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ANALGESICS Pain Management What is pain? – A protective mechanism to warn of damage or the presence of disease – Part of the normal healing process ANALGESICS I. Opioid (narcotic) analgesics 1. Agonists of opioid receptors – morphine hydrochloride, promedol, omnopon, fentanyl, codeine; 2. Agonists – antagonists and partial agonists of opioid receptors – pentazocin, buprenorphine. II. Non-opioid analgesics and non steroidal antiinflammatory drugs - NSAIDs acetylsalicylic acid, paracetamol, analgin, indometacin, butadion, ibuprofen, pyroxicam, diclofenac-sodium, ketorolac, ketoprofen. III. Substances with mixed mechanism (opioid and non-oioid components) tramadole of action The structures that take part in perception of pain: thalamus, hypothalamus, reticular formation, limbic system, occipital and frontal areas of cortex System which conducts and perceives pain - nociceptive System which protects organism from pain – antinociceptive Acute pain Classification of Pain By Onset and Duration Sudden in onset Usually subsides once treated Chronic pain Persistent or recurring Often difficult to treat Major Sources of Pain Source Area Involved Characteristics Treatment Somatic body framework throbbing, stabbing narcotics, NSAIDS Visceral kidneys, intestines, liver aching, throbbing, sharp, crampy narcotics, NSAIDS Neuropathic Nerves burning, numbing, tingling narcotics, NSAIDS, antidepressants, anticonvulsants OPIOID ANALGESICS History of Opioids • Opium is extracted from poppy seeds (Papaver somniforum) • Used for thousands of years to produce: – Euphoria – Analgesia – Sedation – Relief from diarrhea – Cough suppression History cont’d • Used medicinally and recreationally from early Greek and Roman times • Opium and laudanum (opium combined with alcohol) were used to treat almost all known diseases Morpheus is the Greek god of dreams and sleep. Friedrich Wilhelm Adam Sertürner, a German pharmacist, isolated Morphine from opium, in 1805. History and Background • Invention of the hypodermic needle in 1856 produced drug abusers who self administered opioids by injection • Controlling the widespread use of opioids has been unsuccessful because of the euphoria, tolerance and physiological dependence that opioids produce Opioid receptors • group of G-protein coupled receptors with opioids as ligands. • The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. Subtypes of opiod receptors: mu, delta, kappa, epsilon, sigma Opiod Receptor Activation Response Analgesia Respiratory depression Euphoria Dysphoria Decrease GI motility Physical Dependence Mania, hallucination Mu-1 Mu-2 Kappa Delta Sigma Morphine CNS Depressant effects • Analgesia • Indifference to surroundings • Mood and subjective effects • Depression of respiration • Cough centre • Temperature regulating centre • Vasomotor centre Stimulate effects • CTZ (nausea, vimiting) • Edinger Wesphal nucleus (III nerve –producing miosis) • Vagal centre (bradycardia) • Certain cortical areas and hippocampal Morphine can be used as an analgesic to relieve: pain in myocardial infarction pain associated with surgical conditions, pre- and postoperatively (pre-anesthetic medication, balanced anesthesia, surgical analgesia) pain associated with trauma, burns severe chronic pain, e.g., cancer pain from kidney stones, renal colic, ureterolithiasis, etc (pain may be valuable for diagnosis: should not be relived by analgesic unless proper assessment of the patient has been done) traumas of thorax accompanied by cough (morphine depresses central links of coughing reflexes) Acute left-ventricular cardiac failure (cardiac asthma) Reduce preload on heard due to vasodilatation Tending to shift blood from pulmonary to systemic circuit; relieves pulmonary congestion and edema Allays air hunger by depressing respiratory centre Cuts down sympathetic stimulation by calming the patient Applications in Dentistry • Narcotic (opioid) analgesics are extremely effective in reducing acute dental and postoperative pain. • The narcotic analgesics have established a niche for the treatment of pain in those situations where the NSAIDs are less effective. • Hydrocodone, oxycodone, codeine, and occasionally meperidine are the narcotics used to treat dental pain. MORPHINE HYDROCHLORIDE routes of administration subcutaneously and intramuscularly (analgesic action after 10-15 min) oral administration – presystemic elimination ( 20-60 % enters general blood circulation) sublingually – quick absorption i.v. is indicated even in emergency Epidural or intrathecal ( into the spinal canal ) injection produces segmental analgesia lasting 12 hours without affecting other sensory, motor or autonomic modalities Duration of analgesic action – 4-6 hours Maximum single dose of morphine is 0,02 g, maximum daily dose – 0,05 g Side effects of morphine Respiratory depression Vomiting (excitation of starting zone of vomiting center) bradycardia (increasing of tone of n. vagus nuclei) spasm of sphincters of gastro-intestinal tract accompanied by constipations increasing of tone of smooth musculature of urinary and bile-excreting tracts (retentions of urination, bile stasis) Decreasing of BP CONTRAINDICATIONS FOR ADMINISTRATION OF MORPHINE acute respiratory depression renal failure (due to accumulation of the metabolites morphine-3glucuronide and morphine-6-glucuronide) chemical toxicity (potentially lethal in low tolerance subjects) raised intracranial pressure, including head injury (risk of worsening respiratory depression) Biliary colic Precauntation pain that accompanies chronic inflammatory pain children before the age of 2 years Tolerance • Tolerance is a diminished responsiveness to the drug’s action that is seen with many compounds • Tolerance can be demonstrated by a decreased effect from a constant dose of drug or by an increase in the minimum drug dose required to produce a given level of effect • Physiological tolerance involves changes in the binding of a drug to receptors or changes in receptor transductional processes related to the drug of action • This type of tolerance occurs in opioids Addiction • Physical dependence • Physiological dependence • Withdrawal reactions Tolerance and Dependence Withdrawl Reactions Acute Action • • • • • • • • • • • • Analgesia Respiratory Depression Euphoria Relaxation and sleep Tranquilization Decreased blood pressure Constipation Pupillary constriction Hypothermia Drying of secretions Reduced sex drive Flushed and warm skin Withdrawl Sign • • • • • • • • • • • • Pain and irritability Hyperventilation Dysphoria and depression Restlessness and insomnia Fearfulness and hostility Increased blood pressure Diarrhea Pupillary dilation Hyperthermia Lacrimation, runny nose Spontaneous ejaculation Chilliness and “gooseflesh” OMNOPON • contains mixture if opium alkaloids (48-50% morphine) • does not cause spasms of smooth musculature, as it contains alkaloids of isoquinoline raw • is used for analgesia according to all the indications of morphine hydrochloride, for example, colics Promedol (trimeperidine) • produces similar effects to other opioids, such as analgesia and sedation, along with side effects such as nausea, itching, vomiting and respiratory depression which may be harmful or fatal. • duration of analgesic action - 3-4 hours • moderate spasmolytic influence on smooth musculature of internal organs • stimulation of rhythmic contractions of uterus • can be used for analgesia • in case of pain syndrome connected with spasms of smooth musculature Fentanyl • synthetic opioid analgesic of short action • analgesic activity is 300 times higher than of morphine • analgesic effect after intravenous introduction – after 1-3 min, lasts for 15-30 min • used with neuroleptic droperidol (complex drug – “talamonal”) for neuroleptanalgesia fentanyl transdermal system • should be used for longterm (chronic) pain requiring continuous narcotic pain • Is designed to release the drug into the skin at a constant rate ranging from 25 to 100 micrograms/h, Codeine opium alkaloid analgesic action is not strong, but anticough effect is considerable administered as an anticough drug of central action combination with non opiod analgesics (eg. Paracetamol) is supra-additive Pentazocin agonist-antagonist of opioid receptors comparatively with morphine, it is a bit less dangerous in the aspect of addiction development indicated in case of pain of medium intensity in such conditions like other opioid analgesics. In case of strong pain its administration is limited as in case of increasing of dose of the drug excitation appears it can cause increasing of blood pressure and tachycardia that’s why it’s not advised to use in case of acute myocardium infarction if it is administered for people with narcotic addiction manifestations of abstinence develop Buprenorphine • Partly agonist of mu-opioid receptors • Acts longer than morphine (approximately 6 hours) • Analgesic activity is higher than of morphine, that’s why it’s used in doses of 0,3-0,6 mg • In case of breathing depression, which it causes, naloxon is less effective since buprenorphine is slowly released from the connection with mu-receptors • Indicated for pain decreasing in the same situations as other narcotic analgesics • May be used for detoxication and supporting treatment of individuals who is addicted to heroine Acute poisoning with opioid analgesics • • • • • • • • • • Respiratory Depression Euphoria Relaxation and sleep Tranquilization Decreased blood pressure Constipation Pupillary constriction Hypothermia Drying of secretions Flushed and warm skin Triad in case poisoning with morphine Acute miosis (Pinpoint pupils) Cheyne Stokes respiration deep tendon reflexes increased Treatment of acute poisoning Naloxon (antagonist of opioid receptors) intravenously - 0,4-1,2 mg general dose of naloxon should not overcome 10 mg stomach lavage (for morphine enterohepatic circulation is typical) with 0,05-0,1% solution of potassium permanganate and 0,5 % tannin solution suspension of 20-30 g of activated charcoal salt laxative agents (sodium sulfate) forced diuresis atropine sulfate inhalation of carbogen (5-7 % СО2 and 93-95 % O2) NON-OPIOID ANALGESICS Pharmacodynamic Effects • Analgesic • Antipyretic • Anti-inflammatory (except paracetamol) Mechanism of action of non-opioid analgesics • depression of cyclooxygenases activity • decreasing of prostaglandins synthesis in peripheral tissues and in central nervous system • decreasing of sensitivity of nervous endings and depression of transmission of nociceptive impulses on the level of CNS structures • pain-relieving action of non-opioid analgesics is partly connected with their anti-inflammatory activity Effects of COX Inhibition by Most NSAIDS COX-1 Gastric ulcers COX-2 Reduce inflammation Bleeding Reduce pain Acute renal failure Reduce fever NSAIDs : anti-platelet—decreases ability of blood to clot COX Enzyme:Prostaglandin Effects COX-1: beneficial COX-2: harmful Peripheral injury site Brain Inflammation Modulate pain perception Promote fever (hypothalamus) Stomach protect mucosa Platelets aggregation Kidney vasodilation Indications for administration of nonnarcotic analgesics headache toothache backache neuralgias pulled muscles joint pain dysmenorrhea for potentiating of their action – combinations paracetamol with codeine, metamizol with dimedrol, metamizol with codeine Applications in Dentistry • • • • • • • Toothache Post extraction pain Periodontitis Neuritis Stomatitis Arthritis Local usage as keratoplatic agents for hyperkeratosis, hyperesthesia Paracetamol (Acetaminophen) • analgesic and antipyretic drug • maximal effect if the drug is introduced orally – after 2 hours, lasts approximately for 4 hours • in case of durable administration of big doses – damaging of liver and kidneys, production of met-hemoglobin Paracetamol (Acetaminophen) N-Acetyl-P-Aminophenol Classification: analgesic, antipyretic, misc. not an NSAID Mechanism: inhibits prostaglandin synthesis via CNS inhibition of COX (not peripheral)doesn’t promote ulcers, bleeding or renal failure; peripherally blocks generation of pain impulses, inhibits hypothalamic heat-regulation center Paracetamol • • • • • Tablets Suppositories Syrups Soluble tablets Capsules PARACETAMOL Pharmacokinetics: paracetamol Metabolism: major and minor pathways Half-life: 1-3 hours Time to peak concentration: 10-60 min Treatment for overdose: Acetylcysteine Paracetamol Liver Metabolism 1. Major pathway —Majority of drug is metabolized to produce a non-toxic metabolite 2. Minor pathway —Produces a highly reactive intermediate (acetylimidoquinone) that conjugates with glutathione and is inactivated. • At toxic paracetamol levels, minor pathway metabolism cannot keep up (liver’s supply of glutathione is limited), causing an increase in the reactive intermediate which leads to hepatic toxicity and necrosis Acetylsalicylic acid Blocks irreversibly COX As antipyretic and analgesic drug – 0,25 and 0,5 g per time As an anti-inflammatory – 3-4 g per day (for arthritis, myocarditis, pleuritis, bronchitis etc. As platelets inhibitor - for prophylaxis of thrombusformation (in case of ischemic heart disease, thrombophlebitis etc.) – daily dose – 80-100 mg Pharmacokinetics: ASA Absorption: from stomach and intestine Distribution: readily, into most fluids/tissues Metabolism : primarily hepatic • ASA contraindicated for use in children with viral fever –can lead to Reye’s Syndrome • Fatal overdose is possible Similar pharmacokinetics for ibuprofen and related NSAIDs Analgin (metamizol-sodium) Baralgin (maxigan, spazgan, spazmalgon, trigan) metamizol-sodium +pitophenon hydrochloride+pheniverinium bromide Ampoules tablets suppositories Analgesic and spasmolytic activity Traditional and selective COX-2 inhibitors Ketorolak (ketanov) • according to analgesic activity it prevails over effect of acetylsalicylic acid, indometacin and equals to opioid analgesics • moderate anti-inflammatory, antipyretic and anti-aggregate effects • high effectiveness in case of pain in postoperative period, in oncology, during child delivery, traumas, colic • i/m, i/v, orally NOT indicated for chronic pain syndrome Ketoprophen (ketonal) • strong analgesic, anti-inflammatory and antipyretic agent • administered in case of arthroses and arthritis, ancilizing spondilitis, pain of different genesis (after surgeries, in case of traumas, painful menstruations etc.) • administered orally, intramuscularly, in forms of suppositories and ointments TRAMADOL Analgesic activity is similar to the activity of morphine Abuse potential is low Less respiratory depression Hemodynamic effects are minimal In case of intravenous administration effect develops after 5-10 min, if administered orally – after 30-40 min, action lasts for 3-5 hours. Tramadol possesses agonist actions at the μ-opioid receptor and affects reuptake at the noradrenergic and serotonergic systems ADMINISTRATION OF TRAMADOL surgery, traumatology, gynecology, neurology, urology, oncology For all kinds of acute and chronic pain of moderate and considerable intensity, including neuralgias, postoperative, traumatic pain diagnostic and therapeutic interventions oncologic pathology Thank you! QUESTIONS?!