ANALGESICS and its importance in dentistry

Analgesics and importance of it in dentistry

1. ANALGESICS

2. CONTENTS 1.INTRODUCTION 2.OPIOID ANALGESICS 3.CLASSIFICATION OF OPIOIDS 4.IMPORTANT OPIOID DRUGS 5. OPIOID ANTAGONISTS 6.NON-OPIOID ANALGESICS 7. ACTIONS OF ANALGESICS 8.IMPORTANT NSAIDS’s 9.SELECTIVE COX-2 INHIBITORS 10.PRINCIPLES FOR PRESCRIBING ANALGESICS. 11.CLINICAL SIGNIFICANCE OF ANALGESICS IN CONS AND ENDO 12.ADJUVANT DRUGS 13.SPECIAL SITUATION 14.NEUROPATHIC PAIN 15.CONCLUSION

3. ALGESIA /PAIN- Is an ill defined , unpleasant sensation , usually evoked by an external or internal noxious stimulus ANALGESIC- A drug that selectively relieves pain by acting in the CNS or peripheral pain mechanism, without significantly altering consciousness Analgesics are divided into two groups- Opioid / narcotic/ morphine-like analgesics Non- opioid / non-narcotic/ aspirin-like/ anti-pyretic/ antiinflammatory analgesics INTRODUCTION K.D Tripathi’s essentials of medical pharmacology 6 th edition

4. Opium – A dark brown, resinous material obtained from poppy capsule. It has been known from the earliest times. Serturner , a pharmacist, isolated the active principle of opium in 1806 and named it ‘morphine’ after the greek god of dreams Morpheus. In the last century a large number of semisynthetic and synthetic compounds have been developed with morphine-like, antagonistic and mixed agonistic-antagonistic properties OPIOID ANALGESICS K.D Tripathi’s essentials of medical pharmacology 6 th edition

5. Natural opium alkaloids - Morphine, Codeine Semi-synthetic opiates – Heroin/ Diacetylmorphine Synthetic opioids – fentanyl , Pethidine ( meperidine ), methadone, tramadol CLASSIFICATION OF OPIOIDS K.D Tripathi’s essentials of medical pharmacology 6 th edition

6. Also known as narcotic analgesics They are more potent than NSAIDs, and used in low doses less than 15mg They are used most commonly in combination with NSAIDs, to enhance analgesic effect, and gain an anti-inflammatory action Some of the common formulation used in dental practice are- Codeine/ Aspirin Codeine/ Acetaminophen Tramadol / Acetaminophen Oxycodon / Acetaminophen( very powerful) Oxycodon / Ibuprofen ( very powerful) Ghom’s Textbook of Oral Medicine, 3rd edition

7. Mechanism of action : Morphine and other opioids produce their effect by acting on specific opioid receptors through mu(µ), kappa ( κ ) and delta ( δ ) These receptors are abundant in the CNS and other tissues. µ receptors – respiratory depressant+ GI κ receptors- involved in sedation + GI δ receptors- development of tolerance Padmaja udaykumar’s Pharmacology for dental and allied health sciences 4 th edition

8. MORPHINE Pharmacological actions: Analgesia- Morphine alters both the perception and reaction to pain Euphoria, Sedation and hypnosis Respiration-Morphine produces significant respiratory depression Cough center- It directly depresses the cough center and thereby suppresses cough Nausea and emesis- Directly stimulates the CTZ in the medulla causing nausea and vomiting Pupils- Morphine produces miosis Bradycardia on vagal stimulation Causes Hypotension It decreases motility of the gut

9. Precaution and Contraindications- - Avoid opioids in patients with respiratory insufficiency- chronic obstructive pulmonary disease (COPD) -An attack of bronchial asthma can be precipitated by morphine Head injury-morphine is contraindicated as it increases CSF pressure In hypovolemic shock, morphine further decreases BP Opioids potentiates CNS depressants Acute morphine poisoning – Respiratory depression, pin-point pupils, hypotension, shock, cyanosis, coma and death. Specific antidote- Naloxone - 0.4-0.8mg IV repeated every 10-15 min Padmaja udaykumar’s Pharmacology for dental and allied health sciences 4 th edition

10. CODEINE It is methyl-morphine, occurs naturally in opium, and is partly converted in the body to morphine. It is less potent than morphine, also less efficacious, is a partial agonist at mu opioid receptor with a low ceiling effect. Depresses cough center in subanalgesic doses Codeine has less addiction liability and tolerance is uncommon Constipation is the most common side effect It is commonly used as antitussive It is also available in combination with paracetamol for analgesia. It is to be given at bed time ( CODOPLUS- Codeine 30mg+ paracetamol 500mg ) K.D Tripathi’s essentials of medical pharmacology 6 th edition

11. PETHIDINE Pethidine is a phenylpiperidine derivative of morphine. Many of its action resembles that of morphine. Pethidine is 1/10 th as potent as morphine. However , efficacy as an analgesic is equal to morphine The onset of action is more rapid and duration of action is shorter It produces corneal anesthesia It can also be used as preanesthetic medication It is less constipating In toxic doses, pethidine produces CNS stimulation with tremors, restlessness and convulsions instead of sedation. This is because of toxic metabolite- norpethidine K.D Tripathi’s essentials of medical pharmacology 6 th edition

12. TRAMADOL Tramadol is a synthetic codeine analog. It is an effective analgesic but its mechansim of action is not clear It is used in acute and chronic pain, like postoperative pain and neuralgias Adverse effects include drowsiness, dryness of mouth, sedation and nausea. It is a drug of dependence. It may precipitate seizures. It should be avoided in patients on MAO inhibitors because tremadol inhibits serotonin uptake Injected IV 100mg tramadol is equianalgesic to 10mg IM morphine, oral bioavailability is good K.D Tripathi’s essentials of medical pharmacology 6 th edition

13. OPIOID ANTAGONISTS It acts as a competitive antagonists to all type of opioid receptors It promptly antagonizes all the action of morphine including respiratory depression and sedation and precipitates withdrawal syndrome. It also blocks the action of endogenous opioid peptides- endorphins, enkephalins and dynorphins . Duration of action is 3-4 hours Dose- 0.4mg IV Naloxone is the drug of choice for morphine overdosage It can also be used for the diagnosis of opioid dependence- it precipitates withdrawal symptoms NALOXONE

14. NALTREXONE Naltrexone is another pure opioid antagonist. It is more potent than naloxone . It is also used for opioid blockade therapy in post addicts MIXED AGONISTIC AND ANTAGONISTS They include pentazocine , cyclazocine , nalbuphine , buprenorphine . PENTAZOCINE- It is a K receptor agonist It has weak antagonistic properties at mu receptors Central nervous system effects of pentazocine are similar to morphine. It is commonly used opioid analgesic especially in postoperative and chronic pain- abuse liability is less than morphine

15. NON-OPIOID ANALGESICS AND NSAIDs The first clinical reports on the treatment of fever and pain with salicylate -containing natural willow bark remedies were made by the English clergyman Edward Stone in 1763. Salicylic acid was first synthesised by the German Gerland in 1852 and a year later the Frenchman Gerhardt synthesised acetylsalicylic acid. Acetylsalicylic acid was rediscovered by Hoffmann in 1897 and by the turn of the century it had gained worldwide recognition in the treatment of pain and rheumatological disorders.

16. NON-OPIOID ANALGESICS AND NSAIDs NON- SELECTIVE COX INHIBITORS ( Conventional NSAIDs) Salicylates - aspirin Propionic acid derivatives – Ibuprofen, ketoprofen , Naproxen Anthranilic acid derivatives- Mephenamic acid Aryl acetic acid derivative- Diclofenac Oxicam derivative- Piroxicam , Tenoxicam Pyrrolo-pyrrole derivative- Ketorolac Indole derivative- Indomethacin Pyrazalone derivative – Phenylbutazone , Oxyphenabutazone B.. PREFERENTIAL COX-2 INHIBITORS: Nimesulide , Meloxicam K.D Tripathi’s essentials of medical pharmacology 6 th edition

17. C. SELECTIVE COX-2 INHIBITORS- Celecoxib , Etoricoxib , Parecoxib D. ANALGESIC-ANTIPYRETICS WITH POOR ANTI-INFLAMMATORY ACTION- 1.Paraaminophenol derivative- Paracetamol ( Acetaminophen) 2. Pyrazolone derivatives- Metamizol ( Dipyrone ), Propiphenazone 3. Benzoxazocine derivative- Nefopam K.D Tripathi’s essentials of medical pharmacology 6 th edition

18. MECHANISM OF ACTION OF NSAID’s Mainly blocks PG generation PG- Erthema , Oedema , Fever associated with inflammation and generate pain by direct action / sensitising pain receptors PG- produced from arachidonic acid by COX The main mechanism- inhibition of the enzyme cyclooxygenase (COX-1 and COX-2) Interferes with the synthesis of PG- blocking impulse generation that mediates pain K.D Tripathi’s essentials of medical pharmacology 6 th edition

19. PHARMACOKINETICS Absorption – Absorbed well orally , occurs from lungs and nasal and oral mucosa , slow and incomplete through GIT Distribution – Partially bound to plasma proteins Metabolism – By conjugation with glucuronic acid in the liver Excretion – By glomerular filteration in urine within 24 hours K.D Tripathi’s essentials of medical pharmacology 6 th edition

20. ACTIONS OF ANALGESICS ANALGESIC ACTION – Blocks pain sensing mechanism induced by brady-kinin , TNF- alpha , interleukins ANTIPYRETIC ACTION – Blocks the action of pyrogens which in turn reduces body temperature ANTI-INFLAMMATORY – PG-only mediator of inflammation ; analgesics blocks PG synthesis DYSMENORRHEA- Blocks PG synthesis in endometrium ANAPHYLACTIC REACTION- Asthma , Urticaria , Swelling or rhinitis ANTIPLATELET AGGREGATORY- Bleeding time is prolonged DUCTUS ARTERIOSUS CLOSURE K.D Tripathi’s essentials of medical pharmacology 6 th edition

21. SOME IMPORTANT ANALGESICS ASPIRIN Acetylsalicylic acid Pharmacological actions – Analgesics, Antipyretic , Anti-inflammatory Metabolic effects – Decrease blood sugar levels Respiration – Hyperventilation in poisoning CVS- Vasodilation GIT- epigastric distress, Nausea and vomiting Blood – Prolongs BT K.D Tripathi’s essentials of medical pharmacology 6 th edition

22. Uses Analgesics Antipyretic Anti-inflammatory Acute rheumatic fever Post MI PDA Osteoarthritis K.D Tripathi’s essentials of medical pharmacology 6 th edition

23. ADVERSE EFFECTS Nausea and vomiting , epigastric distress Rashes , Urticaria , Asthma , Anaphylaxis Salicylism – Dizziness, Vertigo , Hyperventilation, reversible impairement of hearing and vision Reye’s syndrome – Use of aspirin in children in less than 12 years with influenza or pox Causes life – threatening condition Vomiting , lethargy , delirium, coma , even death If child survives- irreversible brain damage Use of aspirin in children is prohibited in india Acute salicylate poisoning- more common in children. Fatal dose in adults is estimated to be 15-30g, but is considerably lower in children

24. CONTRA-INDICATIONS OF ASPIRIN Peptic ulcer Pregnancy Nursing mother G6PD deficiency – hemolysis Before dental extraction Chronic liver disease Diabetes- aspirin – hypoglycemic action Hepatic damage Chicken pox

25. PHARMACOKINETICS OF ASPIRIN Absorbed from stomach and small intestine 80% plasma protein binding capacity Half life at therapeutic dose = 15-20 min DRUG INTERACTION OF ASPIRIN Increases toxicity of oral- anticoagulants , heparin , oral anti- diabetics , phenytoin Increases action of anti-platelet drugs Decreases action of beta blockers Antacid and activated charcoal decreases aspirin absorption Increases action of insulin and sulphonylureas

26. IBUPROFEN Propionic acid derivative Pharmacological actions –Analgesic, Antipyretic and Anti-inflammatory Uses- Analgesic (dose-400mg, TDS) Antipyretic Anti-inflammatory Dental inflammation RA Osteoarthritis Spondylitis K.D Tripathi’s essentials of medical pharmacology 6 th edition

27. ADVERSE EFFECTS AND CONTRAINDICATION Lesser than aspirin Gastric discomfort , nausea and vomiting Headache, dizziness, blurring of vision Tinnitus, depression may occur Contraindications – Peptic ulcer Pregnant women Lactating women

28. PHARMACOKINETICS AND DRUG INTERACTIONS PHARMACOKINETICS 99% bound to plasma protein Half life is 2 hours Can cross BBB, placenta DRUG INTERACTION- Aggravates actions of aspirin, anti-platelet Decreases action of anti-diuretic, anti-hypertensive. Eg -beta blocker, thiazide K.D Tripathi’s essentials of medical pharmacology 6 th edition

29. PARACETAMOL Para-amino phenol derivative Pharmacological actions- analgesic- antipyretic action but no anti-inflammatory action Uses- Headache, musculo -skeletal pain , dysmenorrhea First drug of choice for osteoarthritis Used in patients in whom aspirin is C/I Pharmacokinetics- Well absorbed orally Plasma half life- 2 hours Dose- 0.5-1gm every 6 hours or TDS, 10-15 mg/kg/doses every 4-6 hours in children Maximum 5 doses in 1 day

30. ADVERSE EFFECTS- Prolonged use- liver damage Acute paracetamol poisoning- Nausea and vomiting, abdominal pain , in later stages hepatic necrosis, renal tubular necrosis, hyperglycemia and coma Treatment- Induce vomiting , gastric lavage ; activated charcoal K.D Tripathi’s essentials of medical pharmacology 6 th edition

31. DICLOFENAC Aryl-acetic acid derivative Pharmacological action- COX inhibitor , analgesic, antipyretic, anti-inflammatory Indication- RA, osteoarthritis, bursitis, post-operative inflammation, spondylitis Adverse effect – Epigastric pain , nausea, headache, dizziness, kidney damage(rare) Half life- 2 hours Dose- 100-200mg BID or TDS Trade name- T. Diclomax-25mg,50mg, 100mg T. Voveran - 50mg

32. KETOROLAC Pyrrolo-pyrrole derivative Pharmacological action – PG inhibitor, relieves pain by peripheral mechanism Indication – Post-operative, dental pain, musculoskeletal pain , migraine Adverse effect- Epigastric pain , nausea , ulceration , loose stools , drowsiness, dizziness Half life -5-7 hours Dose- 10-20mg tablets every 6 hours Trade name – T. Ketorol - 10mg T. Toralac – 10mg Ketanov - 10mg

33. ADVERSE EFFECTS Constipation Respiratory depression Nausea and vomiting Miosis -pin-point pupils Urinary retention CNS effects- stimulation CVS effects – stimulates vagus nerve- bradycardia , postural hypotension , syncope Apnea- newborns Allergic reaction- rashes, urticaria Miscellaneous – tremors, delirium, sedation, lethargy

34. PRECAUTIONS AND CONTRAINDICATION Infants Head injuries Respiratory insufficiency Bronchial asthma Hypotensive states and hypovolemia THERAPEUTIC USES Analgesic Preanesthetic medication Relief of anxiety and apprehension- MI and internal bleeding Acute LVF Cough Diarrhea

35. ANTHRANILIC ACID DERIVATIVE ( FENAMATE) MEPHENAMIC ACID An analgesic, antipyretic and weaker anti-inflammatory drug, which inhibits COX as well as antagonises certain actions of PGs. Mephenamic acid exerts peripheral as well as central analgesic action Uses- Analgesic in muscle , joint and soft tissue pain where strong antiinflammatory action is not needed Effective in dysmenorrhoea Dose- 250-500mg TDS Adverse effects- Diarrhoea is the most important dose related , Skin rashes, dizziness and other CNS manifestation have occured

36. On December 7, the Indian Pharmacopoeia Commission (IPC) issued a drug safety alert about Meftal , a commonly used non-steroidal anti-inflammatory drug (NSAID), saying that its constituent, mefenamic acid, triggers Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, a severe allergic reaction.

37. With the alert issued, the list of fixed combination drugs banned in in India in 2023 for human use, as per  drugscontrol.org .  1. Nimesulide + Paracetamol Dispersible Tablet 2. Chlopheniramine Maleate + Codeine Syrup 3. Paracetamol + Bromhexine + Phenylephrine + Chlorpheniramine + Guaiphenesin 4. Chlorpheniramine + Codeine Phosphate Menthol Syrup 5. fixed dose combination of Paracetamol + Cetirizine + Caffeine 6.  fixed dose combination of Paracetamol + Phenylephrine + Caffeine

38. NIMESULIDE It is a weak inhibitor of PG synthesis with a higher affinity for COX-2 than COX-1. It inhibits leukocyte function , prevents the release of mediators and in addition has antihistaminic and antiallergic properties. Nimesulide has analgesic , antipyretic and anti-inflammatory actions like other NSAID’s Adverse effects of nimesulide are gastrointestinal , dermatological ,somnolence and dizziness Instances of fulminant hepatic failure have been associated with nimesulide and it has been withdrawn from Spain and Turkey Even in india it got banned in the year 2011 much later than other countries. Dose- 100mg BD Tradename - NIMULID, NIMEGESIC, NIMODOL

39. SELECTIVE COX-2 INHIBITORS Selective inhibition of COX-2 was found to be advantageous because COX-2 is involved in inflammation and COX-1 which is protective on gastroduodenal mucosa is spared They also donot inhibit platelet aggregation because COX-1 is involved in platelet function Disadvantage- Clinical studies have shown that the use of selective COX-2 inhibitors increases the risk of cardiovascular and cerebrovascular thrombotic events- may increase the risk of myocardial infarction and stroke Therefore they are only indicated in patients who cannot tolerate NSAID’s and are at high risk of developing peptic ulcer

40. CELECOXIB It is highly selective COX-2 inhibitor It has good anti-inflammatory, analgesic and antipyretic properties but does not affect platelet aggregation It can be useful in acute painful conditions like postoperative pain , dysmenorrhea and dental pain as well as in osteoarthritis and rheumatoid arthritis in patients who cannot tolerate NSAID’s Dose- Anti-inflammatory- 100-200 mg OD-BD

41. PRINCIPLES FOR PRESCRIBING ANALGESICS Oral route preferred when patient is physically able to take medication Except in immediate post-operative period , buccal , sublingual , rectal routes can be considered as alternatives IM route avoided because it is more painful IV or SC routes preferred when parenteral route is needed Mild pain – NSAIDs / Acetaminophen Moderate pain – Opioid / non- opioid + weak Opioid ( eg . Codeine and Codeine combination ) Ghom’s Textbook of Oral Medicine, 3rd edition

42. Severe pain – Long –acting opioids ( Oxycontin , methadone , morphine, transdermal fentanyl ) Constant pain – around the clock analgesics rather than SOS basis Intermittent pain- SOS basis Only one opioid – non- opioid combination analgesic Only one long-acting opioid analgesic Appropriate bowel regimen for all patients on opioid analgesics

43. CLINICAL SIGNIFICANCE OF ANALGESICS IN CONS AND ENDO A variety of drugs and drug combination are used to treat pre-op and post-op dental pain . Pain due to an infected tooth(pulp involvement , periapical lesion ) and post- operative pain following RCT is common An accurate understanding of post-op after RCT allows clinicians to predict and effectively manage it through the prescription of analgesics Pain killers used are acetaminophen ( paracetamol ), opioids (rare), NSAIDs+ acetaminophen Gasner , Noah & Ouanounou , Aviv. (2021). Analgesics and Pain Management Following Root Canal Therapy. Essentials of Dentistry. 1. 10.5152/EssentDent.2021.21006

44. When defenitive care cannot be delivered immediately NSAIDs (Ibuprofen), Acetaminophen Ibuprofen – 400-800mg every 4-8 hours Antibiotics – not effective pain relievers PRESCRIBING FOR PRE-OP PAIN Gasner , Noah & Ouanounou , Aviv. (2021). Analgesics and Pain Management Following Root Canal Therapy. Essentials of Dentistry. 1. 10.5152/EssentDent.2021.21006

45. PRESCRIBING FOR POST-OP PAIN Prescription should vary depending on the expected pain severity based on the procedure performed Patient factors- presence of any medication contraindications, age, pregnancy, and a history of substance abuse should be considered The post-op pain expected following RCT is generally mild to moderate, can usually be managed with OTC medications such as NSAIDs, acetaminophen , or a combination of the two If a greater severity of pain is expected – opioid may be indicated Gasner , Noah & Ouanounou , Aviv. (2021). Analgesics and Pain Management Following Root Canal Therapy. Essentials of Dentistry. 1. 10.5152/EssentDent.2021.21006

46. MILD POST-OP PAIN Expected following most invasive procedures like RCT OTC analgesic recommended Ibuprofen and Acetaminophen If Ibuprofen not C/I -200-400mg every 4-6 hours (max 2.4g ) If C/I, Acetaminophen is indicated -500-1000mg every 4-6 hours( max 4g) Gasner , Noah & Ouanounou , Aviv. (2021). Analgesics and Pain Management Following Root Canal Therapy. Essentials of Dentistry. 1. 10.5152/EssentDent.2021.21006

47. SEVERE POST-OP PAIN Rarely expected following routine RCT, would most likely occur in the case of complicated surgical endodontics Opioid + non- opioid analgesic Codeine/ Oxycodone + Acetaminophen / Ibuprofen If opioid indicated , then combination should be prescribed for maximum of 48 hours Gasner , Noah & Ouanounou , Aviv. (2021). Analgesics and Pain Management Following Root Canal Therapy. Essentials of Dentistry. 1. 10.5152/EssentDent.2021.21006

48. ADJUVANT DRUGS They are not considered analgesics and not used as first line analgesic treatment They could be used alone or in combination with pain killers Examples of this type of drugs are_ Caffeine- It can enhance the analgesic effect of aspirin, acetaminophen, and ibuprofen Hydroxyzine (anti-histamine)- Enhances analgesic effect of opioid , and reduce occurrence of nausea and vomiting related to them Corticosteroid_ They ha s anti-inflammatory action, therefore relieve pain that has inflammatory origin Ghom’s Textbook of Oral Medicine, 3rd edition

49. SPECIAL SITUATIONS Asthmatic patients – acetaminophen Pregnant patient – Acetaminophen or codeine/ acetaminophen ( short term use ) Patients with peptic ulcer , hemophilia , bleeding disorder, or taking anticoagulants – Acetaminophen Patients with ischemic heart disease – Morphine Patients allergic to aspirin – Acetaminophen or opioid / acetaminophen Patients allergic to codeine – NSAIDs or proxyphene ( opioid ) Patients with hepatoxic – Diclofenac Patients with nephrotoxic - paracetamol K.D TRIPATHI’S ESSENTIALS OF MEDICAL PHARMACOLOGY 6 TH EDITION

50. NEUROPATHIC PAIN Patient with neuropathic pain such as trigeminal neuralgia is not responsive to usual analgesic therapy Some psychotropic medications are used to manage such pain – Anti-depressant – amitriptyline , imipramine Anti- convulsants – carbamazepine , clonazepam , valporic acid, gabapentin , Lamotrigine , Topiramate and phenytoin Ghom’s Textbook of Oral Medicine, 3rd edition

51. CONCLUSION In conclusion, through careful consideration of patient needs, appropriate dosage and potential side effects, dental professionals can alleviate discomfort and enhance patient experience during treatment

52. REFERENCES 1. K.D Tripathi’s essentials of medical pharmacology 6 th edition 2. Ghom’s Textbook of Oral Medicine, 3rd edition 3. Padmaja udaykumar’s Pharmacology for dental and allied health sciences 4 th edition 4. Gasner, Noah & Ouanounou , Aviv. (2021). Analgesics and Pain Management Following Root Canal Therapy. Essentials of Dentistry. 1. 10.5152/EssentDent.2021.21006

53. THANK YOU