Non-opioid analgesic agents

CLASSES •Non-steroidal anti-inflammatory drugs •Paracetamol •Noradrenaline and serotonin reuptake inhibitors •tramadol, tricyclic antidepressants •gabapentin, pregabalin •n-methyl d-aspartate antagonists •alpha2 receptor agonists •botulinum toxin ARACHIDONIC ACID •a 20-carbon fatty acid that contains 4 double-bonds, released from membrane phospholipids by phospholipase A2 (PLA2) •precursor of eicosanoids •following mobilisation, arachidonic acid is oxygenated by 4 separate routes •cyclooxygenase or prostaglandin endoperoxide synthase •lipoxygenase •P450 epoxygenase •isoprostane pathway Mediators derived from arachidonic acid

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•PGH synthase-2 (COX-2) •rapidly inducible and tightly regulated •upregulated 20-fold in macrophage, monocytes, synoviocytes, chondrocytes, fibroblasts, osteoblasts and endothelial cells by various inflammatory stimuli •governs increased production of prostanoids that mediate inflammation, pain, and fever •also upregulated in •colorectal adenomas and carcinomas, •breast, head and neck cancers •production decreased by glucocorticoids, cytokines IL-4, IL-13

•both are 60% homologous •small differences lining the COX active sites •COX-2 inhibitor binding site is 25% larger than COX-1 and has a secondary internal pocket off the inhibitor binding site not seen in COX-1 •differences lead to the distinct inhibition profiles between COX-1 and -2 inhibitors

•Acute inflammatory mediators

COX isoenzymes •PGH synthase-1 (COX-1) •constitutively expressed in almost all tissues, always present •responsible for the production of prostaglandins that are important for homeostatic functions •maintaining the integrity of gastric mucosa, •mediating normal platelet function, and •regulating renal blood flow, vascular homeostasis and autocrine response to circulating hormones

NSAIDS •weak organic acids •follows pharmacokinetics for acidic drugs •albumin binding, low pKa, effect of pH on transfer across membrane •except nabumetone, a ketone prodrug that is metabolised to an acidic active drug •effects •inhibit prostaglandin biosynthesis •decrease the production of free radicals and superoxides •interact with adenylyl cyclase to alter the cellular concentrations of cAMP

Non-opioid analgesic agents
Ratio of COX-1/COX-2 inhibition (selectivity)

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•ratios more than 1 indicate more COX-1 selective •the ratio of IC50 of COX-2 to COX-1 defines COX-2 selectivity •IC50 COX-2/IC50COX-1 ratio <0.01 indicates more COX-2 selective (rofecoxib, celecoxib, valdecoxib, parecoxib) Common features of NSAIDs •Upper gastrointestinal side effects •high risk: azapropazone •intermediate risk: diclofenac, piroxicam, naproxen, ketoprofen •low risk: ibuprofen, meloxicam •minimal risk: specific cox-2 inhibitors (coxibs) •Renal effects •in the kidneys COX-2 is constitutively expressed in endothelial and smooth muscle cells of the renal vasculature and in the podocytes of the glomerulus •prostacyclin and PGE2 maintain renal blood flow in states of effective volume depletion such as congestive heart failure, liver cirrhosis, and true volume depletion in chronic diuretic therapy, by antagonising the vasoconstrictive effects of angiotensin II and norepinephrine •NSAIDs use may be associated with acute renal failure in patients with hypovolaemia, altered intrarenal plasma flow, nephrotic syndrome with interstitial nephritis, and papillary necrosis •Haematologic effects •rare, but agranulocytosis and aplastic anaemia are most severe •NSAIDs causes a direct hypoprothrombinaemic effect by depressing vitamin K-synthesis of clotting factors VII, IX, X •NSAIDs displaces warfarin from albumin •platelets contain COX-1 and not COX-2, non COX-2 selective agents demonstrate antiplatelet effects •Cartilage effects •prostaglandins are well-documented modulators of cartilage metabolisms, bone resorption, and ossificaiton •NSAIDs can exacerbate cartilage erosion and produce bony destruction of the femoral head in OA •COX-2 may have a role in cartilage repair •Pulmonary effects •4 to 14-fold increase in COX-2 in asthmatic subjects •COX-2 blockade may be therapeutic in asthma, whereas older NSAIDs can cause bronchoconstriction and oedema

•Cardiovascular effects •causes hypertension •by inhibiting prostaglandin synthesis, NSAIDs interfere with •systemic and renal vasodilatation •glomerular filtration •tubular secretion of fluids and electrolytes •adrenergic neurotransmission •renal-angiotensin-aldosterone system •cardiovascular deaths •Adenoma Prevention with Celecoxib (APC) trial suspended •0.9% (placebo), 2.2% (celecoxib 400mg), 3.0% (celecoxib 800mg) •Prevention of spontaneous Adenomatous Polyps (PreSAP) trial suspended •1.8% (placebo), 1.7% (celecoxib 400mg) •cardiovascular events (MI, stroke, DVT, PE) •2 separate valdecoxib trials, 10 and 14 days, for acute pain after CABG •valdecoxib 40mg twice daily (study 1), and valdecoxib 20mg twice daily (study 2) •risk of cardiovascular events •intravenous form 2%, oral form 1%, placebo 0.5% •Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) suspended •naproxen 220mg vs celecoxib 40mg •apparent increase in CV events in naproxen arm compared to placebo group •Central nervous system effects •headache •confusion •dizziness, •can aggravate •psychiatric illness •epilepsy •parkinsonism •Other effects •peripheral oedema •hyperkalaemia

Salicylic acid and its derivatives •aspirin, acetylsalicylic acid, ASA, has pKa of 3.5 •Pharmacokinetics •absorption •rapidly absorbed from the stomach and upper small intestine, yielding peak plasma concentration within 1-2 hours •acid medium keeps large fraction of the drug in nonionised form, promoting absorption •passage through gastric mucosa may damage mucosal barrier •raising the pH by a buffer to 3.5 or higher, gastric irritation is decreased

Non-opioid analgesic agents
•metabolism •aspirin is rapidly hydrolysed to acetic acid and salicylate by esterases in tissue and blood •salicylate is bound to albumin, as the serum concentration of salicylate increases, a greater fraction remains unbound and available to the tissues •majority undergoes conjugation •pathway is saturable •when aspirin is administered in low dose (600 mg), salicylate elimination is in accordance to first-order and serum t½ is 3-5 hours •with higher dosage, a mix of capacity-limited and zero-order kinetics prevails •at anti-inflammatory dosage (>4g/day), t½ increases to 12 hours or more •elimination •excreted unchanged (2-30% of the salicylate) or as water-soluble conjugated form by the kidney •alkalinisation of urine increases the rate of excretion of free salicylate •Mechanism of action •inhibit cyclooxygenase I and II irreversibly, decreasing the formation of prostaglandins and thromboxane A2 •scavenge free radicals •reduces synthesis of eicosanoid mediators •interferes with the chemical mediators of the kallikrein system •inhibits granulocyte adherence to damaged vasculature •stabilizes lysosomes •inhibits migration of polymophonuclear leukocytes and macrophages into the site of inflammation •Analgesic effect •effective for mild to moderate intensity •peripherally though its effects on inflammation •pain stimuli at subcortical site •alleviates pain from various causes •pain of muscular, vascular and dental origin •postpartum states •arthritis, bursitis •Antipyretic effect •blocks pyrogen-induced production of prostaglandins •blocks central nervous system response to interleukin-1 •IL-1 released by macrophages during inflammatory responses, where its principal role is to activate lymphocytes •reset the temperature control in hypothalamus, facilitating heat dissipation by vasodilatation •Anti-platelet effects •irreversible inhibition of platelet aggregation secondary to inhibition of thromboxane synthesis •action lasts for up to 8 days, until new platelets are formed •lifespan of platelets 8.9 (0.6) days •has longer duration of action than other compounds that inhibit platelet aggregation, such as ticlopidine and dipyridamole •Indications •analgesia •anti-inflammation •antipyresis •inhibition of platelet aggregation •slow cataract formation •lower incidence of colon cancer

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•Adverse effects •gastrointestinal system •gastritis due to •local irritation by the undissolved tablet •absorption in the stomach of unionized salicylate •inhibition of protective prostaglandins •erosive gastritis with bleeding •vomiting due to central stimulation after absorption of large doses of aspirin •central nervous system •salicylism •reversible by reducing the dose •tinnitus, decreased hearing, vertigo •hyperpnoea through direct effect on the medulla, •low toxic concentrations, respiratory alkalosis •higher concentrations, acidosis with accumulation of salicylic acid derivatives and depression of respiratory centre •others •hyperuricaemia with daily dose of 2 g or less •hypouricaemia with daily dose of 4 g or more •mild, asymptomatic hepatitis •especially in patients with systemic lupus erythematosus and rheumatoid arthritis •reversible decrease of glomerular filtration rate •toxic amounts depress cardiac function, and dilate peripheral blood vessels •hypersensitivity •in patients with asthma, and nasal polyps •Contraindications •haemophilia •after viral infection in children, associated with increase in incidence of Reye’s syndrome •Drug interactions •increased absorption with metoclopramide, domperidone •increased excretion in alkaline urine, with antacids, and adsorbents •increased risk of bleeding with anticoagulants, corticosteroids, alcohol •reduced plasma salicylate concentration with corticosteroid •enhanced salicylate toxicity with acetazolamide, ammonium chloride

Non-opioid analgesic agents
•increased toxicity of other drugs •due to displacement from protein binding sites in blood •tolbutamide, chlorpropamide, nonsteroidal anti-inflammatory drugs, methotrexate, phenytoin, and probenacid •reduced excretion of other drugs •acetalzolamide, methotrexate Cox-2-specific inhibitors Celecoxib •Celecoxib has 375-fold selectivity for COX-2 •indicated for relief of signs and symptoms of OA (100mg twice daily) and RA (100-200mg twice daily) in adults •no effect on platelet aggregation •but caution should be exercised if coadministered with warfarin •Contraindications •allergy to aspirin or to other NSAIDs •sulphonamide allergy •Celecoxib is a 4benzenesulphonamide •Pharmacokinetics •absorption •rapid, reaching a maximum serum concentration in three hours •distribution •protein binding 97%, Vdss 400L •metabolism •97% metabolised in liver by CYP2C9 •half-life of 11 hours •excretion •27% via urine, 57% via faeces •Side effects •elevation of liver enzymes •dyspepsia •abdominal pain •endoscopic gastric ulceration •1.5-6% incidence of gastric ulcers, 10-18% with naproxen •systolic hypertension •risk of cardiovascular events, deaths Valdecoxib •sulphonamide derivative •3-4% incidence of endoscopic gastroduodenal ulcers •Pharmacokinetics •absorption •oral bioavailabilty 83% •distribution •protein binding 98%, Vdss 86 L

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•metabolism •half-life 8.1 hours •95% conjugated with glucuronide to form sulphonamide •hydroxylation by CYP2C9/3A4 to minor active hydroxylated metabolite (M1) (minor pathway) •metabolism of M1 forms glucuronide conjugate, glucuronide alcohol, glucuronide •excretion •>90% via urine, <10% via faeces Parecoxib •oral and injectable COX2-selective inhibitor •indicated for perioperative analgesia (20-40mg), opioid sparing at 40mg •a prodrug for valdecoxib •water soluble, when given parenterally, rapidly undergoes amide hydrolysis (non-P450) to form valdecoxib ACETAMINOPHEN / PARACETAMOL •major metabolite of both phenacetin and acetanilide •has antipyretic and analgesic properties •phenacetin has both effects in its own right and that paracetamol formation was not essential for its pharmacological action; however, because a very high proportion is converted to paracetamol during first passage through the liver, phenacetin itself exerts a direct analgesic effect only at very high doses •indicated for mild to moderate pain such as headache, myalgia, postpartum pain, and for patients allergic to aspirin •does not affect platelets, serum uric concentration •Mechanism of action •inhibits brain prostaglandin synthase •weak inhibitor in peripheral tissues •no significant anti-inflammatory effect •Pharmacokinetics •absorption •administered orally •absorption is related to the rate of gastric emptying •peak blood concentration usually reached in 30-60 minutes •distribution •plasma protein binding 25-50 % •Vd 0.8-1L/kg •metabolism •85-90% conjugated with glucuronic acid •the rest is metabolised by hepatic cytochrome P450 mixed function oxidase system into acetaminophen sulphate, which is then conjugated •one of the metabolite, N-acetyl-pbenzoquinoneimine, (an active free radical?) is important in large doses because of its toxicity in both liver and kidney •t½ of acetaminophen is 2-3 hours •relatively unaffected by renal function

Non-opioid analgesic agents
NORADRENALINE AND SEROTONIN REUPTAKE INHIBITORS

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Tramadol •a weak μ receptor agonist and monoaminergic (noradrenaline and serotonin) reuptake blocker •increasing noradrenaline and serotonin concentrations, enhancing serotoninergic and noradrenergic pathways

•elimination •1% excreted in urine unchanged •Adverse effects •Hepatic effects •in therapeutic doses, mild increase in hepatic enzymes may occasionally occur in absence of jaundice •toxicity starts after more than 10 g or 200 mg/kg •plasma concentration more than 300 mg/ml at 4 hours associated with high incidence of liver failure •toxicity probably due to the action of N-acetylp-benzoquinine, an active free radical •normally reacts with sulphydryl groups in glutathione •with large amounts of metabolite, glutathione is depleted, leading to metabolite reacting with sulphydryl groups in hepatic protein leading to central lobular necrosis •hepatic necrosis occurs as a result of intracellular accumulation of Ca++, activation of Ca++-dependent endonuclease, and resultant DNA fragmentation •symptoms include nausea, vomiting, diarrhoea, abdominal pain •Other rare effects •renal damage reported after therapeutic doses •haemolytic anaemia, methaemoglobinaemia •acute pancreatitis •Management of acetominophen poisoning •supportive therapy •protect airway, circulatory support with gastric lavage •activated charcoal •cholestyramine •mannitol •not used now because of resulting electrolyte imbalance •provision of sulphydryl groups to neutralise toxic metabolites (replace depleted SH group) •acetylcysteine 150 mg/kg infusion over 15 minutes, 50mg/kg over 4 hours, and 100 mg/kg over 16 hours •cysteamine 2 g stat + 400 mg at 4, 8, 12 hours •L-methionine 2.5 g every 4 hours up to 10 g

•advantage over other opioids •does not cause respiratory depression or sedation •causes less constipation and addiction than opioids •available as oral, IM, IV preparations •enantioselectively metabolized by cytochrome oxidase isoenzyme P450 2D6, yielding pharmacologically active O-desmethyl metabolite •act mainly through the active metabolite that has weak analgesic actions similar to propoxyphene •mechanism of action may be independent of opioid receptor effects as it is only partially antagonised by naloxone •toxicity •dependence and withdrawal syndromes, seizures and rarely anaphylactoid reactions •Adverse effects •nausea •unspecified central nervous system irritation •sedation •autonomic nervous manifestation •gastrointestinal irritation •vomiting •orthostatic dysregulation •tachycardia •constipation Venlafaxine •it is similar in structure to tramadol •an analgesic with both opioid agonist and monoaminergic activity, inhibiting reuptake of serotonin and norepinephrine •both agents exhibit methoxyphenyl, N,Ndemethylamino and hydroxycyclohexyl groups •metabolism is similar to those of tramadol •enantioselectively metabolized by cytochrome oxidase isoenzyme P450 2D6, yielding pharmacologically active O-desmethyl metabolite

Non-opioid analgesic agents
Tricyclic antidepressants •mechanism of action: inhibition of reuptake of noradrenaline and serotonin •amitriptyline is the only drug with prophylactic efficacy for chronic tension-type headache •however, it is only moderately effective, with headache reduction of approximately 30%, and treatment is often hampered by side effects ANTICONVULSANTS Gabapentin •antiepileptic agent which was initially synthesized to mimic the chemical structure of the neurotransmitter gamma-aminobutyric acid (GABA), but is not believed to act on the same brain receptors, can be used for the management of postherpetic neuralgia in adults •does not modify GABAA or GABAB radioligand binding •is not converted metabolically into GABA or a GABA agonist •is not an inhibitor of GABA uptake or degradation •Mechanism of action •binds to the α2δ subunit (1 and 2) of the voltagedependent calcium channel at the postsynaptic dorsal horns •at clinically relevant concentrations, results in significant reduction of inward Ca++ current (ICa) in neuropathic neurons •analgesia may be due to diminished release of neurotransmitter by sensory neurons, a Ca++-dependent process •Pharmacokinetics •less than 3% of gabapentin circulates bound to plasma protein •metabolism •not appreciably metabolized in humans •elimination •eliminated from the systemic circulation by renal excretion as unchanged drug •elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing •elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance •plasma clearance is reduced in elderly patients, and in patients with impaired renal function, but can be removed from plasma by haemodialysis •dosage adjustment in patients with compromised renal function or undergoing haemodialysis is recommended NMDA RECEPTOR ANTAGONISTS •Role of NMDA receptors in pain •repeated C fibre stimulation can lead to central sensitization and hyperalgesia •development of hyperalgesia involves activation of excitatory amino acids which lead to intracellular events and nitric oxide production

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•activation of the NMDA receptor in tissue injury results in increased pain by altering pain processing in the spinal cord with resulting hyperexcitability •opioid use may enhance NMDA receptor activation resulting in reduced potency of the opioid •neural mechanisms leading to hyperalgesia and tolerance to morphine may involve NMDA receptor activation •NMDA antagonists may alleviate pain by inhibiting central sensitization •use of these drugs in the perioperative period in combination with opioids may improve pain control by preventing the development of pain hypersensitivity. Ketamine •a non competitive antagonist that binds to the phencyclidine binding site of the NMDA receptor •S (+) ketamine has 4 times greater affinity for the NMDA receptor than the R (-) ketamine and twice the potency of R (-) sytereoisomer •has an elimination half-life of 80 to 180 minutes •metabolite norketamine is one third as potent and with a longer half–life it may contribute to the prolonged analgesic action of ketamine •may be useful as adjuvant analgesic in opioid tolerant patients (chronic or cancer pain), and in surgical procedures related to a higher incidence of persistent pain, such as thoracotomy, mastectomy, and limb amputation •ketamine (0.25 mg/kg) in addition to morphine, produced immediate and sustained analgesia in the presence of morphine resistant pain ALPHA2 RECEPTOR AGONISTS •binding of alpha2 receptor agonist reduces Ca++ entry through the voltage-dependent Ca++ channels, diminishing release of neurotransmitter by sensory neurons mediating analgesia •the spinal cord the main site for analgesia although peripheral and supra spinal sites are described Clonidine •can be administered via: oral, parenteral, transdermal, neuraxial, around peripheral nerves and intra-articular Dexmedetomidine •a highly selective alpha2 agonist with a significantly shorter half life, has been use for sedation and analgesia NEUROTOXIN Botulinum toxin •produced by Clostridium botulinum, the bacteria that causes botulism •it produces seven distinct neurotoxins that are neuromuscular paralyzing agents: •Mechanism of action •toxin is internalized into the neurons and binds to the synaptic vesicle membranes, and cleaves proteins (VAMP/synaptobrevin, syntaxin, SNAP-25) involved in the release of transmitter, rendering the vesicles inactive •transmitter is no longer released in response to a neuronal signal and the muscles are paralysed

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