Introduction to pain

Introduction to Pain

• Acute pain signalling follows a pathway: periphery to spinal cord, neurotransmission at the primary afferent synapse, and ascending pathways to the brain
• Pain is an unpleasant sensory and emotional experience linked to potential or actual tissue damage
• Pain is a combination of sensory (discriminative) and affective (emotional) components
• Pain perception is always subjective
• Nociception is the sensory component of pain.
• Activity induced in the nociceptor and nociceptive pathways is not pain itself.

Types of Pain

• Nociceptive pain arises from stimulation of specific pain receptors at the distal end of sensory neurons
• These receptors respond to heat, cold, vibration, stretch, and chemical stimuli from damaged cells
• Non-nociceptive pain arises from within the peripheral and central nervous system
• Non-nociceptive pain is generated by nerve cell dysfunction, with less specific nociceptor involvement
• Somatic pain comes from tissues like skin, muscle, joints, bones, and ligaments
• Somatic pain is often known as musculoskeletal pain
• Receptors that activate somatic pain are specific, such as nociceptors for heat, cold, vibration, and stretch
• Somatic pain is sharp, well-localized, and reproducible by touching/moving the affected area
• Somatic pain may respond to paracetamol, weak opioids, strong opioids, or NSAIDs
• Visceral pain originates from internal organs within body cavities
• Visceral pain receptors are activated by stretch, inflammation, and oxygen starvation (ischaemia)
• Visceral pain is poorly localized and may feel like a vague, deep ache, sometimes cramping or colicky
• Visceral pain frequently produces referred pain
• Visceral pain is usually responsive to weak and strong opioids

Types of Nociceptors

• Mechanical nociceptors are activated by strong shearing force in the skin, such as cuts or strong blows, result in sharp pain
• Polymodal nociceptors respond to many stimuli, including sharp blows, damaging heat (>46°C), and chemicals released by damaged tissue
• Chemicals released by damaged tissue include K+, H+, histamine, prostaglandins, and bradykinin, and result in dull burning pain

Primary Sensory Neurons & Pain Types

• Mechanical nociceptors transmit signals via Aδ (delta) fibres
• Polymodal nociceptors transmit signals via C fibres
• Both types of fibres are primary afferent fibres
• Aβ fibres are very fast, report non-painful innocuous sensations like touch, pressure or vibration, and are heavily myelinated
• Aδ fibers are fast, report mixed noxious and innocuous information, and are myelinated
• C fibres are slow, report potentially damaging/painful information and reflexes, and are unmyelinated
• Aδ fibres transmit low threshold, fast transmission of sharp pain
• C fibres transmit high threshold, slower transmission of dull, burning pain
• Primary afferent fibres enter the central nervous system via the dorsal root ganglia to the dorsal horn

Nociceptive Inputs & Pain Processing

• Nociceptive inputs to the dorsal horn have laminar organization
• Somatotopic organization occurs, organizing signals from each body region
• Synapses with second-order neurons help relay signals up the spinal cord to the brain
• Signals are directly or indirectly (via interneurons) connecting with projection neurons
• Signals going through interneurons amplify or dampen signals
• Substantia gelatinosa equals lamina II, which is where C/Aδ fibres modulate pain at the opioid site of action

Gate Control Theory

• Gate theory of pain was Proposed by Melzack and Wall in 1965
• In the spinal cord dorsal horn (yellow box), T cells are the transmission neuron to the brain
• SG is an inhibitory intrinsic interneuron (GABAergic neuron within substantia gelatinosa)

Neurotransmission

• The primary afferent synapse releases Substance P, NK-1 receptors, AMPA receptors, NMDA receptors and Glutamate
• The incoming Aδ/C fibre 'pain' signals are transmitted with high fidelity to the ascending 'pain' signal
• Substance P is a chemical exchange, a neuropeptide released during prolonged intense pain with amplifying pain that works longer
• Glutamate is the main excitatory neurotransmitter
• AMPA receptors are fast response and quickly activated
• NMDA receptors are slower to activate, essential for long-term and chronic pain risk

Ascending Pathways

• Spinothalamic pathways perceive pain at a subcortical level
• Pain is localized at cortical level
• Signals travel to the limbic system for the affective component of pain

Descending Pathways

• Descending pathways provide feedback control from brain stem nuclei, which are rich in opioids
• These pathways release of 5-HT, noradrenaline, and enkephalin
• This closes the spinal gate

Injury & Plasticity

• Normal acute pain has afferent input, duration, and intensity
• Sensation of pain is physiological
• Persistent/chronic pain states show increased sensitivity due to peripheral and central signalling that causes plasticity
• Changes in pain sensation occur due to injury
• Hyperalgesia is an enhanced painful response to a normally painful stimulus
• Allodynia is a painful response to a normally non-painful stimulus
• Sensitization of peripheral nociceptors occurs by inflammatory mediators
• This is because histamine, H+, prostaglandins, and bradykinin are released at the inflammatory site
• The release of histamine, H+, prostaglandins, and bradykinin result in sensitisation of polymodal nociceptors
• Sensitisation results in peripheral sensitisation

Peripheral vs Central

• The incoming Aδ/C fibre 'pain' signals are transmuted with high fidelity for acute pain
• In chronic pain, the SP & GLU neurotransmitter release is enhances which relieves the voltage blockage of Mg2+
• Pesristent pain leads to facilitated transmission/wind-up
• Persistent pain is still useful because it is still a physiological process, still useful and provides a protective function to help with healing

Analgesic Pharmacology

• There exists no strict distinction with analgesic drug classes, although medication can be considered as OTC (over the counter) and POM (prescribed only) drugs - with side effects being an important consideration
• Eicosanoids are a large family of inflammatory mediators, they are subgrouped into prostaglandins, thromboxane and leukotrienes with varied effects
• PGI2 (Prostacyclin) is a vasodilator and hyperalgesic but stops platelet aggregation
• PGE2 is a vasodilator and hyperalgesic
• NSAIDs inhibit cyclooxygenase, which produces arachidonic acid (AA) metabolites and sensitise peripheral nerve endings, ultimately resulting in the reduction of pain

NSAIDs

• NSAIDs, inhibit cyclooxygenase and prostaglandins
• These are a diverse drug class, with >50 different drugs of various chemical classes like Salicylate, propionate, and phenylacetate
• NSAIDs all have same mechanism of action
• 70000000 people/day are prescribed NSAIDs, and 230000000 people/day take OTC NSAIDs globally

COX-1 vs COX-2

• COX-1 is "Constitutive for cell protection
• COX-2 is "Inducible" for prostaglandin production
• Cytoprotection and haemostasis can be affected by NSAID mechanisms regarding both COX and prostaglandin synthesis - and side effects can manifest with some risk

Gastric Cytoprotection

• Gastric cytoprotection is COX-1 mediated via PGE and PGI
• The process inhibits gastric acid secretion and stimulates gastric mucus secretion
• Gastric cytoprotection is a "vasodilator"
• Vasodilators promote water and electrolyte passage into intestinal lumen
• Promote ulcer healing occurs

NSAIDs Side Effects

• PGs are involved in many functions, resulting in unwanted side effects
• Adverse GIT effects hospitilise 100000 / year in USA
• 34-46% of NSAID users will sustain some GIT damage
• 20000 associated deaths annually
• These include gastrointestinal disturbances and the blockage of platelet aggregation
• Discomfort, dyspepsia, nausea, vomiting, bleeding, and/or ulceration may be signs of this harm
• Haemorrhage risk, and/or prolonged bleeding is a potential effect, along with renal impact in certain individuals
• Hypersensitivity reactions can occur

Ibuprofen

• Risk is shown to be relative to ibuprofen (relative risk = 1)
• Ibuprofen itself at 1200mg/day has risk 2x that of placebo
• If prescribed. take necessary precautions when NSAIDs and analgesics are prescribed, especially regarding existing GI problems

Reducing Negative Side Effects

• Consider "Caution" where only prescribed when GIT risks high and CVD risk low
• Be observant to patients who have a higher risks of some side effects.

Paracetamol

• Some sources consider paracetamol not to be a NSAID
• Is considered to be Analgesic and anti-pyretic but no anti-inflammatory activity in some papers
• Is well absorbed in tablet form and has a peak plasma concentration seen within 30-60 min
• It inhibits CNS prostaglandin synthesis but has limited inhibition of peripheral COX
• May have a CNS specific COX-3 isoform

Paracetamol Mechanism of Action

• Paracetamol inhibits PGHS → Prostaglandin H Synthesis, but has not influence of Peroxides
• Has been linked to endocannabinoid system, 5-HT system as and in NO in research
• Serotonin and Nitric oxide have been implicated in some research
• Action results in the reduction No-related Pain signaling
• Has few and uncommon side effects, can sometime cause Allergic skin rashes
• Kidney damage with prolonged use is possible
• In an OD (10-15 g)
• Can cause Hepatotoxicity, meaning Glutathione induction (acetylcysteine or methionine) within 12hrs can prevent liver damage
• This action may not be seen however until 24-48 hours

Opiods & Narcotics

• Opiods are a diverse drug class, with >50 different drugs of various chemical classes
• These include Morphine analogues, synthetic analogues based on several distinct chemical classes
• These have a similar mechanism of action-
• A Narcotic describes Morphine, codeine in the CNS
• Opium is a - juice extracted from Papaver somniferum and Contains Morphine and mixture of related alkaloids
• This is the material that is "Tabloid"
• An opioid is any substance (natural or synthetic that produces morphine like effects) - while an Opiate is a Synthetic morphine-like drug concept derived from old terminology
• Opium/opioids have been in use for thousands of years, including Tincture of laudenum (~1600),Morphine isolated (~1800), Diamorphine (~1900), and Methadone (~1930)
• Not until recently that the endogeneous opoiods were discovered, and specifically, the receptors
• Three peptides - Dynorphin, endorphin and enkephalin
• Three receptors – μ, δ, κ
• All GPCR negatively linked to adenylate cyclase - with some General cellular inhibition
• Selective opioid receptor agonists include
• Endorphin, Enkephalin, Dynorphin, Morphine,Oxymorphone, Methadone,Fentanyl, Pentazocine, and Buprenorphin

Complex Drug Actions

• Opioids differ in receptor specificity and in their efficacy at the different receptors
• An agonist at one receptor may be a partial agonist at another receptor or an antagonist at a third
• Functional effects of opioid receptor activation include Analgesia and Respiratory depression, Pupil constriction, Reduced GIT motility, Euphoria, Dysphoria, Sedation,Dependence
• These various effects relate to how the drug effects the MOP/DOP/KOP function system,

Analgesic Effects

• Analgesics is Generally effective in acute and chronic pain of various origins/situations such as tissue injury, Inflammation and tumour growth
• They reduce the affective component of pain

Opoid Action at the Cortex Level

• Opioids indirectly excite brain regions that target the brain stem
• brain stem includes the NRM and nuc. raphe magnus
• Descending fibres (5-HT, enkephalin, poss NA) terminate in the dorsal horn
• The analgesics Directly inhibit primary afferent firing and stimulate intrinsic interneurones

Pain Relief

• Potent Opioid receptor include;
• Aspirin 1/360 Strength (cf morphine)
• Codeine/dihydrocodeine 0.1 Strength (cf morphine)
• Tramadol 0.1 Strength (cf morphine)
• Morphine (oral) (1) Strength (cf morphine)
• Oxycodone 2 Strength (cf morphine)
• Morphine (IV/IM) 4 Strength (cf morphine)
• Diamorphine 2-4 Strength (cf morphine)
• Oxymorphone 7 Strength (cf morphine)
• Buprenorphin 40 Strength (cf morphine)
• Fentanyl 100 Strength (cf morphine)

Respiratory Depression

• Respiratory depression is Mediated as a µ receptor function in hand with analgesic therapy
• Brought about by decreased sensitivity of respiratory centre to circulating CO2
• This effect is a specific effect of opioids, cardiovascular depression, unlike anaethestics
• Commonest cause of death in acute opioid overdose
• Can be countered with Naloxone (0.4 mg IV, repeated after 2-3 min)

Active Analgesics

• Active Opiod includes Morphine which operates all receptors and metabolises in the Liver
• Liver metabolises M6G (and 6MAM) , which are active at u receptors and more potent than morphine
• Half life 3 hrs but useful analgesia lasts 3-6 hrs

Side Effects & Usage

• Codeine as a lower affinity drug for opioid receptors with most analgesic in hepatic metabolism (10%)
• Provides mild and moderate pain relief lasting 2-4 hr
• Supresses coughs and diarreah
• Rarely addictive, causes little euphoria, with low respiratory depression risk
• Has Numerous oral formulations with paracetamol and/or aspirin

Concerns for Pain Relief

• Dihydrocodeine has Low efficacy and similar potency to codeine however metabolites in 10% has a resistance if lacking in metabolisning enzyme
• NSAIDs and morphine remain the mainstay of analgesic therapy for nociceptive pain, with both peripheral mechanisms centrally and peripherally targeting pains
• There remains a big clinical need for new analgesics for chronic pain