Peripheral and Central Analgesia

• Methods to relieve pain:

  • Remove peripheral stimulus (eg extract tooth or remove nerve)
  • Interrupt nociceptive input (eg give local anaesthetic so pain signals from the area can no longer be sent)
  • Stimulate nociceptive inhibitory mechanisms
  • Modulate central appreciation of pain
  • Block or remove secondary factors maintaining pain
• At the periphery:

  • Targeting the peripheral "inflammatory soup"
  • Inflammatory soup = algogenic substances being released; wide range

  
• Allogenic substances:

  • All about inflammatory cascade
  • Once tissue damage occurred
  • Release of algogenic substances
  • Potentiate inflammatory cascade
  • Which, in turn, potentiates nociception at neurones
  • Also allows ingress of neutrophils
  • Protects and helps with repair
  • Bottom line: majority of therapeutic targets at periphery are also inflammatory mediators

  
• Peripherally acting analgesia:

  • Mainly targets inflammatory cascade
  • Through inhibition of algogenic substances at or near site injury - therefore reducing the pain that's experienced
  • Types:
  • Paracetamol
  • NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
  • COX-2 inhibitors
• Paracetamol:

  • Analgesic - mechanism of action unknown
  • Anti-pyretic (reduces temperature) - possibly related to Prostaglandin inhibition in hypothalamus
  • Very potent anti-pyretic effect, particularly when administered by IV
  • Weak anti-inflammatory
  • If it's targeting the algogenic substances at the periphery, it's therefore reducing any response that's felt
  • Therapeutic dosages - very safe
  • Can be given orally or via IV
  • Adult 500mg-1g 4 times a day (qds)
  • BUT avoid in patients with pre-existent liver disease
• Paracetamol:

  • Analgesic - mechanism of action unknown
  • Anti-pyretic (reduces temperature) - possibly related to Prostaglandin inhibition in hypothalamus
  • Very potent anti-pyretic effect, particularly when administered by IV
  • Weak anti-inflammatory
  • If it's targeting the algogenic substances at the periphery, it's therefore reducing any response that's felt
  • Therapeutic dosages - very safe
  • Can be given orally or via IV
  • Adult 500mg-1g 4 times a day (qds)
  • BUT avoid in patients with pre-existent liver disease
• Paracetamol metabolism:

  • Hepatic
  • 90% of paracetamol is harmlessly excreted after being converted in the liver, but ~10% is converted via conjugation with Glucuronide producing N-acetyl-p-benzoquinone imine (NAPQI)
  • NAPQI is hepatotoxic (toxic to the liver) => cell death of tissues within the liver
  • NAPQI inactivated by linking with Glutathione to convert it back to being harmless
  • There's a limited supply of Glutathione in people that don't have healthy livers, and in people who have been taking the drug for a prolonged period of time (therefore depleting the supply that has built up)
• Paracetamol overdose:

  • No immediate clinical manifestations
  • If in doubt refer pt to A&E for them to be assessed
  • Dependant on other risk factors - occurs >=150mg/kg (>=75mg/kg) but factors can change how much someone is able to tolerate
  • Liver disease
  • Alcohol abuse or malnourished
  • Early treatment: (4 hours) ingest activated charcoal to absorb any of the excess amount present within the digestive system; (12 hours) with N-acetylcysteine (precursor of Glutathione)
• NSAIDs include:

  • Aspirin
  • Ibuprofen
  • Diclofenac
  • Mefenamic acid
• NSAIDs mechanism of action:

  • Non-selective block of cyclo-oxygenase (COX) enzyme (non-selective, therefore block all forms of it)
  • Some medications may target one form more than the others, but it generally works on all forms
  • Two forms COX-1 and COX-2 (ones mainly involved in effects, but there is a 3rd form that resides in the brain)
• NSAIDs mechanism of action - two forms COX-1 and COX-2:

  • COX-1
  • Important; mainly involved in the production of prostaglandins (PGE₁ and PGE₂)
  • PGE₁ and PGE₂ help synthesis of gastric mucosal mucus and regulate the production of gastric acid
  • Therefore blocking COX-1 has an effect on gastric acid production and can lead to peptic ulcers
  • COX-2
  • Responsible for prostaglandins that are mainly involved in acute pain - side effect we're looking to target
  • Decrease production of other Eicosanoids including different prostaglandins and inflammatory mediators that cause acute pain
• Inhibition of COX enzyme prevents arachadonic acid from being changed into cyclic endoperoxidases, which can then change to a range of forms

  • Leukotrienes are responsible for chemotaxis, mucous production and smooth muscle contraction within lung tissue
  • Prostaglandins are responsible for hyperalgesia, renin release and smooth muscle contraction
  • Prostacyclin is responsible for decreased platelet activation, smooth muscle contraction and hyperalgesia
  • Thromboxane is responsible for platelet activation and smooth muscle contraction

  
• In some cases it may be of therapeutic benefit to target thromboxane to reduce platelet aggregation in patients that are at cardiovascular risk

  
• NSAIDs beneficial effects:

  • Anti-pyretic - through similar pathway to what was thought for paracetamol - inhibition of prostaglandin synthesis in the hypothalamus
  • Analgesic - via inhibition of prostaglandins that are causing hyperalgesia in the periphery
  • Anti-inflammatory
  • Anti-platelet (eg aspirin, which specifically targets thromboxane)
  • Close patent Ductus Arteriosus (Indomethacin used for this treatment)
• Aspirin (Acetylsalicylic acid):

  • Weak organic acid
  • Rapid absorption in the GI tract
  • Analgesic
  • Anti-inflammatory
  • Anti-pyretic
  • Anti-platelet
  • Prevention of thrombo-embolic disorders (eg any conditions that would have clots forming and then have plaques which could cause problems heart disease-wise)
  • Main dental use = 300mg given orally if suspected myocardial infarction (MI) and call ambulance
• Ibuprofen:

  • Low GI (gastrointestinal) and CVS (cardiovascular) risk
  • Proprionic acid derivative
  • 1.2g-2.4g total daily dose
  • Usual adult dental regimen 400mg given orally three times a day (tds)
  • Analgesic and antipyretic - working on prostaglandins through COX-2
• NSAIDs unwanted effects:

  • Gastric ulceration
  • Therefore avoid in pts with pre-existent conditions
  • Platelet effects
  • If dealing with thromboxane, could increase risk that patient will have bleeds
  • Contraindicated if pt already has a bleeding disorder
  • Not in other coagulopathies
• NSAIDs unwanted effects:

  • Can induce asthmatic attack
  • More common in ibuprofen than in aspirin
  • Leukotrienes increase in number, which are responsible for mucous production and smooth muscle contraction in the lungs - as a result of this, bronchospasm can occur for asthmatics
  • Non-selective prostaglandin blocks leads to renal toxicity in patients with kidney problems
  • Because prostaglandins involved in renin release
• NSAIDs unwanted effects:

  • Reyes syndrome (no aspirin <16 years old)
  • Reyes syndrome is a condition where children have swelling of the brain and the liver
  • Thought to be some kind of interaction between a viral infection and aspirin, which is often used to treat it
  • Found that by reducing the prescription of aspirin in those sort of cases, it led to a reduction in the cases of Reyes syndrome that occurred - therefore aspirin contraindicated in those under age of 16
• NSAIDs unwanted effects:

  • Extensive protein binding -> increase drug interactions
  • If pts are taking other medications they are displaced from being protein bound, so you would be increasing the amount of those drugs that are circulating and therefore increasing the effects of those
  • Some have CVS risk profile
  • Diclofenac & Indomethacin the worst
  • Block prostacyclin production => prothrombotic state
• COX-2 inhibitors:

  • Heralded as "Safe Aspirin" as:
  • Selective block of only COX-2
  • Same effect on reducing the hyperalgesia, but wouldn't have the gastric side-effects that come with it
  • Unfortunately increased prostacyclin block -> prothrombotic effect and increased risk of myocardial infarction
  • Known by -oxib suffix: Celecoxib, Paracoxib
  • Sparingly used and not 1st line because of risks associated with them
  • Mechanism of action as per NSAIDs
• Standard "dental" adult peripheral regimens:

  • Paracetamol 500mg-1g 4 times a day (qds)
  • Ibuprofen 200-400mg 3 times a day (tds)
  • Usually stepped
  • Can be together which increases analgesic effect
  • Recommended to take Ibuprofen with meals because it helps the absorption and is better tolerated in the stomach
  • Can be used in conjunction with centrally acting to produce multimodal analgesia:
  • LA
  • Peripherally acting analgesic(s)
  • Centrally acting analgesic (like opioids)
• Opioids:

  • Any directly acting compound whose effects are antagonised by naloxone - which displaces the receptor
  • Can be classified in a number of ways:
  • One of which is by analgesic strength
  • Weak - codeine
  • Intermediate (partial agonists) - Buprenorphine
  • Strong (pure agonists) - Morphine
  • Either pure or partial agonists are opioid receptors
• Opioid receptors:

  • Mu is the main pathway of action that we have for most of the opioids
  • Decreased gut motility - therefore patients taking long-term opioids will be prescribed laxatives too
  • Oxycodeine, diamorphine and pethidine all work by the kappa pathway

  
• Opioids mechanism of action:

  • Bind to opioid receptors centrally and peripherally and produce:
  • Activation of descending inhibitory control over nociception through centres in the periaqueductal grey matter (PAGM)
  • They bind there and produce a signal that leads to the release of serotonin
  • Peripheral afferent hyperpolarisation
  • K⁺ influx, inhibits Ca channel opening into neurone and inhibits cAMP production, therefore stopping depolarisation occurring
  • Inhibits propagation of impulse through stopping neurotransmitter release
• Indications for opioids:

  • Pain is moderate to severe - as opposed to an NSAID when it's just in the periphery and is less wide-spread
  • Pain has significant impact on function
  • Pain has significant impact on quality of life
  • Non-opioid pharmacotherapy has been tried and failed (eg NSAIDs and paracetamol)
  • Patient consents to have continued opioid use closely monitored (for dependence and addiction that can come with this)
• Main uses of opioids:

  • In the treatment of terminal illness (making sure patients are comfortable and the pain is managed)
  • Severe postoperative pain (IV morphine)
  • Orthopaedic, abdominal etc surgery
  • Some more extensive OMFS procedures
  • Treatment of chronic pain unresponsive to first and second line analgesic drugs
  • Repercussions = long-term monitoring; unwanted side effects
• Opioids' unwanted side effects:

  • Respiratory depression - act on central respiratory centres
  • Nausea and emesis
  • Stimulation and chemoreceptor trigger zone in Medulla
  • Often given anti-emetic drugs to help settle the stomach
  • Decreased GI motility - constipation
  • Decreased urinary flow - inhibits urinary voiding reflex and Morphine including production of ADH
  • Pupillary effects
  • Excitatory effect on Edinger-Westphal nucleus (oculomotor nerve)
  • Important in head injuries
  • Dependence
• Opioid tolerance vs dependence:

  • Pts can become tolerant to opioids as time goes on
  • Tolerant to depressive agonist effects (respiratory depression, analgesia) - so can be reduced over time
  • Dependence on medications begins within 24 hours if morphine given IV
  • Chronic exposure to opioids leads to:
  • Body increasing number of receptors & therefore their sensitivity
  • The cells also increase their response
  • A physiological response by body to the lack of a substance it expects to be provided - body expects more of the drug, and when it's not provided there are side effects - can lead to addiction
• Opioid tolerance vs dependence:

  • Addiction BSP (British Society of Pain) entity and involves 4Cs:
  • Compulsive use
  • Impaired control over use
  • Continued use despite consequences
  • Craving
  • Addiction can be managed by methadone:
  • High affinity for μ receptors
  • Long half life
  • Reduces withdrawal symptoms from opioids, but then patient will need to be tapered down from Methadone too
• Opioid overdose:

  • Indicated by severe contraction of the pupils or really slow breathing rate
  • May also be unconscious or experiencing euphoria
  • Diagnosis - miosis, bradypnoea
  • Management:
  • ABC (airway, breathing, circulation) 100% - administer high flow O2
  • Naloxone - 0.2mg-0.4mg given intravenously
  • Repeat every 2-3 mins up to max 10mg
  • Guided by state of respiration NOT conscious level
  • Note:
  • Short half life of Naloxone
  • Therefore may induce withdrawal state when it wears off, so patient would need to be monitored
• Opioids most commonly encountered:

  • Morphine
  • Codeine
  • Tramadol
• Morphine:

  • Extensive 1st pass metabolism if given orally
  • Only ~20% original dose reaches systemic circulation
  • As a result of this, in severe cases, morphine is usually given by IV; it's more effective
  • IV dose titrated 1-10mg four hourly
  • PCA (patient-controlled administration) option - small amounts with lock out period
  • Can mean lower dose; patient only taking as much as they feel they need rather than a doctor having to guess how much they need
• Morphine:

  • Hepatic and renal metabolism
  • Excreted via kidneys
  • Pharmacologically active metabolite produced - metabolically active when excreted
  • Therefore dose needs to be reduced in patients with renal disease
  • Sustained release (SR) formulations can produce a longer effect and can mean that the levels in the plasma are more stable as opposed to short acting ones that can create a peak, then a plateau and then rapidly a trough
• Codeine = methylmorphine:

  • 10% converted into Morphine in liver
  • The other 90% stays as codeine and has a weak efficacy at μ receptors - that's how it produces analgesia
  • Potent anti-tussive - suppresses cough reflexes
  • Dosing regimen 30-60mg orally 4 times a day (qds)
  • Multimodal analgesia - can be used alongside analgesics
  • Constipation side effect
  • Minimal risk because of weaker efficacy at μ receptors:
  • Reduced effect on respiratory depression
  • Reduced chance of dependence or addiction
• Tramadol:

  • Weak agonist at μ receptors but also inhibits:
  • Noradrenaline reuptake
  • Serotonin reuptake
  • Causes less constipation, dependence, and respiratory depression
  • Can increase mood (make them feel better)
  • Risk: seizure threshold and serotonin syndrome (high blood pressure, fast heart rate, increases in body temperature, smooth muscle contraction and skeletal muscle contraction)