Non-Opioid Analgesia Flashcards
(13 cards)
What drugs are considered to be ‘non-opioid analgesics’?
Paracetamol/ Acetaminophen
Non-steroidal anti-inflammatories such as…
Aspirin/Acetylsalicylic acid
Ibuprofen
Naproxen
Diclofenac
Nabumetone
Etoricoxib
Celecoxib
Lumiracoxib
Outline the therapeutic effects of paracetamol and describe its mechanism of action
Paracetamol is utilised in the treatment of mild to moderate pain and fever, as it has both an analgesic and anti-pyretic effect when administered. It’s effects may be enhanced when used in conjunction with NSAIDs or weak opioids, and when administered with strong opioids, can aid in ‘opioid sparing’ - strategies that minimise opioid use while maintaining effective pain relief.
There is uncertainty regarding paracetamol’s exact mechanism of action, it is thought that its anti-pyretic effect may be a result of prostaglandin inhibition within the hypothalamus. Hypotheses relating to the analgesic effect of paracetamol suspect that the inhibition of various isoforms of cyclooxygenase (an enzyme required for the conversion of arachidonic acid into compounds such as prostaglandins and thromboxane) is involved, as prostaglandins are responsible for inflammation related pain symptoms, although paracetamol does not inhibit COX in peripheral tissues, and therefore has little anti-inflammatory effects in the peripheries. It is also believed that paracetamol interferes with nocioception associated with spinal NMDA (N-methyl-D-aspartate) receptor activation, contributing to its analgesic effect.
How can paracetamol be administered?
Orally - As a tablet, capsule, suspension, solution or effervescent tablet
Rectally - As a suppository
Intravenously - As a solution for infusion
The intravenous route should only be used when the enteral route is unavailable or not suitable (e.g in patients with pyrexia or mild-moderate pain with risk factors for hepatoxcity such as pre-existing hepatic conditions or a history of alcoholism, or who are unable to swallow an oral solution/tablet - generally not utilised in clinical practice often)
What is the maximum dose of paracetamol that an adult can receive orally, rectally or intravenously per day?
Oral & Rectal- Maximum 4g per day (0.5-1g every 4-6 hours)
Intravenously - If adult is above 51kg = Maximum 4g per day, if adult is below 51kg = Maximum 60mg per kg, per day
What are the main risks associated with paracetamol use?
Overdose and Hepatotoxicity
What is cyclo-oxygenase?
Cyclo-oxygenase (COX) is an enzyme that acts on arachidonic acid to produce prostanoids (metabolites of arachidonic acid) i.e prostaglandins, prostacyclins, and thromboxanes. Prostanoids play a significant role in the inflammatory process, mediating various aspects of the inflammatory response:
Prostoglandins (e.g PGE2, PGD2, PGF2a)- Promote excitability of peripheral somatosensory system, contributing to pain exacerbation, they also contribute to vasodilation and increased vascular permeability. They also amplify the signals of cytokines, promoting the inflammatory response. Are also involved in the development of fever, by acting on the hypothalamus to induce increased body temperature. They also have an effect on gastric mucosal protection
Thromboxanes (e.g Thromboxane A2/TXA2)- Promotes vascular permeability (contributing to oedema), vasoconstriction, platelet activation and aggregation (contributing to the formation of a platelet plug in epithelial injury)
Prostacyclins (e.g PGI2) - Promotes vasodilation and platelet disaggregation
There are two distinct isoforms of COX: COX-1 & COX-2
COX-1 is constitutively expressed in most cells, and is primary responsible for homeostatic prostanoid synthesis.
At sites of inflammation, cytokines stimulate the induction of COX-2.
What is the mechanism of action of NSAIDs?
NSAIDs produce their anti-inflammatory, anti-pyretic and analgesic effect by inhibiting the action of COX, thus inhibiting the synthesis of prostaglandins. COX isoforms possess a long channel, which is wider in COX-2, non-selective NSAIDs (apart from aspirin) enter the channels in both enzymes and block then by binding with hydrogen bonds to an arginine halfway down, this reversibly inhibits the enzymes by preventing the access of arachidonic acid.
Aspirin acetylates COX enzymes (introduces an acetyl group into the COX enzymes) at serine 530 (an amino acid residue within the active site of COX enzymes), this irreversibly inhibits the COX isoforms.
Selective COX-2 inhibitors are generally larger molecules, which prevent inhibition of COX-1 as they cannot enter their channels.
What drugs are considered non-selective COX inhibitors?
Salicylic Acid Derivatives:
Aspirin
Propionic Acid Derivatives:
Ibuprofen
Naproxen
Others:
Diclofenac
Indometacin
Nabumetone
What is the main limitation of non-selective COX inhibitor use?
Inhibition of prostoglandin synthesis in the gastric mucosa frequently results in gastrointestinal damage, which can result in symptoms such as dyspepsia, nausea and gastritis, or can result in more serious adverse effects such as peptic ulceration, GI bleeding and perforation. It is thought that inhibition of COX-1 is responsible for the adverse gastrointestinal effects of non-selective COX inhibitors. While they are termed non-selective COX inhibitors as they have an inhibitory effect on both isoforms, most non-selective COX inhibitors are somewhat selective for COX-1.
What drugs are considered selective COX-2 inhibitors?
Etoricoxib
Celecoxib
Lumiacoxib
What is the main benefit of using a selective COX-2 inhibitor over a non-selective COX inhibitor?
They demonstrate similar efficacy as analgesic, anti-pyretic anti-inflammatories when compared to non-selective COX inhibitors, but the incidence of gastric perforation, obstruction and bleeding is reduced by at least 50%
What are the potential limitations of using a COX-2 inhibitor as opposed to a non-selective COX inhibitor?
They have been associated with an increased incidence of myocardial infarction, and are generally more expensive than their non-selective counterparts
What types/classes of drug have the potential to interact with NSAIDs (Non-selective and COX-2 selective) and potentially cause adverse effects?
ACE Inhibitors, ARBs & Diuretics - As prostaglandins play a role in stimulating renin release, anti-hypertensives that act on renal prostaglandins (e.g furosemide) or modify their effects (ACE inhibitors, ARBs, other diuretics)/ act on the RAAS, may not be as effective when used in conjunction with NSAIDs (although this effect is often minimal). It is also thought that combined used of NSAIDs and anti-hypertensives may increase the risk of nephrotoxicity.
Beta Adrenoceptor Antagonists - Some non-selective COX inhibitors (including indomethacin and flurbiprofen, but not naproxen or aspirin) have been found to interact with beta-blockers, reducing their anti-hypertensive effect.
Aspirin/ Other NSAIDs - Associated with an increased risk of bleeding and peptic ulceration
Warfarin - Concurrent use of NSAIDs and anti-thrombotics such as warfarin is associated with increased risk of GI bleeding
SSRIs - Concurrent use of NSAIDs and SSRIs is associated with increased risk of GI bleeding due to inhibited platelet adhesion and function associated with SSRI use.
Lithium - NSAIDs are associated with an increase in lithium concentration, possibly linked to NSAID mediated inhibition of renal prostaglandins leading to decreased lithium excretion
Oral Corticosteroids (Prednisolone, betamethasone, dexamethasone, hydrocortisone) - Combined use of oral corticosteroids and NSAIDs may increase the potential for serious GI bleeding and peptic ulceration.
