Faculty: Dr. Lynn L. Olegario, FPARM Drugs To Treat Pain Main drugs used for their analgesic effects: Non-opioid (ex: NSAIDs) Opioids Adjuvant Drugs (ex: anti-convulsants) OPIATES Opium, has a characteristic odor & bitter taste with its chief active ingredient : Morphine
Also present are Methylmorphine (codeine), thebaine, noscapine, papaverine
Diacetylmorphine (heroin)
Papaver Somniferum OPIOIDS Natural Opiates Semi-synthetic Opiates Synthetic Opiates Endogenous Opiates Opiate antagonist Opioids: Mechanism of Action Pre-synaptically, bind at opioid receptors inhibiting the release of substance P and glutamate Post-synaptically, bind at the opioid receptors, inhibiting neurons to open potassium channels that hyperpolarize the cell OPIOID Classification 1) Strength: Weak / Strong
2) Action: Pure Agonists Partial agonists Mixed agonists-antagonists Opioid Classification, Strength: WEAK Opioids Codeine Tramadol Opioid Classification, Strength: STRONG Opiods Butorphanol Fentanyl Meperidine Morphine Nalbuphine Oxycodone Opioid Classification, Mode of Action Agonists - opioids that mimic the effects of morphine Antagonists - opioids that oppose the effects of morphine. Sometimes called morphine antidotes Agonist-antagonists - opioids that mimic some effects and oppose other effects of morphine Opioid Classification,Mode of Action: EXAMPLES Pure agonists Morphine, hydromorphone, codeine, oxycodone, methadone, levorphanol, meperidine Agonist-antagonists Mixed agonist-antagonist Nalbuphine, butorphanol, pentazocine, dezocine Partial Agonist buprenorphine Antagonists Naloxone, naltrexone Opioid Receptors and Effects of Stimulation Receptor Effects mu1 analgesia, euphoria, priritus, nausea, constipation
Opioid receptors are found in the central nervous system Below are the different types of opioid receptors OPIOIDS: Principles of Dosing 1. Doses should be adjusted in each patient to achieve pain relief with an acceptable level of adverse effects.
2. There is no ceiling or maximum recommended dose for full opioid agonists. OPIOIDS: Principles of Dosing 3. Use around the clock dosing for continuous or frequently recurring pain.
4. Consider as needed dosing for dose finding and for rescue dose.
Transitory flare of pain in patients otherwise controlled with chronic opioid therapy Breakthrough Pain Rescue Dose Analgesic given in addition to the around the clock analgesic dose to relieve the breakthrough pains 1) Spontaneous 2) Incident 3) End-of-dose failure T im e
P e rs is te n t P a in
RTC Opioid Rescue Dose Breakthrough Pain Preferred Treatment Routes of Administration Oral route is generally preferred Alternative routes needed for patients with: Impaired swallowing Gastrointestinal obstruction Need for rapid onset of analgesia Problems in managing complex oral regimen
Routes of Administration Non-invasive Oral Transdermal Intranasal Sublingual Buccal Routes of Administration Invasive Parenteral Bolus: Intramuscular Intravenous Subcutaneous Parenteral infusions: IV/ SC Intraspinal: epidural intraspinal Intraventricular: Ambulatory PCA Opioid Effects: Degree of Tolerance Developed High Intermediate Limited/None analgesia bradycardia miosis euphoria, dysphoria constipation mental clouding sedation antagonist actions respiratory depression antidiuresis nausea/vomiting cough suppression Adverse Effects of Opioids o Constipation o Nausea/ vomiting o Sedation o Changes in cognition, mood or perception o Dry mouth o Pruritus o Urinary retention o Myoclonus o Respiratory depression 22 Naloxone is given at titrated doses until patient shows signs of lightening up with acceptable vital signs and analgesia maintained. ANALGESIA SIDE EFFECTS OPIOID REVERSAL Morphine Misconceptions Morphine will cause Addiction Tolerance to morphines analgesic effects Causes dangerous respiratory depression Will make the patient zombie Hastens death Drugs To Treat Pain Main drugs used for their analgesic effects: Non-opioid (ex: NSAIDs) Opioids Adjuvant Drugs (ex: anti-convulsants) ADJUVANT ANALGESICS Defined as drugs with other indications that may be analgesic in specific circumstances Numerous drugs in diverse classes Multipurpose ADJUVANT ANALGESICS Class: Examples: Antidepressants amitriptyline, desipramine, nortriptyline, paroxetine, venlafaxine, citalopram, others
response to tissue injury dilatation of blood vessels increased permeability & increased receptiveness of leukocytes accumulation of inflammatory cells at site of injury.(polymorphonuclear neutrophil leukocytes, macrophages; basophils & eosiniphils)
Inflammatory responses produced & controlled by interactions of varied inflammatory mediators derived from leukocytes and some from the damaged tissues Inflammation Pathophysiology:
Inflammatory mediators include Histamine Kinins (bradykinin) Neuropeptides (substance-P, calcitonin gene- related peptide) Cytokines (interleukins) Arachidonic acid metabolites (eicosanoids) Inflammation Pathophysiology:
Arachidonic acid metabolites: the Eicosanoids
involved in the majority of inflammatory reactions most anti-inflammatory therapy is based on the manipulation of their biosynthesis family of polyunsaturated fatty acids formed from arachidonic acid (* Biosysnthetic pathway) Inflammation Pathophysiology: Arachidonic acid
Derived from phospholipids of cell membranes, mobilized by action of enzyme phospholipase A2 Further metabolized by: By cyclooxygenase produce classical prostaglandins, thromboxanes & prostacylin (prostanoids) By lipoxgenase produce leukotrienes Actions of the Eicosanoids in the Inflammatory Reaction Prostanoids Actions in Inflammation Classical Prostaglandins PGD2, PGE2, PGF2
Thromboxane A2 (TXA2)
Prostacyclin (PGI2) Produce increased vasodilation, vascular permeability & edema in an inflammatory reaction; prostaglandins also sensitize nociceptive fibers to stimulation by other inflammatory mediators. Platelet aggregation & vasoconstriction.
Inhibition of platelet aggregation & vasodilatation. Actions of the Eicosanoids in the Inflammatory Reaction Leukotrienes Actions in Inflammation LTB4, LTC4
Increase vascular permeability, promote leukocyte chemotaxis (and cause contraction of bronchial smooth muscle) Drugs To Treat Pain Main drugs used for their analgesic effects: Non-opioid (ex: NSAIDs/Non-selective & Selective) Opioids Adjuvant Drugs (ex: anti-convulsants) Anti-inflammatory Drugs Main drugs used for their broad-spectrum anti- inflammatory effects:
Non-steroidal Anti-inflammatory (NSAIDs/Non-selective) COX2- Selective inhibitors Steriodal anti-inflammatory drugs (glucocorticoids) Exert their effect by inhibiting the formation of eicosanoids thru the enzyme cyclooxygenase Anti-inflammatory Drugs: CHEMICAL CLASSIFICATION NSAIDs/Non-selective COX Inhibitors: 1. Salicylic acid derivatives 5. Arylpropionic acids 2. Para-aminophenol derivatives 6. Anthranilic acids 3. Indole & indene acetic acids 7. Enolic acids 4. Heteroaryl acetic acids 8. Alkanones
Steroidal anti-inflammatory Drugs (Glucocorticoids) NSAIDs 1900s (mid) ; synthetic agents MOA similar to salicylates Cornerstone of therapy for pain and inflammation Over the counter medication (>30 billion tabs / year) 1/3 of elderly take NSAIDs daily 70% report NSAIDs intake at least once a week HISTORY 1898 : Aspirin introduced 1960s : NSAIDs introduced Early 1970s : NSAID inhibition of COX enzyme proposed 1988-1992 : COX-1 & COX-2 isoenzyme hypothesized Early 1990s : COX-2 gene isolated 1994 : COX-2 enzyme characterized 1999 : COX-2 selective inhibitors introduced
Anti-inflammatory Drugs:NSAIDs Diverse group of drugs possessing ability to inhibit both forms of the enzyme cyclooxygenase, involved in metabolism of arachidonic acid. Mechanism of action: Irreversible inhibition ?How- acetylation of the active site; example is Aspirin Competitive inhibition ?How- acts as a competitive substrate; example is Ibuprofen Reversible, non-competitive inhibition ?Example is Paracetamol; has a free-radical trapping action interfers with production of hyperoxidases which has a role in cyclooxygenase activity Anti-inflammatory Drugs:NSAIDs Diverse group of drugs possessing ability to inhibit both forms of cyclooxygenase. 2 Cyclooxygenase Isoforms: COX1- expressed in most tissues, esp. platelets, gastric mucosa & renal musculature; involved in physiological cell signalling - most adversed effects of NSAIDs due to inhibition of COX1 COX2 - induced at sites of inflammation & produces prostanoids involved in inflammatory responses - analgesic & anti-inflammatory effects of NSAIDs due to inhibition of COX2
Anti-inflammatory Drugs:NSAIDs NSAIDs work by inhibition of cycloooxygenase inhibition of prostaglandin synthesis therapeutic effects.
Clinical Effects : Analgesic effect Anti-inflammatory Antipyretic effect Not all NSAIDs possess these 3 actions to exactly same extent!
Major Clinical Effects of NSAIDs Clinical Action Mechanism of Action Analgesic action A peripheral effect due to inhibition of prostaglandin synthesis at the site of pain & inflammation. Prostaglandins do not produce pain directly, but sensitize nociceptive fiber endings to other inflammatory mediators (bradykinin, histamine, 5-HT) amplifies pain message. Most effective against pain with inflammatory component. Small component of central effect in reducing prostaglandin synthesis in the CNS. Major Clinical Effects of NSAIDs Clinical Action Mechanism of Action Anti- inflammatory action Prostaglandins produce increased vasodilatation, vascular permeability & edema in an inflammatory reaction. Inhibition of prostaglandin synthesis reduces this part on the inflammatory reaction. NSAIDs do not inhibit the numerous other mediators involved in an inflammatory reaction; thus inflammatory cell accumulation is not inhibited Major Clinical Effects of NSAIDs Clinical Action Mechanism of Action Antipyretic action During fever, leucocytes release inflammatory pyrogens (interleukin-1) as part of immune system acts on thermoregulatory center in the thalamus increase in body temperature. This effect mediated by an increase in hypothalamic prostaglandins (PGEs), the generation of which is inhibited by NSAIDs. NSAIDs do no affect temperature under normal circumstances or in heat stroke. Anti-inflammatory Drugs:NSAIDs NSAIDs work by inhibition of cycloooxygenase inhibition of prostaglandin synthesis therapeutic effects.
Indications: Musculoskeletal & joint diseases (strains, sprains, rheumatic problems, arthritis, gout, etc) Analgesia for mild to moderate pain relief (headaches, dysmenorrhea; symptomatic relief in fever)
NON-SELECTIVE NSAIDs NSAIDs and Its Effects Chemical Class Analgesic Antipyretic Anti- inflammatory Salicylic acids Salicylic acid derivatives + + + Propionic acids Arylproprionic acids + + + Acetic acids Indole & indene acetic acid + + ++ NSAIDs and Its Effects Chemical Class Analgesic Antipyretic Anti- inflammatory Oxicams Enolic acids/ Oxicams + + ++ Pyrazolones Phenylbutazone +/- + ++ NSAIDs and Its Effects Chemical Class Analgesic Antipyretic Anti- inflammatory Fenemates Anthranilic acids + + +/- Para-Aminophenols Para-aminol derivatives + + - Anti-inflammatory Drugs:NSAIDs
Contraindications: NOT BE GIVEN to patients with GASTROINTESTINAL ULCERATION or BLEEDING; previous HYPERSENSITIVITY to any NSAID Caution for patients with ASTHMA & when RENAL function is impaired Adverse Effects: Common esp in elderly, chronic users Less common, liver disorders & bone marrow suppression
General Adverse Effects of NSAIDs System Adverse Effect Cause Gastro- intestinal
Dyspepsia, nausea vomiting Ulcer formation & potential hemorrhage risk in chronic users Inhibition of the normal protective actions of prostaglandins on the gastric mucosa. (PGE2 & PGI2 normally inhibit gastric acid secretion, inc mucosal blood flow, & have a cytoprotective action) Renal Renal damage/ nephrotoxicity Promotes salt & water retention Inhibition of PGE2 & PGI2- mediated vasodilatation in the renal medulla & glomeruli Others Bronchospasm, skin rashes, other allergic-type reactions Hypersensitivity reaction/ allergy to drug Preventive Measures to Reduce NSAID- Induced GI Toxicity Short duration of therapy Lower dose Using antacids , PPI (i.e. omeprazole), PG- analogue (misoprostol) Avoid co-therapy (coumadin , NSAIDs, ASA ,steroids ) Treat H. pylori bacteria Non Steroidal Anti-inflammatory Drugs Salicylic acid derivatives - Aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine, olsalazine Para-aminophenol Derivatives - Acetaminophen Indole & indene acetic acids Indomethacin, Sulindac Heteroaryl acetic acids Tolmetin, Diclofenac, Ketorolac Arylpropionic acids- Ibuprofen, Naproxen, Flurbiprofen, Ketoprofen, Fenoprofen, Oxaprozin Anthranilic acids (fenamates) - Mefenamic acids, Meclofenamic acid Enolic acids - Oxicams (Piroxicam, Meloxicam) Alkanones - Nabumetone
- 1800s (late); willow bark extract - formulated , introduced by Bayer - reduce fever, pain, inflammation - salicylism and other side effects
Aspirin NSAIDs: SALICYLATES Pharmacological Properties 1) Analgesia- low intensity pain; from integumental structures; examples: headache, myalgia & arthralgia 2) Antipyresis- lowers body temp rapidly & effectively 3) Respiration - increase O2 consupmtion & CO2 production - directly stimulate respiratory center hyperventilation 4) Acid-Base Balance & Electrolyte Pattern - initially respiratory alkalosis 5) Cardiovascular Effects: - therapeutic dose no direct effect - larger doses dilate peripheral vessels - toxic amounts depress circulation SALICYLATES Pharmacological Properties 6) Gastrointestinal Effects- epigastric distress; nausea & vomiting - gastric ulceration & hemorrhage, erosive gastritis - exacerbation of peptic ulcer symptoms 7) Hepatic & Renal Effects - cause hepatic injury; retention of salt & water 8) Uricosoric Effects- dose dependent 9) Effects on the Blood prolongation of the bleeding time 10) Effects on Rheumatic, Inflammatory & Immunological Process - suppress antigen-antibody reactions 11) On pregnancy- not teratogenic; low birth weights; 3rd trimester: anemia, antepartum& postpartum hemorrage, prolonged gestation 12) Local Irritant Effects- keratolytic action for warts, fungal infections. Methylsalicylate for external use SALICYLATES Pharmacokinetics and Metabolism Absorption: orally- rapidly; stomach & upper small intestine - plasma conc found in <30minutes - peak value reached within 1 hour rectally- slower; incomplete integumentary- rapid esp applied as liniments Distribution: most body tissues; cross placental barrier; 80-90% of bound to plasma proteins Biotransformation & Excretion - excreted in the urine - plasma half-life for aspirin is 15 min - salicylate is 2-3 hours for low doses; 12 hours for anti-inflammatory doses SALICYLATES Therapeutic Uses: alleviate fever, pain & inflam
Systemic uses: Sodium salicylate & Aspirin 1) Antipyresis- fever is deleterious; relief when fever is lowered - dose: Adult = 325-650 mg orally every 4 hours Children= 50-75 mg/kg/day in 4/6 div doses 2) Analgesia- nonspecific relief of pain; same dose for fever 3) Rheumatoid arthritis:Juvenile Rheumatoid Arthrtis
Other Uses- prophylaxis for platelet hyperaggregability such as in coronary heart disease - for inflammatory bowel disease, as suppository - hypertensive pregnant women SALICYLATES Toxic Effects Salicylate Intoxication: dose varies with preparation of salicylate - 10 to 30 grams; 4.7 gr. fatal in children Signs & Symptoms: Salicylism - Headache, dizziness, tinnitus, difficulty in hearing, dimness of vision, mental confusion, lassitude, drowsiness, sweating, thirst, hyperventilation, nausea & vomiting - pronounced CNS disturbances; acid-base balance disturbance; hemorrhagic phenomena - an acute medical emergency! Aspirin Hypersensitivity- allergic reactions SALICYLATES ASPIRIN ( Acetyl salicylic acid) Brand Name: - Anthrom - Enteroprin - Aspec-EC - Rhea Aspirin - Aspilets - Tromcor - Astrix - United Home Aspirin - Bayer Aspirin - Cor-30 * Aggrenox - Cor-80 * Alka-Seltzer - Cortal PARA-AMINOPHENOL DERIVATIVES: ACETAMINOPHEN Pharmacological Properties: phenacetin - analgesic & anti-pyretic effects similar to Aspirin BUT has anti-inflammatory effect. Antipyretic effect due to ability to inhibit cyclooxygenase in the brain Pharmacokinetics & Metabolism: Absorption- rapid, almost complete absorption from GIT - plasma conc peaks in 30-60 minutes; half-life about 2 hours after therapeutic dose; uniform distribution - binding to proteins is variable Therapeutic Use: Adult= 325-1000 mg, >4000 mg/day Children= 40-80 mg/age/weight Toxic Effects: Allergic reaction; hepatoxixity PARA-AMINOPHENOL DERIVATIVES: ACETAMINOPHEN ACETAMINOPHEN (Paracetamol) Brand Name: - Acet/Acet-MS/Acet-ES - Detramol - Opigesic - Aeknil - DLI Paracetamol - Parvid - Alvedon 500 - Dolexpel - Pharex Paracetamol - Anaseran - Essendol - Baropyrine - Febrinil - Retalgan - Betanol - Flurinol - Rexidol - Biogesic - Gendol - Saridon - Bioseran - Gifaril P - Tempra - Calpol/Calpol Six Plus - Meforagesic - Tylenol - Corgic/Corgic Plus - Naprex - Ultragesic - Crocin - Nektol - Winadol PARA-AMINOPHENOL DERIVATIVES: ACETAMINOPHEN ACETAMINOPHEN (Paracetamol) Brand Name: * AlaxanAlaxan FR * Neozep/Neozep Forte * A-P-Histalin * Norgesic/Norgesic Forte * Bioflu * Parafon forte * Buscopan Plus * Relaxid * Decolgen Forte * Restolax * Decolgen No-Drowse * Sinutab Extra Strength/Sinutab * Decolgen Reformulated *Tuseran Forte (Reformulated) * Dolcet * Doloneurobion *Muskelax * Myracof-T * NafarinA
INDOLE & INDENE ACETIC ACIDS INDOMETHACIN (Indocid, Infree) Pharmacological Properties: anti inflammatory, analgesic & antipyretic effects similar to aspirin Pharmacokinetics & Metabolism: Absorption- rapidly, almost complete from GIT - peak plasma concentration 1-2 hrs; urine excretion Drug Interaction: Probenecid concurrent use increase conc Therapeutic Uses: not commonly used; more effective for Ankylosing spondylitis, Osteoarthritis Gout; single dose up to 100 mg at bedtime. Combine with others Toxic Effects: Gastrointestinal complaints Hematopoietic reactions- neutopenia, thrombocytopenia & rarely aplastic anemia INDOLE & INDENE ACETIC ACIDS SULINDAC (Clinoril) Pharmacological Properties: less potent as Indomethacin Pharmacokinetics & Metabolism: - 90% absorbed after oral; peak plasma concentration within 1-2 hrs; excreted in urine and feces Therapeutic uses: RA, OA & AS; Gout; 400 mg/day Toxic Effects: less GIT & CNS side effects ETODOLAC (Lodine) Pharmacological Properties: selective COX2 inhibitor Pharmacokinetics & Metabolism: rapidly absorbed orally; 99% bound to plasma proteins Therapeutic Uses:200-400mg for post-op analgesia, OA, RA
COX-2 SELECTIVE INHIBITORS COX-2 selective inhibitors GI adverse effects of non-selective NSAIDS led to development of COX-2 selective inhibitors Aspirin 1900 Phenylbutazone 1950 1980 1995 2000 Indometacin 1990 Mechanism of action of aspirin determined Ibuprofen Diclofenac Celecoxib Rofecoxib 2005 Valdecoxib Etoricoxib Prexige
Traditional NSAIDs 1960 1970 COX-2 identified Naproxen Parecoxib Anti-inflammatory Drugs Main drugs used for their broad-spectrum anti- inflammatory effects:
Non-steroidal anti-inflammatory drugs (NSAIDs) Steriodal anti-inflammatory drugs (glucocorticoids) Corticosteroids - 1900s (early) ; wonder drug; strong anti-inflammatory/analgesic Phospholipids Phospholipase A Arachidonic Acid ( PG, thromboxanes, prostacyclins) Lipooxygenase Cyclooxygenase (leukotrienes, bradykinin) (-) Steroids Steroidal Anti-inflammatory Drugs (Glucocorticoids) Profound generalized inhibitory effects on inflammatory responses result from their effects in altering activity of certain-responsive genes. Mechanism of action: Reduced production of acute inflammatory mediators ?prevent formation of arachidonic acid from membrane lipid by inducing synthesis of a polypeptide called lipocortin. ?lipocortin inhibits phospholipase A2 , the enzyme responsible for mobilizing arachidonic acid from cell membraneinhibit formationof prostaglandins & leukotrienes Reduced number & activity of circulating immunocompetent cells, neutrophils & macrophages Decreased activity of macrophages & fibroblast involved in chronic stages of inflammation Steroid Side Effects Cushing's Osteoporosis Cataract AVN Hyperglycemia Acne Hirsutism Infection
Recommendation... Pain Management: ETIOLOGY BASE & MECHANISM BASE (Pharmacologic Treatment)
NOCICEPTIVE: VISCERAL PAIN Corticosteroids Intraspinal local anesthetic agents NSAIDs Cox2 Muscle relaxants Opioid via any route
Pain Management: ETIOLOGY BASE & MECHANISM BASE (Pharmacologic Treatment) Recommendation.... NOCICEPTIVE: SOMATIC PAIN Acetaminophen Corticosteroids Local anesthetic either topically or by infiltration Non-steroidal anti- inflammatory drugs (NSAIDs) Cox-2
Pain Management: ETIOLOGY BASE & MECHANISM BASE (PHARMACOLOGIC TREATMENT) Recommendation... NEUROPATHIC PAIN Anticonvulsants Corticosteroids Neural blockade NSAIDs Cox 2 Opioids via any route Tricyclic antidepressants