Pain and Analgesia PDF

PAIN AND ANALGESIA Elizabeth Cohen, PharmD, BCPS YSN 6020 Advanced Pharmacology Learning Objectives Explain the differences between nociceptive and neuropathic pain Compare and contrast classes of analgesic medications Discuss the role of non-opioid analgesics in the management of pain Rev...

PAIN AND ANALGESIA Elizabeth Cohen, PharmD, BCPS YSN 6020 Advanced Pharmacology Learning Objectives Explain the differences between nociceptive and neuropathic pain Compare and contrast classes of analgesic medications Discuss the role of non-opioid analgesics in the management of pain Review the various opioid classes and specific opioid medications Calculate the equianalgesic dose of an opioid regimen when converting to another regimen Analyze state laws and federal regulations pertaining to the prescribing of controlled substances Identify the necessary components of a controlled substance prescription Describe ethical and legal standards of prescribing of controlled substances Review the Connecticut Prescription Monitoring Program and its use in regards to the prescribing of controlled substances Discuss Substances of Misuse and appropriate treatment Identify appropriate candidates for migraine prophylaxis and create and analgesic regimen Pain: The 5th Vital Sign “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” -International Association for the Study of Pain “Whatever the experiencing person says it is, existing whenever s/he says it does.” -Margo McCaffery, 1968 Part III: Pain Terms, A Current List with Definitions and Notes on Usage" (pp 209-214) Classification of Chronic Pain, Second Edition, IASP Task Force on Taxonomy, edited by H. Merskey and N. Bogduk, IASP Press, Seattle, ©1994. McCaffery, M. (1968). Nursing practice theories related to cognition, bodily pain and main environment interactions. Los Angeles: University of California Los Angeles. Causes of Pain Indwelling Surgery Muscle Pain Cancer Catheters Procedural Claudication Injury/trauma Infection Pain Nerve Fibromyalgia Arthritis Headache Damage Types of Pain Acute Surgery, acute illness, trauma, labor, procedures Typically nociceptive Chronic Changes in nerve function and transmission over time Cancer Nociceptive or neuropathic Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015.  Joint Somatic Tendon/muscle Skin Types of Pain Thoracic Pelvic Visceral Abdominal Nociceptive Pain: Mechanism Transmission Afferent nociceptive pain fibers synapse in dorsal horn of spine Glutamate Substance P Aspartate Perception Affected by cognition and behavior Modulation Endogenous opiate system N-Methy-D-aspartate (NMDA) receptors Raphe nuclei in brainstem Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Types of Pain: Neuropathic Pain Results from damage or impairment of nervous system Peripheral damage Alteration of nerve fiber sensitivity, development of collateral nerve fibers Central damage Hyperexcitability of central neurons, NMDA activation, central disinhibition Examples: Postherpetic neuralgia Diabetic neuropathy Fibromyalgia Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Management of Pain Non-pharmacologic Relaxation, acupuncture, nerve stimulators, heat/cold, massage Pharmacologic Oral, intravenous, sublingual, topical… Goals of therapy Decrease pain Improve quality of life Improve function Decrease side effects Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Evaluating Pain - PQRST Provocation/Palliation What caused the pain? What makes it better/worse? Quality/Quantity What does it feel like? Region/Radiation Where is the pain located? Does it radiate? Severity scale Timing When did the pain start? How long does it last? When does it occur? WHO Pain Ladder Nersesyan H, Slavin KV.Therapeutics and Clinical Risk WHO: World Health Organization Management. 2007;3(3):381-400. analgesics Types of Analgesics Acetaminophen Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Adjuvants Antidepressants Antiepileptics Topical agents Antimigraine Opioids Non-opioid analgesics acetaminophen Acetaminophen (Tylenol®) Commonly abbreviated as APAP Proposed mechanism: weak COX-1 and COX-2 inhibitor May also act centrally by activating serotonergic pathways Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill; 2015. Graham GG, et al. Am J Ther. 2005;12(1):46-55. Acetaminophen: Therapeutic Use Analgesic and antipyretic properties Does not provide anti-inflammatory benefits First-line analgesic in osteoarthritis Useful for treatment of fever in children Appropriate for mild-moderate pain or as an adjunct in the treatment of severe pain Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. Acetaminophen: Dosing and Administration Dosage and Administration Adults: 325-1000 mg every 4-6 hours (MAX dose 4 grams/day) Cirrhosis max 2 grams/day Pediatrics: 10-15 mg/kg/dose, max 5 doses/day Oral tablet, oral suspension (160 mg/5 mL), rectal or IV (Ofirmev®) Some formulations contain benzyl alcohol, propylene glycol, polysorbate 80 MANY combination products Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Acetaminophen: Products Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Acetaminophen: Adverse Effects Usually well tolerated at therapeutic doses Can cause rash or hypersensitivity reactions occasionally Majority of adverse reactions are associated with overdose (acute or chronic) Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. Acetaminophen: Warnings and Contraindications Contraindications History of hypersensitivity Severe hepatic impairment Severe active liver disease Warnings/precautions Chronic ethanol misuse → increased risk of liver damage Hepatic impairment Malnutrition Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Acetaminophen: Pregnancy and Lactation Not associated with teratogenicity May be linked to behavior problems Excreted in low concentrations in breast milk First line analgesic in pregnancy if non-pharmacologic therapy is inadequate Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Acetaminophen: Overdose Leading cause of: Drug-induced liver failure Suicide-related death Unintentional overdose ALF: Acute liver failure Lee WM. Clin Pharmacol Ther. 2010 Sep;88(3):289-92. Acetaminophen: Overdose Clinical presentation – divided into four stages Stage Timeframe Symptoms Stage 1 0-24 hours May be asymptomatic or have non-specific symptoms (nausea/vomiting, malaise, pallor, diaphoresis) Stage 2 24-48 hours Onset of hepatic injury; LFTs increase (AST is most sensitive marker), hepatic encephalopathy, hypoglycemia, metabolic acidosis Stage 3 72-96 hours Fulminant hepatic failure, encephalopathy, coma, hemorrhage (rare), hepatorenal syndrome, death Stage 4 >96 hours Recovery phase, hepatic regeneration, normalization of AST, pH, PT/INR, lactate Hoffman RS, et al. eds. Goldfrank’s Toxicology Emergencies, 10e. New York, Ny: McGraw-Hill; 2015. Acetaminophen: Overdose N-acetyl cysteine Defendi GL. Consultant For Pediatricians. 2013;12(7):299-306 Acetaminophen: Overdose Management: N-acetylcysteine – ideally within 8 hours of ingestion 21 hour IV regimen or 72 hour oral regimen Adverse reaction: anaphylaxis Supportive care, liver transplantation Strategies for reducing overdose Limitations on APAP content of combination products Standardization of OTC concentrations Limit max dose to 3 grams/day when taken without healthcare provider supervision (OTC) Hoffman RS, et al. eds. Goldfrank’s Toxicology Emergencies, 10e. OTC: Over the counter New York, Ny: McGraw-Hill; 2015. Question What is the maximum 24-hour dose of acetaminophen for the general population? A. 2 grams B. 4 grams C. 6 grams D. 8 grams NSAIDs NSAIDs Nonsteroidal Anti-Inflammatory Drugs Wolfe MM, et al. N Engl J Med. 1999; 340:1888-1899. NSAIDs Mechanism of action: inhibition of cyclooxygenase (COX), inhibiting prostaglandin synthesis Two forms of COX enzyme: COX-1 and COX-2 COX-1: Produces prostanoids for gastric epithelial cytoprotection and for hemostasis COX-2: Produces prostanoids involved in inflammation and possibly in cancer Both COX-1 and COX-2 can contribute to inflammation and pain Newer NSAIDs have been developed targeting COX-2 specifically to avoid GI side effects Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. NSAIDs: Therapeutic Use Anti-inflammatory, antipyretic, and analgesic effects First-line analgesia for inflammatory musculoskeletal injuries and disorders such as rheumatoid arthritis Useful for treatment of fever in children Appropriate for mild-moderate pain or as an adjunct in the treatment of severe pain Not typically recommended for chronic use due to adverse effects Wolfe MM, et al. N Engl J Med. 1999; 340:1888-1899. NSAIDs: Dosing and Administration Drug Oral Adult Dose Half-Life (hours) Non-Selective Aspirin 325-650 every 4-6 hours 0.25 Diclofenac 50-75 mg 4x/day 1.1 Etodolac 200-300 mg 4x/day 6.5 Ibuprofen 600 mg 4x/day 2 Indomethacin 50-70 mg 3x/day 4-5 Nabumetone 1000-2000 mg once daily 26 Naproxen 375 mg 2x/day 14 Ketorolac (IM, IV, oral) 10 mg every 4-6 hours oral 2-6 IV 30mg, IM 60mg Selective COX-2 Celecoxib 100-200 mg 2xday 11 Meloxicam 7.5-15 mg once daily 20 Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. NSAIDs: Adverse Effects GI effects - nausea, diarrhea, abdominal pain, gastric ulcers, GI bleed Hematologic effects – inhibition of platelet activation, increased bruising, bleeding Renal effects – salt and water retention, edema, hyperkalemia Cardiovascular effects – MI, stroke, thrombosis Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. NSAIDs: Warnings and Contraindications Contraindications History of hypersensitivity reactions Age < 6 months Warnings/precautions Asthma (can cause bronchospasm) Heart failure Coronary artery disease/MI Renal impairment Hepatic impairment (increased risk of bleeding) Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. NSAIDs and Renal Dysfunction Decreased renal blood flow and filtration rate Occurs with chronic use, especially with high does Caution with concomitant ACE Inhibitors and diuretics Prostaglandins dilate here Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. NSAIDs and Cardiovascular Risk Class effects: Fluid retention Edema Hypertension Myocardial Infarction Congestive heart failure COX-2 specific NSAIDs significantly increase risk of MI, stroke, and thrombosis Rofecoxib (Vioxx®) withdrawn from market Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. NSAIDs and Bleeding Risk Reduction in protective prostaglandins ➔ GI bleeding, ulceration Combine with Proton Pump Inhibitor or misoprostol (prostaglandin analog) Enteric coating Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. NSAIDs: Pregnancy and Lactation Contraindicated during 3rd trimester Prolonged gestation and labor, increased peripartum blood loss Fetal effects: bleeding, premature closure of ductus arteriosus, pulmonary hypertension, impaired renal function Lactation: trace amounts found in breast milk Risser et al. Am Fam Physician. 2009;80(12):1371-1378. NSAIDs: Drug Interactions Angiotensin-converting enzyme (ACE) inhibitors Renal dysfunction, decreased effectiveness of ACE inhibitor Serotonin reuptake inhibitors (SSRIs, SNRIs) Increased frequency or severity of GI complications Corticosteroids Increased frequency or severity of GI complications Warfarin Increased risk of bleeding, displacement of warfarin from plasma proteins Lithium Reduced renal excretion of lithium, increased toxicity Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. NSAIDs: Ibuprofen Brand names: Motrin®, Advil®, Caldolor® IV Also available as an ingredient in many OTC pain and cough/cold remedies Non-selective NSAID, available as OTC (200mg) and as Rx (600- 800mg) Dose: typically 200-400mg orally every 4-6 hours for pain, can give up to 800mg/dose Max of 3200mg/day IV formulation uncommonly used due to availability of ketorolac IV UpToDate, Post TW (Ed), UpToDate, Waltham, MA. NSAIDs: Naproxen Brand names: Aleve®, Naprosyn®, Anaprox® Non-selective NSAID, available as OTC (220mg) and Rx Dose: typically 250mg every 6 hours or 500mg every 12 hours UpToDate, Post TW (Ed), UpToDate, Waltham, MA. NSAIDs: Ketorolac Brand names: Toradol® Non-selective NSAID, available as Rx only Can be given by oral, intramuscular, and intravenous routes Therapeutic use: short-term management of moderate to severe acute pain requiring analgesia at the opioid level UpToDate, Post TW (Ed), UpToDate, Waltham, MA. NSAIDs: Ketorolac Dosing IM – 60mg initially, then 30mg every 6 hours IV – 30mg every 6 hours Oral – 20mg initially, then 10mg every 4-6 hours Therapy limited to 5 days duration Dose adjustments: Age ≥ 65: reduce dose by ½ Renal impairment: reduce dose by ½ in mild to moderate; use contraindicated in severe impairment UpToDate, Post TW (Ed), UpToDate, Waltham, MA. NSAIDs: Meloxicam Brand names: Mobic® Somewhat selective for COX-2, available as Rx only Dose: 7.5-15mg once daily Contraindicated for treatment of pain after CABG surgery Potentially useful for longer-term use due to COX-2 selectivity and once-daily dosing UpToDate, Post TW (Ed), UpToDate, Waltham, MA. NSAIDs: Celecoxib Brand names: Celebrex® Generic released in 2014 COX-2 selective, available as Rx only Dose: 100-200mg once or twice daily Indicated for treatment of osteoarthritis and rheumatoid arthritis pain Increased risk of cardiovascular events associated with use – contraindicated for use after CABG surgery UpToDate, Post TW (Ed), UpToDate, Waltham, MA. NSAIDs: Aspirin Salicylate, irreversibly inhibits COX enzymes Inhibits formation of prostaglandins including thromboxane A2, which is required for platelet aggregation Duration of antiplatelet effects last the lifetime of the platelet Available as oral and rectal formulations Much higher doses are required for analgesia and antipyretic compared to antiplatelet effects Dose: for pain, 325-650mg orally (300-600mg rectally) every 4-6 hours Max: 4g/day Enteric coated tablets reduce GI side effects Can cause Reye’s syndrome in children aged < 12 years UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Question Which of the following serious adverse effects has been shown to occur more frequently with COX-2 selective NSAIDs? A. Myocardial infarction B. Renal impairment C. GI ulcers D. Hepatic impairment Adjuvant Analgesics Neuropathic Pain Harder to treat than nociceptive pain First line agents Antiepileptics (gabapentin, pregabalin) Antidepressants (duloxetine, venlafaxine, amitriptyline) Second line agents Lidocaine patch Capsaicin Tramadol Finnerup et al. Lancet Neurol. 2015 Feb;14(2):162-73. Topical Agents Lidocaine (Lidoderm®) Patch Local anesthetic Minimal systemic absorption 12 hours on, 12 hours off Capsaicin Depletes substance P from nociceptive nerve fibers Causes burning, stinging, erythema Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Musculoskeletal Pain Spasmolytics Baclofen Tizanidine Skeletal muscle relaxants Clyclobenzaprine (Flexeril®) Methocarbamol (Robaxin®) Carisoprolol (Soma®) Metaxalone (Skelaxin®) Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015.  Cannabinoids for Chronic Pain BMJ 2021;374:n2040 Summary of Evidence Summary of Evidence Summary of Individual Considerations Question Which of the following antidepressant medications has been shown to benefit patients with neuropathic pain? A. Fluoxetine B. Sertraline C. Vortioxetine D. Amitriptyline Migraines Migraines Primary headache, episodic in nature Often associated with triggers, usually sensory stimuli Pathogenesis Dysfunction of sensory control system in thalamus and brainstem Activation of cells in trigeminal nucleus leads to release of vasoactive peptides Serotonin and dopamine appear to play a role DiPiro JT, et al. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Pathogenesis https://www.youtube.com/watch?v=tA-KvkH-0GY Diagnosis of Chronic Migraine Full neurologic exam is required ≥ 5 attacks in 3 months lasting 4-72 hours At least 2 of the following: Unilateral pain Throbbing Aggravation by movement Moderate or severe intensity AND at least 1 of the following: Nausea/vomiting Photophobia and phonophobia Aura: 25% of patients, focal neurological symptoms that usually occurs before migraine DiPiro JT, et al. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Migraines: Management Non-pharmacologic Healthy lifestyle Minimizing stresses, avoiding excess caffeine and alcohol Yoga, meditation, hypnosis Pharmacologic Abortive therapy Caution about “medication overuse headache” Preventive therapy > 5 attacks/month Individualize therapy DiPiro JT, et al. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Treatment of Migraine: Rescue Therapy NSAIDs OTC: Excedrin® Aspirin 250 mg, acetaminophen 250 mg, caffeine 65 mg Butalbital compounds: Fioricet® (Butalbital 50mg, acetaminophen 300mg, caffeine 40mg +/- codeine 30 mg) Fiorinal® (Butalbital 50mg, aspirin 325mg, caffeine 40mg) Antiemetics (e.g. metoclopramide, prochlorperazine) Most effective if taken early during attack Also work for other types of headache Opioids: little role DiPiro JT, et al. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Fioricet®, Fiorinal® Schedule III controlled substances Dose: 1-2 capsules every 4 hours as needed; max 6 capsules/day Adverse reactions: Hangover effect, GI upset, CNS depression Caution in patients with hypersensitivity to aspirin/acetaminophen Overuse leads to tolerance and possible dependence, which can lead to overuse headache Not recommended first-line UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Antiemetics/Prokinetics Mechanism: antiserotonin, anticholinergic, antidopaminergic, and antihistamine effects Can also treat nausea associated with migraine Metoclopramide Dose: 20mg IV x1 Adverse effects: akathisia (more severe in children), flushing, hallucination (rare) Prochlorperazine Dose: 10mg IV x1 Adverse effects: akathisia, hypotension, blurred vision UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Singh A, et al. Management strategies for acute headache in the emergency department. Emerg Med Pract. 2012 Jun;14(6):1-23. Treatment of Migraine: Rescue Therapy: Triptans Selective agonists for 5-HT1D and 5-HT1B receptors Proposed mechanisms Inhibit release of vasodilating peptides by activating serotonin receptors on presynaptic trigeminal nerve endings Direct vasocontrictive effect Individual response varies between agents DiPiro JT, et al. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Triptans: Class Effects Chest discomfort/chest pain Contraindicated with coronary artery disease Cardiovascular workup recommended if risk factors First dose given in office Also contraindicated in cerebrovascular disease, uncontrolled hypertension Drug interactions Serotonin syndrome with other serotonergic drugs Do not give sumatriptan, rizatriptan, or zolmitriptan within 2 weeks of monoamine oxidase inhibitors (MAOIs) Avoid eletriptan with CYP 3A4 inhibitors DiPiro JT, et al. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Treatment of Migraine: Rescue Therapy: Triptans Max Dose/Day Drug Routes Onset (hours) Single Dose (mg) (mg) Almotriptan Oral 2.6 6.25-12.5 25 (Axert®) Eletriptan Oral 2 20-40 80 (Relpax®) Frovatriptan Oral 3 2.5 7.5 (Frova®) Naratriptan Oral 2 1-2.5 5 (Amerge®) Rizatriptan (Maxalt®, Maxalt Oral 1-2.5 5-10 30 ODT®) Sumatriptan Oral, nasal, 1.4 (0.2 for 25-100 oral, 20 nasal, 6 200 (Imitrex®) subcutaneous, rectal subcutaneous) subcutaneous, 25 rectal Zolmitriptan Oral, nasal 2.5-5 2.5-5 10 (Zomig®) Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Treatment of Migraine: Rescue Therapy: Ergot Alkaloids Mechanism: Non-selective serotonin receptor agonists Constrict intracranial blood vessels Inhibit trigeminovascular inflammation Dihydroergotamine (DHE): intranasal (Migranal®), IM, subcutaneous, IV Dose: IV: 0.5-1mg, may repeat every hour up to 3mg/day IM, SubQ: 0.5-1mg, may repeat every hour up to 2mg/day Intranasal: 1 spray (0.5mg) in each nostril, may repeat in 15 minutes up to 4 sprays (2mg) IDiPiro JT, et al. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Treatment of Migraine: Rescue Therapy: Ergot Alkaloids Adverse effects Severe peripheral, myocardial, and brain ischemia Nausea/vomiting (significant!) Contraindications: Renal or hepatic failure Coronary, cerebral, or peripheral vascular disease Uncontrolled hypertension Pregnancy and lactation Potent CYP 3A4 inhibitors Do not use within 24 hours of triptan IDiPiro JT, et al. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Migraine: Prophylaxis Indications for prophylaxis: Frequent or long lasting migraine headaches Migraine attacks that cause significant disability or diminished quality of life despite appropriate acute treatment Contraindication to acute therapies Serious adverse effects of acute therapies Risk of medication overuse headache Menstrual migraine American Academy of Neurology. Neurology 2000. 55:754. Treatment of Migraine: Prophylaxis Drug Class Established Efficacy Probably Effective Possibly Effective Depakote (divalproex sodium) Anticonvulsants Tegretol (carbamazepine) Topamax (topiramate) Elavil (amtriptyline) Antidepressants Effexor (venlafaxine) Lopressor (metoprolol) Tenormin (atenolol) Beta-blockers Bystolic (nebivolol) Inderal (propranolol) Corgard (nadolol) Motrin (ibuprofen) NSAIDs Aleve, Naprosyn (naproxen) Triptans* Amerge (naratriptan) *short-term menstrually Frova (frovatriptan) Zomig (zolmitriptan) related migraine only Atacand (candesartan) ACEi/ARB Prinivil (lisinopril) Catapress (clonidine) Alpha-agonists Tenex (guanfacine) magnesium co-Q10 Herbals, vitamins butterbur feverfew estradiol riboflavin Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults. Report of the Quality Standards Subcommittee of the American Academy and the American Headache Society. Neurology. 2012;78:1337-1345. Holland S, Silberstein SD, Freitag F, Dodic DW, Argoff C, Ashman E. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1346-1353.  CGRP (calcitonin gene-related peptide) Antagonists Migraine patients have increased CGRP → neurogenic inflammation and vasodilation Used for the prevention of migraines Seem to be fairly well tolerated Harvey P, et al. US Pharm. 2020;45(1):21. CGRP Antagonists for Treatment Ubrogepant (Ubrelvy) Approved in February 2020 To relieve symptoms in oral tablet Rimegepant (Nurtec ODT) Approved February 2020 Relief of symptoms in ODT form Question You would like to prescribe almotriptan to a patient with migraines. Before giving her the prescription, you counsel her that this medication: A. Should be used every day at the same time each day B. Can be taken as often as necessary to relieve pain C. Can cause a sensation of chest tightness and pressure D. Unlike Ergot alkaloids, this medication is not associated with rebound headache Opioid Medications Opioids: Pharmacologic Actions Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. Opioids: Therapeutic Effects Reduce perception of pain in the central nervous system (CNS) Occurs without loss of consciousness Provides symptomatic relief of pain Analgesia is dose dependent Therapeutic effects are best achieved through dose titration Cough Suppression Codeine used more often than morphine Mechanism of action is mediated depression of cough reflex center of the medulla Doses lower than those required to produce analgesic effects or depress respiration Opioids: Adverse Effects Pupillary miosis Pupil constriction occurs at therapeutic opioid doses Central effect of the oculomotor nerve Chronic users will continue to have constricted pupils Itching Secondary to histamine release from mast cells Constipation Reduced GI motility Tolerance will NOT develop to this side effect Patients on long-term opiates should be on a bowel regimen Nausea/vomiting Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Opioids: Severe Adverse Effects Respiratory depression Respiratory control centers in brain Occurs in a dose-dependent manner Potentially life threatening Hypotension Caused by histamine release from mast cells → vasodilation Bradycardia Direct effect on cardiac pacemaker cells True opioid allergy (IgE Mediated or T-cell mediated) Bronchospasm Very low blood pressure/shock Angioedema Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Opioids: Therapeutic Use Opioid therapy should be considered only if expected benefits will outweigh risks Immediate release opioids should be prescribed initially The lowest effective dose should be utilized for the shortest duration possible Avoid concurrent prescription of benzodiazepines when feasible Centers for Disease Control and Prevention. CDC Guideline for Prescribing Opioids for Chronic Pain – United States, 2016. Morbidity and Mortality Weekly Report. 2016 Mar 15. https://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm Opioids: Contraindications and Precautions Contraindications Significant respiratory disease Comatose patients (unless used for palliative care for a dying patient) Hypersensitivity to structurally similar opioid medications Warnings/precautions Bowel obstruction CNS depression Delirium tremens Head trauma Renal impairment (for renally cleared opioids) Respiratory disease (COPD, cor pulmonale, etc.) Seizure disorders Opioids: Pregnancy and Lactation Fetus can become dependent in utero Neonatal withdrawal syndrome Irritability Hyperactivity High pitched cry Tremor Vomiting Seizure Require treatment for withdrawal with morphine and clonidine Lactation excreted in breast milk Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Opioids: Functional Classes Codeine Fentanyl Heroin Hydrocodone Full agonists Hydromorphone Methadone Morphine Oxycodone Oxymorphone Partial Agonists Buprenorphine Antagonists Naloxone Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Opioids: Structural Classes Morphine Natural Codeine Oxycodone Phenanthrenes Hydromorphone Synthetic Oxymorphone Hydrocodone Meperidine Phenylpiperidines Fentanyl Phenylheptanes Methadone Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Opioids: Codeine (C-II) Dosing and Administration Pediatric dose: 0.5-1 mg/kg/dose every 4 hours prn Adult dose: 15-60 mg every 4 hours prn Pharmacokinetics Onset: 0.5-1 hour Duration: 4-6 hours Half-life: 3 hours Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; April 1, 2015. Opioids: Codeine Metabolism: hepatic Glucuronidation to codeine-6- glucuronide CYP 2D6 to morphine (active) CYP 3A4 to norcodeine Excretion: via urine CYP 2D6 Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; April 1, 2015. Codeine Product Availability Codeine (C-II): Oral tablet (15 mg, 30 mg, 60 mg) Oral solution (30 mg/5 mL) Tylenol with codeine® Used frequently in post-operative period Dose based upon codeine component Commercial availability: Oral solution/suspension (12 mg codeine, 120 mg acetaminophen per 5 mL) (C-V) Oral tablet (C-III) Tylenol #3®: 300 mg acetaminophen /30 mg codeine phosphate Tylenol #4®: 300 mg acetaminophen /60 mg codeine phosphate Codeine: Tonsillectomy for OSA OSA: Obstructive Sleep Apnea Opioids: Morphine Sulfate (C-II) Dosing and Administration (oral, opioid naïve) Pediatric dose: 0.15-0.3 mg/kg every 3-4 hours prn Adult dose: 15-30 mg every 4 hours prn Pharmacokinetics Onset Oral: ~ 30 minutes IV: 5 – 10 minutes Duration: 3 – 5 hours (extended release 8 – 24 hours) Half-life: Children 1 – 2 hours Adults 2 – 4 hours Available as tablet, capsule, solution, and injection Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; April 1, 2015. Opioids: Morphine Sulfate Both active and inactive metabolites are potentially toxic At risk: elderly, renal dysfunction, hemodialysis Recommendation: monitor for ADRs closely, consider initiation of a different opioid (hydromorphone, oxycodone, fentanyl are options) Avoid long-acting (daily) formulations in high-risk populations Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; April 1, 2015. Opioids: Hydromorphone (C-II) Dosing and Administration (oral, opioid naïve) Pediatric dose: 0.03 – 0.06 mg/kg every 4 prn Adult dose: 2 - 6 mg every 4 hours prn Availability IV, IM, subcutaneous, epidural, oral Immediate release (Dilaudid®) Extended release (Exalgo®) Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; April 1, 2015. Opioids: Hydromorphone Pharmacokinetics Bioavailability: 62% Onset Immediate release 15-30 min Extended release 6 hours Duration Immediate release 3-6 hours Extended release 13 hours Half-life: 2-3 hours Metabolism: hepatic, glucuronidation to inactive metabolites Excretion: via urine Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; April 1, 2015. Opioids: Oxycodone (C-II) Dosing and Administration (oral, opioid naïve) Pediatric dose: 0.1-0.2 mg/kg every 4-6 hours prn Adult dose: 5-15 mg every 4 hours prn Available as Tablet Capsule Solution Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; April 1, 2015. Opioids: Oxycodone Pharmacokinetics Onset: Oral 10-15 min Duration Immediate release 3-6 hours Extended release 50 morphine milligram equivalents per day) Prolonged use (> 90 days) of opioids for nonmalignant pain Comorbidities (respiratory disease, renal/hepatic dysfunction, depression, older age, dementia) Concomitant ingestions (alcohol, benzodiazepines) Symptoms of Opioid Overdose Respiratory depression (slow breathing or apnea, cyanosis) Hypotension, bradycardia Depressed mental status Miosis (pinpoint pupils) Hyporeflexia Opioids: Overdose: Naloxone (Narcan®) Mechanism: competitively inhibits binding of opioids to their receptors Common available routes of administration: Intravenous (onset in 1-2 minutes) Intramuscular (onset 6 minutes) Intranasal (onset 3-4 minutes) Duration: 20-90 minutes Initial dose: IV – 0.04 to 0.05mg IM – 0.4 to 2mg Intranasal – 4mg Naloxone “Adverse Effect”: Opioid Withdrawal Blocking opioids from binding to receptors will precipitate withdrawal in opioid-dependent patients If this occurs, allow symptoms of withdrawal to diminish If necessary, can administer additional lower doses of naloxone Caution: significant nausea/vomiting may occur Risk of aspiration Consider pretreatment with an antiemetic Opioid Withdrawal Symptoms Tremor Anorexia Nausea Muscle Vomiting Diaphoresis spasms Rhinorrhea Irritability Anxiety Diarrhea Opioids: Preventing Use Disorder Establish goals before initiating therapy Use lowest effective dose Use non-opioid adjunctive agents Maintain close relationship with patient and ensure follow up is possible Regularly re-evaluate need for therapy Katzung BG, Trevor AJ. Eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill;2015. Contracts Example Dr. ______ has explained the risks and benefits of chronic opioid therapy for my chronic pain. I, ____________, understand that I must abide by the rules of this contract or I will not be given opioids. I will only fill my prescription at one pharmacy (Pharmacy name: _______) I will take this medication exactly as prescribed. I understand that this medication will be prescribed at the minimum dose for the minimum amount of time necessary to treat my pain. Willis DR, et al. Fam Pract Manag. 2010 Nov-Dec;17(6):22-27. Opioid Use Disorder Treatment Programs Section 1262 of Consolidated Appropriations Act 2023 removed federal requirement to have a waiver to prescribe medications for opioid use disorder Revised 42 CFR Part 8 published February 2024 To provide services for OUD patients, OTPs must successfully complete the certification and accreditation process and meet other requirements outlined in 42 CFR 8. Requirements include: OTPs must be both certified and accredited; Licensed by the state in which they operate; and Registered with the Drug Enforcement Administration (DEA), through their local DEA office. Permanently puts in place flexibilities from COVID-19 Public Health Emergency Expands access to care and removes all language and rules pertaining to Drug Addition and Treatment Act (DATA) Shifts regulation from FDA to SAMSHA (Substance Abuse and Mental Health Services Administration) https://www.samhsa.gov/medications-substance-use-disorders/statutes- regulations-guidelines Opioid Use Disorder Treatments Oesterle TS, et al. Mayo Clin Proc. 2019;94(10):2072. Connecticut Law on Opiate Overdose Public Act No. 16-43 Licensed health care professionals may administer an opioid antagonist to any person to treat or prevent opioid-related overdose Such provider shall not be held liable for any damages in a civil action or subject to criminal prosecution for administration of an opioid antagonist All emergency medical services must be trained to use and equipped with an opioid antagonist (including state troopers) Health Assistance InterVention Education Network for Connecticut Health Professionals (HAVEN) Enables the establishment of a confidential assistance program for health care professionals suffering from physical or mental illness, emotional disorder or chemical dependency Can refer yourself of a colleague: 860-276-9196 Does not engage in the practice of medicine or mental health care Education and Prevention Early identification and intervention Provides referral for evaluation and treatment Resources for Prescribers CT Prescription Monitoring Program Central database of Schedule II-V drugs Pharmacies in and out of state submit data once per week More information: 860-713-6073 or [email protected] www.ctpmp.com White House Opioid Overdose Toolkit Prescription Monitoring Program (PMP) Online database which records prescription data for controlled substances for use by healthcare providers in patient care Purpose – provider overview of patient’s controlled substance use, improve quality of care, and combat prescription misuse, use disorder, and overdose All states now have some functioning program Not all states have PMPs that communicate with other states Therefore some information may still be missing depending on the state in which a prescription is filled National Alliance for Model State Drug Laws http://www.namsdl.org/prescription-monitoring-programs.cfm Prescription Monitoring Program (PMP) Public Act 15-198: Effective 10/1/2015 Prior to prescribing > 72 hour supply of any controlled substance (schedule II – V) to any patient, prescribers are required to review the patient’s records in the Connecticut Prescription Monitoring and Reporting System (CPMRS) Whenever prescribing controlled substances for the continuous or prolonged treatment of any patient, the prescriber must review, not less than once every 90 days, the patients records in CPMRS Connecticut Department of Consumer Protection http://www.ct.gov/dcp/cwp/view.asp?a=1620&q=411378&dcpNav_GID=1881 Discussion Other Substances of Misuse Dependence vs. Use Disorder Dependence = physical dependence Exhibits withdrawal symptoms when drug is removed Use Disorder = psychological dependence Compulsive, relapsing drug use despite negative consequences Increases in dopamine reinforce misuse Non-addictive Drugs of Misuse Don’t activate dopamine Effect 5-HT and NMDA receptors Examples LSD PCP Dextromethorphan Ketamine More hallucinogenic effects Nicotine Withdrawal Symptoms Irritability Sleep problems Treatment Nicotine replacement with lozenges, gum and patches Combination should be used ex. Patch and gum Dosed based on number of cigarettes smoked daily and time of day for first cigarette Varenicline (Chantix) – blocks the reward system of nicotine 0.5mg once daily for days 1 – 3, then 0.5mg twice daily for days 4 – 7, then 1mg twice daily for 11 weeks; starting 1 week before quit date May continue for additional 12 weeks to maintain success Bupropion (Zyban) – 150mg daily for 3 days, then 150mg twice daily for up to 6 months Benefits of Quitting Benzodiazepines and Barbituates Often misused in combination with other drugs Reduce anxiety during opioid withdrawals Symptoms of withdrawal occur within days and last 1-2 weeks Irritability Insomnia Phono and photophobia Depression Muscle cramps No good treatment options, require tapering Alcohol Withdrawal symptoms 6 – 12 hours: tremor, n/v, sweating, agitation, anxiety 12 – 24 hours: hallucinations 24 – 48 hours: generalized seizures 48 – 72 hours: delirium tremens (5-15% mortality) Immediate withdrawal requires benzodiazepines for treatment Alcohol Dependence Treatment Naltrexone (opioid antagonist) Oral 50mg daily Must be opioid free before initiating Reduces cravings for alcohol Acamprosate (Campral) NMDA antagonist and GABA agonist 333mg – 666mg TID, without food Avoid in severe renal impairment Avoid cravings Disulfiram (Antabuse) – causes severe discomfort Inhibits aldehyde dehydrogenase leading to accumulation of acetaldehyde 500 mg once daily 1 -2 weeks 250mg daily long term No longer commonly used Assessment Question MR is a 35 year old who has been smoking 1 pack per day for 15 years. They have a cigarette with their morning coffee. There are no other smokers in the home. What would you want to recommend to stop smoking? What instructions would you give her? Summary Nociceptive pain is managed with opioid and adjuvant analgesics Acetaminophen should be avoided in patients with severe hepatic failure or chronic alcoholism NSAIDs are associated with cardiovascular, renal, and hematologic side effects Neuropathic pain is more difficult to relieve than nociceptive pain Rescue therapy for acute migraine attacks should be restricted to less than 10 times per month to avoid rebound headache PAIN AND ANALGESIA Elizabeth Cohen, PharmD, BCPS YSN 6020 Advanced Pharmacology