Selva Viñals, Carla

Universitat Autònoma de Barcelona. Facultat de Biociències

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Carla Selva Viñals. Grau en Ciències Biomèdiques, Universitat Autònoma de Barcelona Introduction MOH Aeotiology Paracetamol Self-Medication and Medication-Overuse Headache Paracetamol MOH Conclusions  Response to non-noxious stimuli  Increase in responsiveness to suprathreshold stimulation  Expansion of pain area  Recruitment of nociceptive neurons from higher levels   Hyperalgesia  Allodynia  Involvement of serotonin system Repetitive activation of nociceptive pathways Chronic paracetamol administration Acute paracetamol administration  Paracetamol as the cause • Extracellular 5-HT levels increase. • Maximal number of cortical 5-HT2A receptors decrease. • Down-regulation of postsynaptics 5-HT2A receptors: ↓binding-sites. • Descending serotoninergic pathways inhibit nociceptive stimuli by: •Hyperpolarization of projection neurons or central terminalis of primary afferent fibers. •Excitation of inhibitory interneurons containing GABA and enkephalin. • Extracellular 5-HT levels decrease. • 5-HT2A receptors density increase. • Up-regulation of 5-HT2A receptors: ↑ binding sites. • 5-HT2A activation → ↑ COX-2 (nociceptive messenger). • Loss of analgesic efficacy, restoration of sensitivity, hyperalgesia, potentiation of nociceptive transmission.  5-HT2A receptors density increase Paracetamol and Sensitisation Up-regulation of 5-HT2A receptors: ↑ binding sites 5-HT levels decrease 5-HT depletion   ↑ COX-2 in the parietal cortex ↑ activation  5-HT2A receptors Pain Central Sensitisation • Nociceptors become more sensible • Enlargement of the receptive fields • Activation of previously silent           nociceptors • Biological and functional changes           in the trigeminal nucleus • Changes in PAG Repetitive activation of C and unmyelinated fibers (≥0,5 Hz) Biochemical changes ↑ glutamate and substance P ↑ calcitonin gene-related peptide Removal of voltage-dependent blockade by Mg2+ Cascade mediated by neuronal receptors NMDA-like Aberrant and apoptosis of GABAergic neurons Distortion of pain Genetic changes MAPK Regulation of key gene products Fos activation in the cerebral cortex PAG changes Release of free oxygen radicals PAG tissue damage Increased iron deposition Irreversible oxidative changes in PAG NMDA receptors recruited Transient ↑ intracellular Ca2+ in postsynaptic neurons Calmodulindependent protein kinases activation  Substantial changes in postsynaptic cells ↑ membrane excitability Changes in genetic transcrip-tion NO synthase activation ↑ NO production and stimulation transmitter release LTP Synaptic potential long-lasting changes Summation of changes over time Wind-up ↑ dorsal horn respon-siveness Direct effect of paracetamol on the capacity of the brain to inhibit pain 5-HT involvement Mixture of Both causes "Off-cells" inhibition "Off-cells” from ventro-medial medulla cannot inhibit nociception "On-cells" activation Nociception facilitation in trigeminal nucleus caudalis Nociception increase and Central Sensitisation • One of the principal mechanisms involved in MOH development lies in the integrity of serotonin system, either with serotonin or its 5-HT2A receptor. It is curious how an acute intake of paracetamol can lead to analgesia whereas a chronic intake leads to the opposite: pain.    • Another of the main mechanisms are central sensitisation and cellular changes that suffer nociceptive neurons, either by repetitive activation of these pathways or the involvement of paracetamol in central sensitisation.  Abbreviations used:  • Central sensitisation (CS) • Central Nervous System (CNS) • Cyclooxygenase (COX) • Cytoplasmic (CY) • Long-term potentiation (LTP)    • Medication-Overuse Headache (MOH) • Non-steroidal anti-inflammatory drugs (NSAID) • Over-the-counter (OTC) • Periaqueductal Grey Matter (PAG) • Serotonin (5-HT)  • OTC NSAID. • Analgesic and antipyretic effects, not anti-inflammatory. • Central effect (ability to penetrate into the brain), inhibition of COX-3. • Mechanisms contributing to its antinociception effect: Legend: AA – Arachidonic acid AM404 - N-arachidonoylaminophenol  APAP – Paracetamol CB1R – Cannabinoid 1 receptor COX – Cyclooxygenase FAAH – Fatty acid amide hydrolase KOR – Kappa opioid receptor MOR – Mu opioid receptor NAPE – N-acylphosphatidylethanolamine    NAT – N-acyltransferase NO – Nitric Oxide PA – Palmitic Acid PAG – Periaqueductal Grey PC – Phospatidylcholine PE – Phospatidylethanolamine PEA – Palmitoylethanolamide PLD – Phospolipase D PPAR-α – Peroxisome proliferator-activated receptor-α  RVM – Rostral Ventral Medulla     Objective: make a bibliography review in order to establish how paracetamol overuse can cause MOH and to investigate the pharmacological and physiopathological mechanisms involved in MOH development. Most commonly self-used NSAID to treat headache globally: Ibuprophen, Aspirin, Paracetamol (the most used in Europe).  General unawareness of the risk of developing MOH.  The term MOH first appeared in 2004. Headache ≥ 15 days/month Regular taken analgesics ≥ 15 days/month Regular overuse of analgesics for ≥ 3 months Resolves after 2 months of discontinuation of analgesics MOH • Paracetamol • Aspirin • Opioids • Ergotamine • Butalbital • Caffeine  combinations High risk of developing MOH • Triptans • Short-acting NSAIDs Medium risk of developing MOH • Long-acting NSAIDs • Dihydroergotamine • Tramadol • Neuroleptics Low risk of developing MOH Only individuals with a primary headache develop MOH.  Epidemiology: • 1,5% global population (2,6% ♀, 0,19 ♂). • Spain: 1,41%  population (2,6♀ and 0,2%♂). Cellular adaptation in the brain Chronic exposure causes an impairment of the modulatory neurons in the CNS (abnormal membrane transduction). Glucose metabolism alteration Increased glucose metabolism in insula (pain experience). • In general, type headache diagnosis is difficult, especially with MOH, which is a recent-discovered pathology. That is the reason why physiopathological and pharmacological mechanisms involved in MOH are little known. However, this topic is under investigation and some important findings and interesting hypotheses have been discovered.   • There are two principal aetiological groups of MOH that are interconnected; they imply reiterated use of paracetamol and repetitive activation of nociceptive pathways. This activation is basically due to treatment of the pain symptoms but not the real cause or origin of headache. ↓ 5-HT and 5-HT2a receptors up-regulation ↑ substance P release ↓  inhibitory control Hydrolysis of inositol phosphate  ↑ CSD frequency and Fos  Hyperexcit-ability cortex and trigeminal neurons Ca2+ release from cellular store ↑ CY Ca2+  LTP Paracetamol addiction (Hypoteses) • Compulsive reward-seeking. • Behaviioural sensitisation induced by drug administration in addiction. • Dopamine involvement: pain and reward. Central Sensitisation Methods: bibliographical search in PubMed and ScienceDirect, specially scientific papers and reviews. Figure 2. Possible paracetamol action mechanisms   Figure 1. Paracetamol chemical structure Figure 3. MOH features   Figure 4. Paracetamol effects in acute and chronic administration Figure 5. Mechanisms involving pain with paracetamol chronic administration Figure 6. Mechanisms involving CS due to a repetitive activation of nociceptive pathways  Figure 7. Mechanisms involving CS due to chronic paracetamol administration 

Paracetamol self-medication and medication-overuse headache

http://ddd.uab.cat/pub/tfg/2013/112854/TFG_carlaselvavinals.pdf

Paracetamol self-medication and medication-overuse headache

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