Narcotics and Analgesics Pharmacology By Linda Self

Pain Universal, complex, subjective experience Number one reason people take medication Generally is related to some type of tissue damage and serves as a warning signal

Scope of the Problem Increases as Baby Boomers age 25 million people suffer acute pain related to surgery or injury Chronic pain affects 250 million Americans Is a multibillion dollar industry Much ignorance exists about this complaint

Gate Control Theory of Pain Gate control theory of pain is the idea that physical pain is not a direct result of activation of pain receptor neurons, but rather, its perception is modulated by interaction between different neurons

Gate Control Theory of Pain Nerve fibers (A delta (fast channels)) and C fibers (slow channels) transmit pain impulses from the periphery Impulses are intercepted in the dorsal horns of the spinal cord, the substantia gelatinosa In this region, cells can be inhibited or facilitated to the T-cells (trigger cells)

Gate Control Theory of Pain cont. When cells in the substantia gelatinosa are inhibited, the ‘gate’ to the brain is closed When facilitated, the ‘gate’ to the brain is open

Gate Control Theory of Pain Similar gating mechanisms exist in the nerve fibers descending from the thalamus and the cortex. These areas of the brain regulate thoughts and emotions. Thus, with a pain stimulus, one’s thoughts and emotions can actually modify the pain experience.

Pathophysiological Response Tissue damage activates free nerve endings (nociceptors) of peripheral nerves Pain signal is transmitted to the spinal cord, hypothalamus, and cerebral cortex Pain is transmitted to spinal cord by A-delta fibers and C fibers

Pathophysiological Response A-delta fibers transmit fast, sharp, well-localized pain signals C fibers conduct the pain signal slowly and produce poorly localized, dull, or burning type of pain Thalamus is the relay station for incoming stimuli, incl. pain

Pain Fibers and Pathways A delta fibers found in the skin and muscle, myelinated, respond to mechanical stimuli. Produce intermittent pain. C fibers distributed in the muscle as well as the periosteum and the viscera. These fibers are unmyelinated, conduct thermal, chemical and strong mechanical stimuli. Produce persistent pain.

Inhibitory and Facilitatory Mechanisms Neurotransmitters—chemicals that exert inhibitory or excitatory activity at post-synaptic nerve cell membranes. Examples include: acetylcholine, norepinehprine, epinephrine, dopamin, and serotonin. Neuromodulators—endogenous opiates. Hormones in brain. Alpha endorphins, beta endorphins and enkephalins. Help to relieve pain.

Opioid Receptors Opioid receptors—binding sites not only for endogenous opiates but also for opioid analgesics to relieve pain. Several types of receptors: Mu, Kappa, Delta, Epsilon and Sigma.

Mu Receptors Location: CNS incl. brainstem, limbic system, dorsal horn of spinal cord Morphine sulfate and morphine sulfate agonists bind to Mu receptors

Sources of Pain Nociceptive—free nerve endings that receive painful stimuli Neuropathic –damaged nerves

Narcotic Analgesics Relieve moderate to severe pain by inhibiting release of Substance P in central and peripheral nerves; reducing the perception of pain sensation in brain, producting sedation and decreasing emotional upsets associated with pain

Narcotic Analgesics Can be given orally, IM, sub q, IV or even transdermally Orally are metabolized by liver, excreted by kidney—caution if compromised Morphine and meperidine produce metabolites Widespread effects: CNS, Resp., GI

Narcotics—Mechanisms of Action Bind to opioid receptors in brain and SC and even in periphery

Indications for Use Before and during surgery Before and during invasive diagnostic procedures During labor and delivery Tx acute pulmonary edema Treating severe, nonproductive cough

Contraindications to Use Respiratory depression Chronic lung disease Chronic liver or kidney disease BPH Increased intracranial pressure Hypersensitivity reactions

Changing Philosophy on Pain Undermedicated Titrate to comfort

Management Considerations age-specific considerations Morphine often drug of choice—non-ceiling. Other nonceiling drugs include: hydromorphone, levorphanol and methadone Use non-narcotic when able Combinations may work by different mechanisms thus greater efficacy (e.g. Tylenol w/codeine)

Route selections Oral preferred IV most rapid—PCA allows self administration. Basal dosage. More effective, requires less dosing. Epidural, intrathecal or local injection Can use rectal suppositories or transdermal routes

Dosage Dosages of narcotic analgesics should be reduced for clients receiving other CNS depressants such as other sedative-type drugs, antihistamines or sedating antianxiety medications

Scheduling Give narcotics before encouraging turning, coughing and deep breathing in post-surgical patients Automatic stop orders after 72h In acute pain, narcotic analgesics are most effective when given parenterally and at start of pain

Individual Drugs Agonists have activity on mu and kappa opioid receptors Agonist/antagonists have agonist activity in some receptors; antagonists in others. Have lower abuse potential than pure agonists; because of antagonism—can produce withdrawal symptoms Antagonists are antidote drugs

Agonists Alfenta (alfentanil)—short duration Codeine Sublimaze or Duragesic (Fentanyl)—short duration Dilaudid (hydromorphone) Demerol (meperidine)—preferred in urinary and biliary colic, less resp. depression newborns Morphine OxyContin

Agonists cont. Darvon (propoxyphene) Ultram (tramadol) Methadone

Agonists/Antagonists Have lower abuse potential than pure agonists Buprenex (buprenorphine) Nubain (nalbuphine) Talwin (pentazocine) Stadol (butohanol)—also in nasal spray

Antagonists Revex (nalmefene)—longer duration of action than Narcan Narcan (naloxone) ReVia (naltrexone)-used in maintenance of opiate-free states in opiate addicts

Dietary and Herbal Supplements Zostrix (capsaicin)—from cayenne peppers; topical indicated for post-herpetic neuralgia, neuropathic pain=Substance P

Cancer Give on a regular schedule Oral, rectal and transdermal are preferred over IV Oxycodone and a non-narcotic analgesic may have additive effects MS or other for severe pain Long acting for chronic pain with fast acting meds for “break-through pain” May use TCAs, anti-emetics, stool regimen

Management of Withdrawal Symptoms Methadone Clonidine (norepinephrine) Gradually decrease dosing so not to cause withdrawal s/s

Analgesic,Antipyretic, and Anti-inflammatory Drugs Mechanism of action—inactivate cyclo-oxygenases, enzymes required for the production of prostaglandins ASA and traditional NSAIDs inhibit both COX 1 and COX 2 COX 1 is present in all tissues esp. GI, kidneys, endothelial cells and in platelets

Cox 1 cont. Prostaglandins important in: Protection of kidneys and stomach Regulate vascular tone and platelets in CV system

COX 2 Found in brain, bone, kidneys, GI tract, and the female reproductive system Overall, prostaglandins produced by COX 2 are associated with pain and inflammation

Actions of the COX’s Act on hypothalamus to decrease response to pyrogens and reset the thermostat Prevent prostaglandins from increasing the pain and edema produced by other substances released by damaged cells COX 1-Antiplatelet activity for life of platelet—7-10 days plus interfere w/blood coagulation and increase risk for bleeding

Indications for Use Treat mild to moderate pain or inflammation Musculoskeletal disorders; HA; dysmenorrhea, minor trauma and surgery Low dose ASA for risk of MI or stroke Celebrex is indicated for familial polyposis

Contraindications to Use PUD GI or bleeding disorders Hypersensitivity reactions Impaired renal function If allergic to ASA In children, ASA contraindicated in presence of viruses=Reye’s syndrome Celebrex if allergic to sulfonamides

Reye’s Seen in children under 15 after an acute viral illness Results in encephalopathy, fatty infiltration of the liver, pancreas, kidneys, spleen, and lymph nodes Cause is unknown

Contraindications Toradol (ketoralac) not used in labor and delivery or during any major surgery OTC preps contraindicated in alcoholics due to possible liver damage

Aspirin (ASA) Home remedy for headaches, colds, influenza and other respiratory infections For fever For inflammation ASA and COX 2 are ok, COX 2 have little effect on platelet function

ASA cont. Poisoning can occur with large doses. Saturate the metabolic pathway, slow elimination and cause drug accumulation If overdose, measure serum levels Recognize s/s: N/V, fever, fluid and lyte deficiencies, tinnitus, decreased hearing, hyperventilation, confusion, visual changes>>>>delirium, stupor and coma

ASA salicylism Gastric lavage Activated charcoal IV bicarbonate so more rapid excretion hemodialysis

NSAIDS Propionic acid derivatives such as ibuprofen, ketoprofen (Orudis), naproxen and fenoprofen (Nalfon) Acetic acid derivatives include indomethacin (Indocin), sulindac (Clinoril) and tolmetin (Tolectin)---these drugs have more severe adverse reactions than the proprionic acid derivatives

NSAIDS IV indomethacin is approved for the tx of patent ductus arteriosus in premature infants. Remember: patent ductus is a communication between the pulmonary artery and the aorta

NSAIDS Toradol (ketoralac) is used only for pain. Is the only NSAID that can be given by injection. Use limited to 5 days as can cause bleeding. Oxicam drugs include Mobic (meloxacam) and Feldene (piroxicam) Celebrex (celecoxib) Affect bleeding only while drug is still in the system

Effects of Nonsteroidals on Other Drugs Decrease effects of ACEI, beta blockers and diuretics Affect sodium and water retention Inhibit renal prostaglandin synthesis

Acetaminophen Equal in effectiveness to ASA in analgesic and antipyretic effects Lacks anti-inflammatory actions Ethanol induces drug-metabolizing enzymes in liver. Resulting rapid metabolism of acetaminophen produces enough toxic metabolite to exceed glutathione. Need glutathione to inactivate toxic metabolites. P. 114

Acetaminophen Poisoning Toxicity occurs with 20g or more. Creates toxic metabolite that is inactivated by glutathione. OD supply of glutathione is depleted and toxic metabolite damages liver cells Not to exceed 4g/day Treatment—gastric lavage, charcoal, antidote is Mucomyst (acetylcysteine). Provides cysteine, a precursor to glutethione.

Drugs used in Gout and Hyperuricemia Zyloprim (allopurinol)—prevents or treats hyperuricemia Uric acid is formed by purine metabolism and an enzyme xanthine oxidase. Allopurinol prevents formation by inhibiting xanthine oxidase.

Antigout Medications Colchicine—used to treat or prevent acute attacks of gout. Drug of choice for acute attacks. Decreases inflammation by affecting leukocytes. Benemid (probenecid) increases urinary excretion of uric acid. Not effective in acute attacks. Anturane (sulfinpyrazone) uricosuric similar to Benemid. Not for acute attacks.

Guidelines for Treating Gout Maintenance drugs are Zyloprim, Benemid and Anturane Colchicine needed for several weeks to prevent acute attacks while serum levels are being lowered Need high fluid intake, alkaline urine to prevent renal calculi

Drugs Used for Migraines Selective serotonin 5-HT1 receptor agonists Increase serotonin in the brain Constrict blood vessels Contraindicated in patient’s with history of MI,, angina, uncontrolled htn.

Drugs used for migraines Drugs vary in onset with sub q sumatriptan acting the most rapidly and starting within 10 minutes; most clients get relief within 1-2 hours Drugs are metabolized in the liver by monoamine oxidase or by cytochrome p450 enzymes; sub q administrations causes more adverse effects than the oral drugs

Migraine Meds Ergotamine tartrate—ergot alkaloid used only in tx of migraine Work by constricting blood vessels Most effective when given sublingual or by inhalation Contraindicated in pregnancy, htn, PVD, CAD, renal or hepatic disease and even in severe infections

Guidelines for Treating Migraine Start out with acetaminophen, aspirin, or other NSAIDs Moderate to severe migraines, sumatriptan or other related drugs are useful For severe and frequent migraines, prophylaxis is indicated. Use ASA and NSAIDs.

Guidelines for Treating migraines For menstrual migraines, start tx one week before and during menses Other drugs indicated for tx include beta adrenergic blocking agents such as Inderal

Guidelines for Treating Arthritis Control pain and inflammation Rest, exercise,and PT Osteoarthritis—COX1, COX2, glucosamine, intraarticular injections of corticosteroids or hyaluronic acid (Synvisc) to act as shock absorber

Rheumatoid Arthritis NSAIDs Corticosteroids Immunosuppressants—methotrexate Enbrel, Remicade and Arava. Affect tumor necrosis factor and other cytokines.

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