA and dorsal horn.
• They directly inhibit primary afferent firing or stimulate intrinsic interneurones.

Analgesic Potency of Opioid Receptor Agonists

• Depending on route of entry, efficacy changes from Low -> High
• It affects potency levels and their actions.

Opioid Respiratory Depression

• Mediated by µ receptors, so occurs hand in hand with analgesic therapy in the sensitivity circulating area.
• Respiratory depression is a specific effect of opioids cardiovascular related, but naloxone is used to treat it's overdose.

Morphine Overview

• Active at all receptors and further metabolised in the liver: (M6G (and 6MAM) also active at µ receptors.
• The half life is 3 hrs but useful analgesia 3-6 hrs.

Codeine Characteristics

• A Low affinity for opioid receptors and most analgesic efficacy comes from hepatic metabolism (~10%) to morphine.
• Often combined to control diarrhoea.

Dihydrocodeine Details

• It has Low efficacy and is in 10% of population but has a similar potency to codeine.
• They resistant to codeine.

Current Pharmacological Agents

• NSAIDs and morphine remain the mainstay of(analgesic therapy and are designed to have longer effects.
• Needed there needs to be a bigger clinical study for effective anaglesics for chronic pain, so that we can find long term solutions.