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The Patient in Pain: Pathopharmacologic Principles Wanda Lovitz, APRN Pathopharmacology of Pain: Objectives Explain role of nociceptors in pain. Differentiate between A-delta & C-fiber neurons. Discuss the neurotransmission modulation of pain receptors in the spinal cord and brain. Discuss the endogenous analgesic mechanisms. Compare and contrast the three classifications of analgesics. Describe the Classification, MOA, Indications, Adverse Reactions, and significant nursing implications for selected opioid and nonopioid, and adjuvant analgesics. Pain is both a protective and an unpleasant physical and emotionally disturbing sensation originating in PAIN RECEPTORS that respond to a number of stimuli that threaten tissue integrity Nociceptors • “Pain receptors” • None/very few in: – Specialized receptors – Brain – Peripheral pain fibers – Alveoli with Free Nerve Endings • Widely distributed in: – Skin, dental pulp, periosteum, meninges – Some internal organs – Deep tissues Nociceptive stimuli • Nociceptive stimuli – stimuli of such intensity, that they cause, or are close to causing, tissue injury – receptors respond to sharp objects, electric current, application of heat and cold to the skin – receptors also respond to chemical stimuli • chemical mediators • Low intensity…..nociceptors are not activated Inflammation and Pain • Signs & Symptoms of inflammation produced by chemical mediators – PAIN, swelling, redness, heat, immobility • Chemical mediators are present in the plasma and activated by tissue injury – Histamine – Achidonic acid metabolites- leads to the production of inflammatory mediators • PROSTAGLANDINS AND LEUKOTRIENES WHAT ARE PROSTAGLANDINS? • • • • Chemicals that promote INFLAMMATION, PAIN AND FEVER They also protect the lining of STOMACH from effects of acid Promote BLOOD CLOTTING by activating platelets Also affect KIDNEY function- dilate blood vessels leading to the kidneys • Enzymes that produce prostaglandins –cycloxygenases (COX) • 2 TYPES OF COX ENZYMES – • Both produce prostaglandins that promote inflammation, pain, and fever But ONLY COX-1 activates platelets and protects the stomach – COX-1 Block this and can have clotting problems and GI problems – COX-2 Block this and reduce pain, fever, and inflammation PAIN Stimulus is OUTSIDE the CNS Stimulus is WITHIN the CNS Nociceptive (Pain receptors) Activated in response to actual or impending tissue injury Neuropathic Arises from DIRECT injury to nerves Consequence is NOCICEPTIVE pain Referred to as NEUROPATHIC pain Trauma to CNS or PNS NOCICEPTIVE Pain Somatic Pain Involves MS system •Complaints • Constant • Achy •Location • Well-localized in skin and subcutaneous tissues • Less well-localized in bone • Muscle • Blood vessels • Connective tissues •Examples • • • • • • • • Incision pain Bone fractures Bony metastases Degenerative joint/spinal disease Osteoarthritis Rheumatoid arthritis Peripheral vascular disease Chronic stasis ulcersc Visceral Pain: Involves organs •Complaints • • • • Cramping Splitting N/V Diaphoresis •Location • Originates in internal organs or linings • Poorly localized • Diffuse • Deep •Examples • • • • • • • • • Kidney stones Appendicitis Bladder spasms Constipation Organ metastases Spastic bowel Inflammatory bowel dx Heart attack Chronic hepatitis NEUROPATHIC Pain Neuropathic pain: Involves nerves •Complaints • • • • • • Shooting Burning Electric-shock Sharp Numb Motor weakness •Location • Originates in injury to peripheral nerve • Spinal cord • Brain • Poorly localized •Examples • Diabetic neuropathy • Postherpetic neuralgia • Tumor related nerve compression • Phantom limb pain • Trigeminal neuralgia • Central post-stroke pain Physiology of Pain: Nociception Stages of nociception 1. TRANSDUCTION • • Painful stimuli converted to action potentials at the sensory receptor Substances/chemical mediators released as a result of direct injury and inflammation – Prostaglandin an important mediator –lowers the pain threshold – Many other neurotransmitters and neuropeptides involved in pain transmission 2. TRANSMISSION • Action potentials move from peripheral receptors to the spinal cord and then the brain – A delta and C fibers are the primary sensory fibers Stages of nociception 3. PERCEPTION • Brain receives the pain signals and interprets them as painful – – – Influenced by attention, distraction, anxiety, fear, fatigue, previous experience and expectation Pain threshold Pain tolerance 4. MODULATION • Synaptic transmission of pain signals is altered – – – Presynatic inhibition Opioids such as endorphins mediate presynatic inhibition Morphine mimics the effect of endorphins The body does make attempts to rid of its own pain… Its main defense mechanism: ENDORPHINS (endogenous) Located in brain & close to pain receptors in nerve fibers, ascending/descending pathways In fact, morphine is referred to as the “exogenous endorphin” Dorsal horn – connects peripheral and CNS • The chemical mediators translate the noxious stimulus into ACTION POTENTIALS that are transmitted to the DORSAL HORN of the spinal cord The dorsal horn of the spinal considered the “GATEWAY” between two sensory nervous systems • Pathway of Pain…..Block the pain…..Relieve the pain • Gate Control Theory – If we can BLOCK the pain before it gets to the brain, we can STOP the pain Dorsal Horn of Spinal Cord GATE CONTROL THEORY: This gate can OPEN and CLOSE To better understand Gate Control Theory… let’s first look at types of nerve fibers There are 4 TYPES OF NERVE FIBERS that carry impulses to the brain: Nerve Fibers A – delta Small diameter Myelinated – Rapid transmission of pain Pain is sharp, stinging,cutting, and pinching. Is localized C fibers Small diameter Unmyelinated –Slow transmission of pain Pain is dull, burning, aching. Poorly localized A- alpha Large diameter Do NOT transmit pain signals A- beta Large diameter Do NOT transmit pain signals Gate Control Theory • Built around the premise that: – LARGE DIAMETER nerve fiber stimulation • (A alpha & A beta) – causes the gates to CLOSE » aka – touch, rubbing skin, massage, distraction, acupuncture, etc – SMALL DIAMETER nerve fiber stimulation • (A delta & C fibers) • causes the gates to OPEN • aka nociceptor stimulation – Two pathways of pain transmission: » FAST PAIN – A delta myelinated fibers » SLOW PAIN…C fibers unmyelinated fibers Gate Control Theory: Explanation • Activation of nerves that DO NOT transmit pain signals – A alpha – Large diameter nerve fibers – A beta – Large diameter nerve fibers – Can INTERFERE with signals from pain fibers • A delta – Small diameter nerve fibers • C fibers – Small diameter nerve fibers • Thus INHIBITING an individual’s perception of pain • Theory works best with ACUTE pain Pathophysiology of Pain Control The Gate is OPEN an and pain is perceived CLOSING the Gate with acupuncture – diminishing the pain What NON-PHARMACOLOGIC measures can nurses take to decrease pain? • Adjuvant therapy: – Massage (hand massage), therapeutic touch, application of heat and cold, music therapy,TENS units, distraction • ALL stimulate the large diameter A alpha and A beta • Remember that stimulation of these fibers “CLOSES THE GATE” IMPORTANT CONCEPT for anyone managing the patient’s pain… If one can inhibit the nerve impulse BEFORE it reaches the thalamus/cortex, one can decrease the PERCEPTION OF PAIN. Managing the Patient’s Pain Pharmacologically… Blocking PAIN from the BRAIN OPIOID NON-OPIOID ADJUVANT Morphine Sulfate non-NSAID acetaminophen/Tylenol gabapentin/Neurontin pregablin/Lyrica Commonly rx for neuropathic pain Classified as: anticonvulsant although rarely used for seizure control Morphine antagonist/antidote naloxone/Narcan NSAID (non-selective COX inhibitor) acetyl salicylic acid/ASA/BayerAspirin hydromorphone/Dilaudid meperidine/Demerol NSAID (non-selective COX inhibitor) Ibuprofen/Advil & Motrin codeine sulfate NSAID (non-selective COX inhibitor) naproxen/Naprosyn & Aleve oxycodone + acetaminophen/Percocet NSAID (selective COX-2 inhibitor) celecoxib/Celebrex hydrocodone + acetaminophen/Lortab,Vicoden,Norco NSAID (non-selective COX inhibitor) ketorolac/Toradol oxycodone + ASA /Percodan tramadol/Ultram (atypical opioid) Antidote for acetaminophen acetylcysteine/Mucomyst 3 Classifications of Analgesics (analgesics relieve pain without causing loss of consciousness) OPIOID analgesics any drug that has actions similar to morphine Agonists Morphine Sulfate Antagonists naloxone/ Narcan NONOPIOID analgesics Tylenol NSAIDS (including ASA) ADJUVANT THERAPY Other drug classifications that help relieve (usually neuropathic) pain gabapentin (Neurontin) pregabalin (Lyrica) 3 Classes of Opioid Receptors 1. Mu MOST IMPORTANT pharmacologically Opioid analagesics act primarily by activating mu receptors Activation results in analgesia, RESPIRATORY DEPRESSION, euphoria, decreased GI motility, miosis & sedation Can cause physical dependence 2. Kappa weak activation by opioids 3. Delta no activation by opioids Classification of Opoids 1. Opioid Agonist ◦ Analgesia, resp depression, etc 2. Opioid Antagonist ◦ Reversal of resp depression & CNS depression ◦ Used as ANTIDOTE to reverse action of opioids Opioid Agonists MOA: Combine with opiate receptors to produce an analgesic effect by altering one’s PERCEPTION of pain Blocks nociceptive transmission Indications for use: Moderate to severe pain Pain Scale of greater than 3 Mild 1-3 Mod 4-6 Severe 7-10 What is the ceiling effect? Definition: Ceiling Effect ↑ dosing results does not result in pain relief, only side effects Example: Analgesic ceiling effect of Tylenol is 4Gm/24H. Giving more than 4Gm will not provide increased analgesia, but could increase SE ‘Tis a good thing → there is NO CEILING EFFECT for PURE OPOIDS (Morphine, Fentanyl) We can continue to increase the dose until pain is relieved!! Opioid Agonists: Adverse Effects o PUPIL CONSTRICTION – sign of toxicity/overdose o RESPIRATORY DEPRESSION opioid-naïve pts) (esp. o CONSTIPATION, CONSTIPATION, CONSTIPATION! o May lead to a paralytic ileus o CNS depression - COMA o N/V o Physical tolerance & (physical & psychological) dependence o Hypotension o Urinary retention o Pruritis What is a paralytic ileus? Is considered a “pseuo-obstruction” There is a partial or complete blockage of the bowel May be caused by opioids d/t decreased peristalsis The bowel sounds are very diminished or absent There is abdominal distension and pain Opioid Agonists: Interactions – Additive RESPIRATORY DEPRESSANT effects with other CNS depressants: • ETOH • Antihistamines (Benadryl, Claritin, Zyrtec) • Barbiturates (Seconal, Phenobarbital) • Benzodiazepines (Xanax, Valium) • Phenothiazines (anti-psychotics –Thorazine, Haldol) Opioid Agonists: Morphine • *morphine sulfate (Duramorph, MS – GOLD STANDARD Contin, Roxanol) DRUG OF CHOICE for SEVERE pain – Pure opoid agonist – Drug effect: analgesia, sedation, euphoria, respiratory depression, cough suppression, and suppression of bowel motility – Prototype; schedule II – – Derived from opium (poppy plant) moderate to high potential for abuse – Indications: Acute or chronic severe pain • • • Without causing loss of consciousness PO chronic pain; high doses 2° first-pass effect IV, extended/immediate release, epidural – Give very slowly IV; over 4-5 minutes (7-10/0-10) MOA: Morphine ---- a mu agonist mimics the action of endogenous opioids at the mu receptors → morphine binds to the mu receptor and creates a response Opiod Agonist: hydromorphone/Dilaudid • Opoid similar to morphine – Semi-synthetic • Schedule II • Indication: SEVERE pain Opioid Agonists: Demerol • meperidine hydrochloride (Demerol)* – Synthetic opioid – Schedule II – Indications: Moderate to Severe Pain • Weaker than morphine & shorter duration of action • • • • Less respiratory depression PO is half as effective as IV Lots of drug/drug interactions Short T1/2 – With REPEATED doses, Demerol breaks down to toxic metabolite normeperidine • DOSE DEPENDENT ADVERSE REACTION: CNS stimulation/seizures! – AHCPR (1992) – avoid in pain management when multiple doses will be given • So….only used when one or two doses will be given Opioid Agonists: Oxycodone • *Oxycodone – Schedule II – THE #1 drug used across the street on med-surg floors • SEMI-SYNTHETIC DERIVATIVE OF CODEINE – po only – Indications: Moderate to severe pain – More potent (10X) than codeine!! – Drug of abuse! • Oxycodone & acetaminophen (*Percocet) • Oxycodone & ASA (Percodan) • Time-released (Oxycontin) – High abuse potential. Reformulated in 2010 making the tablets harder to crush and “snort” Opioid Agonists: fentanyl/Duragesic – *fentanyl /Duragesic – schedule II – Indications: – Synthetic opioid for moderate- severe pain/surgical induction/ and CHRONIC PAIN • Less potential for resp depression and abuse – Adverse Reactions: • Pure opoid agonist: similar actions to Morphine –0.1 mg = 10 mg morphine so 100X as potent as Morphine – Transdermal duration patches (“Duragesic Patch”) – (onset = 6 hrs) 72 hour • Also IV, IM • Fentanyl Oralet – a lozenge (with handle) available for anesthetic pre-medication for kids/adults Opioid Agonists: Codeine • *codeine sulfate – Schedule II – codeine alone Schedule III – codeine combined with another analgesic – DERIVED FROM OPIUM – • Drug Effect: Analgesic,sedation,euphoria Effect is dose dependent – Analgesic (30 mg) – Anti-tussive (10 mg) – Indications: • • – – Often given WITH ASA or acetaminophen for added analgesia opioid + nonopioid = synergistic effect • – – mild to moderate pain like morphine, but WEAKER Ex.: “Tylenol #3” PO – has ceiling effects Side Effects are dose limiting Why is codeine very effective for some and not effective for others? • Codeine is a PRODRUG – inactive when administered and must be converted to an active form to be effective • Liver converts about 10% of each dose of codeine to morphine via the CYP2D6 enzyme • People who lack the effective gene for CYP2D6 cannot convert codeine to morphine – So codeine is NOT effective • People who are ultrarapid metabolizers (carry multiple copies of CYP2D6 gene) rapidly convert codeine to morphine – Codeine is unusually effective Opoid Agonist: Hydrocodone Schedule III → changing to Schedule II • Most widely prescribed drug in US Lortab/Vicoden/Norco – for mild to moderate pain (hydrocodone + acetameinophen) Tussionex – for coughs (hydrophone + chlorpeniramine) • Indications: • • Relieve mild to moderate pain and cough Cough suppressant – • Combined with antihistamines and nasal decongestants Analgesic effect similar to codeine – Is 6X more potent than codeine • In the USA must beCOMBINED WITH other drugs: – For analagesia: acetaminophen, aspirin, or ibuprofen – For cough: antihistamines, and nasal decongestants Opioid Antagonist • *naloxone (Narcan) • MOA: – BINDS to opioid receptors but DOES NOT ACTIVATE the receptor; onset < 2 minutes – Route: Parenteral only • Indications for use: – ANTIDOTE to reverse the effects of morphine and morphine like drugs (opioids) • Respiratory depression - physical stimulation unsuccessful • Pinpoint pupils shallow/< 8 breaths/min) • Decreased LOC MOA: Narcan – a mu antagonist it binds to the receptor and BLOCKS the response of the opioid Inhaled Naloxone/Narcan Stops heroin and other opioid substances from reaching the brain Dr. Wermeling, a pharmacy professor at the University of Kentucky developed this nasal spray form of naloxone/Narcan to help in the treatment of potentially fatal drug overdoses from heroin and other opioid substances. On the fast track for approval from the FDA Opioid Antagonists: Something to consider… – You totally, instantly, take away their analgesia – ½ life of Narcan is only 60 minutes – Could slip back into respiratory depression ATYPICAL non-opioid centrally acting tramadol/Ultram analgesic: • Ultram is an non-opioid analgesic • Former NOT a controlled substance • Now a Schedule IV (6/2014) d/t increasing recognition of potential for abuse • Indications: – – Moderate to severe pain PO agent MOA: – Binds weakly to the mu opioid receptor – Relieves pain through weak agonist activity at mu opioid receptors – Inhibits the uptake of serotonin and norepinephrine Adverse Effects: Rarely any serious AE Sedation, dizziness, h/a, dry mouth, constipation Rare: Seizures; can be fatal when combined with other CNS depressants Adjuvants: gabapentin/Neurontin and pregablin/Lyrica Classification: anticonvulsant Indications ◦ To COMPLEMENT the effects of opioids ◦ Used specifically for neuropathic pain 1. 2. 3. enhance analgesia from opioids help mange concurrent symptoms that exacerbate pain treat SE of opioids • MOA – thought to spontaneously suppress neuronal firing • Side Effects – drowsiness, dizziness, visual problems – Only partial reversal with Narcan NON-OPIOID Analagesics • NSAIDS – Non-steroidal anti-inflammatory drugs • Nonselective COX inhibitors • Selective COX-2 inhibitors • acetaminophen/Tylenol – not a “TRUE” NSAID – no anti-inflammatory properties Non-opioid Analgesics/NSAIDS: • acetylsalicylic acid (ASA) prototype SALICYLATE & NSAID: – With caffeine (Excedrin) – With antacids (Ascription, Bufferin) – Enteric-coated (Ecotrin) • ibuprofen (Advil, Motrin) • naproxen/Aleve,Naprosyn – the NSAID that is the hardest on the kidneys • ketorolac/Toradol – PARENTERAL (IM/IV) NSAID • celecoxib/Celebrex – COX-2 selective NSAID – Little inhibition of COX-1 so less GI problems Indications and MOA of NSAIDS • Indications: – mild to mod pain – inflammation – fever – prevention of heart attack and stroke (ASA only) • MOA: – Block a key enzyme of inflammation - cyclooxygenase • Cyclooxygenase converts arachidonic acid to prostaglandins and leukotrienes • PROSTAGLANDINS CAUSE INFLAMMATION • There are 2 types of cyclooxygenase – COX-1 – COX-2 NSAIDS BLOCK PROSTAGLANDINS COMMON SIDE EFFECTS OF NSAIDS • Non-selective COX inhibitors (inhibit BOTH COX-1/COX-2) – ASA, ibuprofen, naproxen • GI upset,stomach ulcers, GI bleeding • n-v-d • constipation • rash • edema – kidney failure • SOA in some- asthma • SELECTIVE COX-2 inhibitors: – celecoxib/Celebrex • less problems with GI • does not interfere with clotting • can cause serious cardiovascular thrombotic events – BLACK BOX WARNING BLACK BOX Warning for NSAIDS Serious Side Effects! Cardiovascular Risk: NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk." Gastrointestinal Risk: NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events." SE UNIQUE to the NSAID Aspirin • Reye’s Syndrome • Salicylate poisoning/toxicity – Acute • n/v • seizures, cerebral edema – Chronic • n/v • TINNUITUS – ringing in the ears • hearing loss No Aspirin for kids!!! What is Reye’s Syndrome – Reye’s Syndrome: • A rare life-threatening illness that can affect the brain and liver • Occurs in children < 15 who have been given ASA to treat a viral infection – Can cause brain and liver damage – high mortality rate – NEVER GIVE ASA FOR ANY REASON IN TREATING CHILDREN WITH VIRAL INFECTIONS –use Tylenol and ibuprofen instead Injectable NSAID: ketolorac/Toradol • The most potent NSAID • INDICATIONS: Toradol is used to treat acute/SHORT TERM moderate to severe pain – Primarily POST-OP pain. Five days or less • Given parenterally: IM or IV – TORADOL PROVIDES POWERFUL ANALGESIA WITH MINIMUM ANTI-INFLAMMATORY ACTION – Analagesic effect similar to morphine • MOA: • Without the respiratory depression suppresses prostaglandin synthesis • SE: • similar to all NSAIDS Increase GI ulcers with extended use. Nonopioid Analgesics: acetaminophen/Tylenol • MOA: – unknown; prostaglandin synthesis in the CNS? – Ø anti-inflammatory properties • Not a true NSAID! • Indications for use: – Mild to moderate pain – (Also fever) • Limitation: – Does have a ceiling effect Nonopioid Analgesics: acetaminophen/Tylenol Adverse effects: ◦ Large amounts (acute) hepatic necrosis Ceiling effect: Adult: do not exceed 4g/day! ◦ Large amounts (long-term) liver failure and nephropathy Antidote: *acetylcysteine (Mucomyst) Remember, too much Tylenol can kill your LIVER! Healthy liver Liver after Tylenol OD Advantages of Tylenol • Rarely causes GI upset – May take anticoagulants concurrently • Kids may take with colds/viral illnesses • (NOT associated with Reye’s Syndrome) Nonopioid Analgesics/NSAIDS – Pearls for Practice • Can alternate true NSAIDs with acetaminophen (different MOA’s) • Good to give in conjunction with opioids for moderate to severe pain – If giving with “Percocet, be careful not to supplement with acetaminophen – want to protect that liver! (true NSAID is better choice) • Choose true NSAID’s (not Tylenol) if inflammation is the causative factor