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71-1 ACUTE PAIN MANAGEMENT No Pain, Much Gain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level I Gina M. Carbonara Baugh, PharmD CASE SUMMARY A 58-year-old man presents to the Family Practice Center with a 2-day history of nausea, vomiting, and epigastric and RUQ abdominal pain. The patient states that the pain began several hours after eating a large meal. The pain intensified and was associated with escalating nausea and vomiting. The vomiting finally ceased but the abdominal pain has persisted and is made worse after meals. The pain is now dull, constant, and “bores” to his back. Lying up in bed or sitting in a chair seems to relieve some of the pain. Since the initial episode, his appetite has decreased and he has been avoiding fried or fatty foods. He denies any change in stool color or consistency. The clinical information provided suggests a diagnosis of acute alcoholic pancreatitis. Opioid therapy is indicated for the treatment of moderate-to-severe pain for this patient. The patient’s acute pain must be managed appropriately with frequent assessment for effectiveness and the presence of side effects. Because this patient reports an allergy to morphine which appears to be a true type I hypersensitivity type reaction, this drug is contraindicated for the management of his pain. QUESTIONS Problem Identification 1.a. Create a list of the patient’s drug therapy problems. • Acute epigastric abdominal pain requiring drug therapy. • Hepatic disease (elevated liver function tests) possibly resulting from alcohol abuse. • Hypertension inadequately controlled on a diuretic and angiotensin II receptor blocker (acute pain may elevate blood pressure); further evaluation is needed to assess adequacy of treatment regimen. • Hydrochlorothiazide may precipitate acute pancreatitis. • Hypokalemia secondary to hydrochlorothiazide, which could result in acute abdominal discomfort. • Type 2 diabetes inadequately controlled with multiple medications (glipizide and exenatide) and basal insulin glargine; further evaluation is needed to assess the adequacy of the treatment regimen. • Exenatide has been linked to acute pancreatitis, which can present with abdominal pain. • Dyslipidemia managed with atorvastatin that requires further evaluation to assess adequacy of treatment regimen. Hypertriglyceridemia may precipitate acute pancreatitis. 1.b. What clinical information indicates the presence of an acute pain syndrome? • Abrupt onset of acute abdominal pain after a high-fat meal. • Pain reported as 6/10 on physical exam. • Hypertension (BP 160/95 mm Hg). 1.c. What is the pathophysiologic basis for the development of acute pain? • There are various types of pain, including nociceptive pain and neuropathic pain. Acute pain is a sensation caused by stimuli producing changes in the neural networks in the brain secondary to tissue damage that often lasts only a short time and remits once the tissue damage is repaired. Nociceptive pain can be somatic or visceral, depending on where the tissue damage has occurred.1 Pain arising from internal organs is visceral pain, and pain arising from the skin, bone, joints, or muscles is somatic pain. Visceral pain is often described as cramping and gnawing in nature and is most responsive to opioid therapy, whereas somatic pain is often localized and described as aching, squeezing, stabbing, or throbbing and is responsive to acetaminophen, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and various other treatments.1,2 • The pathophysiology of nociceptive pain can be described by the four processes of transduction, transmission, perception, and modulation.1 In acute pain, free nerve endings (nociceptors) are stimulated in response to noxious stimuli, and then the sensation is transmitted through the nerve fibers of the primary afferent system. When the transmission is through A-delta (Aδ) nerve fibers, the pain is generally sharp and localized, whereas when it is transmitted through C-afferent fibers, the pain can be described as dull and aching.2 The pain is then perceived by the brain, and finally the sensation is modulated through various processes that affect how the body responds to the pain and medications used to treat the pain. One way that pain is modulated is via the production of endogenous opioid peptides.1 In this process, endogenous opioid compounds (enkephalins, beta-endorphin) bind to opioid receptors in the central nervous system (CNS) and mediate the effect of analgesia. Neurotransmitters, such as norepinephrine and serotonin, are also involved in this complex endogenous modulation system.1 Inflammation may be part of the nociceptive pain process causing endogenous chemicals such as substance P to be released and activate other nociceptors.1 1.d.Could the patient’s problem have been caused by drug therapy? • Yes, various medications have been associated with the development of acute pancreatitis. The patient is currently taking hydrochlorothiazide, and thiazide diuretics have been associated with acute pancreatitis, although the exact mechanism is not known.3 • This patient is also currently taking exenatide. Thirty-six cases of pancreatitis were reported soon after its market appearance. There is an epidemiologic (albeit inconclusive) association between exenatide use and the development of acute pancreatitis (including hemorrhagic pancreatitis).4 Acute pancreatitis can cause a variety of GI side effects, such as nausea and vomiting, but abdominal pain of varying intensity is most common. • Atorvastatin, an HMG-CoA reductase inhibitor, has also been associated with elevated hepatic enzymes, cholestasis, jaundice, and rarely pancreatitis.5 Copyright © 2017 by McGraw-Hill Education. All rights reserved. Acute Pain Management Charles D. Ponte, BS, PharmD, BC-ADM, BCPS, CDE, CPE, FAADE, FAPhA, FASHP, FCCP, FNAP • Moderate epigastric pain and mild guarding with abdominal palpation. CHAPTER 71 71 • Dull, constant, moderate RUQ epigastric pain “boring” to his back for 2 days. 71-2 Desired Outcome SECTION 6 2.What are the goals of pharmacotherapy in this case? • Acute pain: Relieve the patient’s abdominal pain with the appropriate drug, increase his functional status, minimize adverse effects, and treat the underlying condition causing the pain. • (Presumed) acute alcoholic pancreatitis: Relieve the patient’s abdominal pain, minimize the risk of complications, and prevent further pancreatic damage. Neurologic Disorders • Hypertension: Determine the need to adjust the medication regimen based on prospective blood pressure monitoring and assessment of medication adherence. The blood pressure goal for persons with diabetes is <140/90 mm Hg.6 • Hyperglycemia: Determine the need to adjust the medication regimen based on concomitant illnesses and upon review of blood glucose records and prospective blood glucose monitoring. Rule out causes including concomitant illnesses, nonadherence to current regimen, and disease progression. Obtain A1C level if none obtained within the previous 3 months. Treat to A1C goal of <7%.6 • Dyslipidemia: Determine need to adjust current medication regimen based upon review of current lipid profile. Consider adding a fibric acid derivative. • Heartburn: Determine frequency and severity of heartburn symptoms, assess adequacy of current medication regimen with an H2-receptor antagonist, and determine need for diagnostic testing. • Hypokalemia: Initiate potassium supplementation with an appropriate oral dosage form. Goal serum potassium should be 4.0 mEq/L for persons with diabetes and/or a history of cardiovascular disease. Therapeutic Alternatives 3.a. What feasible pharmacotherapeutic alternatives are available for the treatment of acute pain? The pharmacologic treatment options for visceral pain include corticosteroids, intraspinal local anesthetic agents, NSAIDs, and opioids.2 Nonopioid agents: • Acetaminophen (APAP) has analgesic and antipyretic properties, and it is recommended for use in minor pain. It has comparable effectiveness to aspirin, but it does not have peripheral anti-inflammatory activity or effects on platelet function. Acetaminophen has fewer GI and renal adverse effects than NSAIDs. The maximum recommended daily dose for adults is 4 g. ✓Hepatic toxicity has been associated with acute acetaminophen overdose as well as with usual doses in certain highrisk conditions or situations (eg, alcohol ingestion, cachexia or malnutrition, and concomitant drugs that induce hepatic enzymes).7 • NSAIDs (aspirin, choline salicylate, diflunisal, meclofenamate, mefenamic acid, etodolac, diclofenac, ibuprofen, fenoprofen, ketoprofen, magnesium salicylate, naproxen, and ketorolac), and cyclooxygenase-II enzyme selective inhibitors (celecoxib) are recommended for mild-to-moderate acute pain. NSAIDs relieve pain by inhibiting prostaglandin synthesis. NSAIDs must be used with caution in patients who are at risk for GI bleeding (>60 years old, history of a GI event, or taking medications such as corticosteroids that may cause bleeding).2 There is the possibility of increased cardiovascular events in Copyright © 2017 by McGraw-Hill Education. All rights reserved. patients taking NSAIDs, and it has been recommended that cyclooxygenase-II enzyme inhibitors only be used when there are no other therapeutic options available, and that their dose and duration of therapy should be limited.2 Opioids: • These agents act by binding to μ, δ, and κ opioid receptors located in the central and peripheral nervous systems and block the transmission of pain and release of neurotransmitters that may be responsible for transmitting pain. Analgesia results because the perception of pain within the CNS as well as the patient’s emotional response to pain are altered, therefore modifying the sensory and affective response.8 • Opioid adverse effects include nausea, vomiting, constipation, urinary retention, sedation, altered mental status, respiratory depression, vertigo, and hypotension. Tolerance to opioidinduced side effects can be seen after a few days of administration. If the side effects do not lessen over time, adjunctive drug therapy, such as an antiemetic or stimulant, may need to be initiated. Importantly, tolerance to constipation does not occur and requires the use of routine stimulant laxatives for persons requiring chronic opioid therapy.7,9 • True type 1 hypersensitivity (anaphylactic) reactions are uncommon after administration of opioid agonists. If this does occur, an opioid from a different chemical class may be prescribed under close medical supervision. Opioid classes include the phenanthrenes (morphine-like), phenylpiperidine (meperidine-like), and diphenylheptane (methadone-like). Opioids are also commonly associated with the release of histamine resulting in itching (local or diffuse), flushing, or urticaria. If appropriate, a trial of oxymorphone or fentanyl may be an option because they have been associated with less histamine release and therefore less itching and urticaria.7 Premedication with antihistamines may also be helpful.7 • Tolerance to the analgesic effects of opioids is a common phenomenon, and its causes are complex and multifactorial. Tolerance is suspected when larger doses of an opioid are required to achieve the same level of analgesia once seen with lower doses. Physical dependence is commonly observed in patients requiring chronic opioid analgesics and is manifested by signs and symptoms of withdrawal after abrupt discontinuation or rapid dose reduction of the medication.7 • Opioid analgesics available in a parenteral form for severe pain are listed below:7 ✓Morphine is considered the prototypic opioid analgesic. The most common adverse effects include respiratory depression, nausea, vomiting, constipation, and CNS effects (somnolence, dizziness, and euphoria). Based on this patient’s allergic signs of hives and mild wheezing, morphine and drugs in the phenanthrene (morphine-like) class would not be recommended. These agents include hydromorphone and oxymorphone. ✓Hydromorphone is more potent and has a shorter duration of action than morphine, but it has a similar safety and efficacy profile. ✓Meperidine has similar efficacy to morphine but a shorter duration of action and a greater risk for adverse effects. Its use should be limited to a few days because of the risk for accumulation of a renally excreted toxic metabolite (normeperidine) that can precipitate agitation, tremors, seizures, and myoclonus. Meperidine should be avoided in patients with impaired renal function because normeperidine can accumulate. Meperidine should also be avoided in patients 71-3 ✓Methadone has a long plasma half-life and accumulates with continuous dosing, and therefore it should be used with caution in the elderly. Methadone is more often used for the treatment of chronic pain. ✓Levorphanol has a long plasma half-life that increases with continuous administration of the drug. Central analgesics: • Tramadol relieves pain by two mechanisms of action. It is a weak μ-opioid receptor agonist, and it also inhibits the reuptake of the neurotransmitters, serotonin and norepinephrine. The most common side effects are nausea, dizziness, drowsiness, and constipation.7 3.b.What economic, psychosocial, and ethical considerations are applicable to this patient? • The patient is a retired bar owner living on a farm; therefore, his income, insurance status, and accessibility to healthcare services need to be evaluated. This may impact the type of medications prescribed for the patient at the time of discharge. • Given his history of chronic alcohol abuse, the potential for opioid abuse/dependency should be evaluated prior to initiating opioid analgesics. Optimal Plan 4.a. What drug, dosage form, dose, schedule, and duration of therapy are best for this patient? • A new medication should only be initiated if intolerable side effects occur before adequate pain relief is achieved. Side effects that should be monitored include altered mental status, constipation, urinary retention, respiratory depression, somnolence, and mood changes. Due to intrapatient variability in opioid response, switching from an opioid class or to a different class all together are legitimate therapeutic strategies.7 • Previously, meperidine would have been considered a therapeutic option for acute pain relief for this patient. However, as discussed previously, significant adverse effects can occur and its contemporary use is mostly limited to the treatment/ deterrence of rigors associated with general anesthesia, blood product transfusions, and certain drugs. Outcome Evaluation 5.What clinical and laboratory parameters are necessary to evaluate the therapy for achievement of the desired therapeutic outcome and to detect or prevent adverse effects? • Monitor the patient frequently (every 30–60 minutes) at the beginning of therapy to assess analgesic efficacy and to detect any untoward effects from the drug. This will allow for therapeutic changes if needed. Importantly, monitoring (albeit somewhat less frequently) should still continue indefinitely for patients who are well controlled on a specific analgesic regimen.2 • Observe the patient’s behavioral response to pain. Specifically, observe the patient for unusual facial expressions, guarding, or rubbing of the abdomen. • Interview the patient for his self-report of the effectiveness of the pain medication. A single dimension pain instrument (eg, visual analog scale and verbal numeric scale) can be used to evaluate treatment effectiveness. Pain assessment should be an ongoing process despite adequate pain relief and a lack of adverse effects.2 • PCA may be an effective treatment option for this patient. A PCA pump is a programmable infusion pump that allows the patient to administer IV analgesics when necessary to control pain. With a PCA pump, the patient has the capability to selfadminister small bolus doses of an opioid until a subjective level of comfort is achieved. In some instances, the patient may also receive a predetermined continuous IV infusion of the drug. There are several built-in safety features associated with PCA pump technology, including predetermined bolus dose lockout times and 1- or 4-hour maximum allowable doses of the opioid.7 Patients using PCA must be monitored the same as other patients receiving strong opioid analgesics. • Complete a focused physical exam of the abdomen. Light and deep palpation of the abdomen can be useful in eliciting changes in pain and/or guarding resulting from the use of opioid analgesics. • The patient has reported an “allergy” manifested by hives and mild wheezing with previous morphine therapy. Therefore, an agent from a different opioid class should be used for this patient. Fentanyl would be the best therapeutic option for this patient because it is available for use in a PCA pump. • Monitor for adverse effects from the pain medications, such as constipation (number of stools per day), drowsiness, mood changes, and difficulty urinating.2,7 • Measure vital signs, including pulse, respiratory rate, and blood pressure to assess the degree of pain relief and to monitor for drug-related adverse effects.2 Acute pain and opioid analgesics can both be associated with changes in vital signs such as blood pressure, heart rate, and respiratory rate. Importantly, the likelihood of opioid-induced respiratory depression can be minimized with careful ongoing assessment of respiratory status including pulse oximetry. 4.b. What alternatives would be appropriate if the initial therapy fails or cannot be used? • Monitor amylase and lipase periodically since opioids can elevate serum concentrations due to their effects on the hepatobiliary system.9 Monitoring would be especially important to distinguish disease progression (eg, hepatobiliary disease and biliary colic or pancreatitis pain) from drug-induced changes. • If the patient does not obtain adequate pain relief from the initial dosing of the prescribed medication, the dose should be • Monitor electrolyte levels, specifically potassium, as hypokalemia can contribute to abdominal pain. ✓Fentanyl 10–50 mcg with a 5- to 8-minute lockout period. Copyright © 2017 by McGraw-Hill Education. All rights reserved. Acute Pain Management ✓Oxymorphone has a higher potency than morphine but has a similar safety and efficacy profile. slowly titrated upward to achieve adequate pain relief. Once the appropriate dose is determined, it should be continued with regular patient monitoring for efficacy and toxicity.2 If the higher dose causes intolerable side effects, it may be reasonable to administer a lower dose of the drug with a revised lock-out period or consider changing to another appropriate opioid. CHAPTER 71 taking monoamine oxidase inhibitors because it can cause an accumulation of serotonin leading to cardiovascular or neurological adverse effects. Meperidine was purported to have an advantage over other opioids in producing less smooth muscle spasm of the sphincter of Oddi, resulting in less pain in patients suffering from biliary colic or pancreatitis. However, evidence of its superiority in this regard over other opioids is lacking.10,11 Fentanyl is structurally related to meperidine with a higher potency and shorter duration of action. It can be administered via a patient-controlled analgesia (PCA) pump. 71-4 Patient Education SECTION 6 6.What information should be provided to the patient to enhance adherence, ensure successful therapy, and minimize adverse effects? Fentanyl: • Your doctor has written orders for you to receive an analgesic to help alleviate some of the abdominal pain that you are experiencing. Neurologic Disorders ✓Fentanyl is the medication that you will be receiving for treatment of your moderate-to-severe pain. ✓Please tell us if you have ever received fentanyl and had an adverse effect from the medication, because you report hives and mild wheezing with morphine therapy. ✓You will be receiving fentanyl by a PCA pump to achieve a rapid onset of action. You will be able to use the pump as needed to deliver a dose of medication. ✓ You may experience some side effects from this pain medication, including drowsiness, dizziness, headache, or blurred vision. Other side effects that are less common include difficulty breathing, severe rash or hives, a decrease in your heart rate, or difficulty urinating. Please talk to your nurse or physician immediately if any of these do occur. ✓Be careful sitting up or standing when you first begin using this medication because of the potential for dizziness or lightheadedness. ✓You may also sleep more for the next few days because this medication does cause some drowsiness, and you may have not been sleeping well for the past few days because of the pain. ✓ Fentanyl often causes constipation, so a stool softener and/or laxative will be added to your drug regimen. ✓Fentanyl may also cause a dry mouth. You may suck on ice chips, sugarless candy, or sip water while receiving this medication if this is troublesome. ✓Please tell us if your pain does not get better, if it worsens, or if you experience any adverse effects. ✓Psychological dependency to opioids for the treatment of acute pain is rare, but the potential for physical dependency should be considered. ✓Physical dependence is something that occurs when a patient takes a drug such as morphine to help control pain for a number of days. Your body gets used to the drug, and if it is abruptly stopped, you may experience physical withdrawal.7 Symptoms might include runny nose, tearing, sweating, abdominal pain, difficulty sleeping, and diarrhea. ✓When your pain is controlled and you no longer need your medication, it is important that we discontinue the fentanyl very slowly. This will prevent side effects such as a withdrawal reaction. ■■ FOLLOW-UP QUESTIONS 1.What is the most likely cause of this patient’s inadequate pain control? • The dose of fentanyl may be inadequate for the level of pain that the patient is experiencing. The lock-out period for the PCA pump may also be too long. Importantly, because the medication is only being delivered in a bolus fashion without a basal dose, the patient may be hesitant to dose himself for a variety of reasons (eg, fear of psychological dependency or Copyright © 2017 by McGraw-Hill Education. All rights reserved. adverse effects, stoicism, and hesitancy to bother the nursing staff). • The patient may have experienced inadequate (or worsening) pain control due to the potential for opioids to induce spasm of the sphincter of Oddi.9 The patient’s complaint of urinary hesitancy may result from the opioid effects on the tone of the vesical sphincter of the bladder complicated by the physical finding of an enlarged prostate gland. 2.What are the revised management goals for this patient? • Eliminate or significantly reduce the patient’s acute pain based on patient self-reports using a single-dimension pain instrument, physical exam, and clinical parameters. • Eliminate or reduce the patient’s nausea by switching to an alternative strong opioid analgesic or coadminister an appropriate antiemetic agent. • Improve the patient’s urinary difficulties and continue to monitor urine output. Switching to another opioid would offer no advantage since all opioids can potentially affect bladder function. However, tolerance may develop over time. A Foley catheter may be required temporarily if opioid analgesics are continued indefinitely. The patient could be cautiously switched to an alternative strong nonopioid analgesic (eg, parenteral ketorolac) with careful monitoring for efficacy and tolerability. 3.What therapeutic alternatives would be appropriate for this patient? • Because the patient did report an allergy of hives and mild wheezing to morphine therapy, it is recommended to use medications in a different opioid class. Therefore, a medication in the diphenylheptane class may be an option. Oral methadone may be initiated if treatment with fentanyl is inadequate. 4.What clinical and laboratory parameters are necessary to evaluate the therapy for achievement of the desired therapeutic outcome and to detect or prevent adverse effects? • Monitor the efficacy of the new medication regimen: ✓Interview the patient and ask him to rate his pain using a single-dimension visual analog pain scale once the PCA is initiated. ✓Perform a physical exam focusing on the abdomen. ✓Continue to monitor for adverse effects from the opioid analgesic. ✓Continue monitoring urinary output for urinary retention due to the opioid analgesic. Therapy may need to be changed based on these results. ✓Continue to monitor the patient’s vital signs, including respiratory rate, blood pressure, and heart rate. This will also help to evaluate the tolerability and effectiveness of the pain medication. ✓Continue to monitor for nausea, vomiting, drowsiness, mood changes, and other opioid adverse effects. Monitoring for constipation should be ongoing and appropriate therapy with a stool softer and/or a stimulant/polyethylene glycol laxative should be initiated. ✓Monitor lipase and amylase levels due to possible increases resulting from the administration of opioids. 5.What is the role of the pharmacist in the management of patients with acute pain? • The pharmacist should assist in the selection of the most appropriate medication for patients with acute pain. This should be based, in part, on pharmacokinetic or pharmacodynamic 71-5 • The pharmacist is also responsible for appropriate medication dispensing, which includes interpreting the orders from the prescriber; providing the correct drug, strength, and dose of the medication; and communicating the directions for the proper administration of the medication. The pharmacist may also need to assist with drug preparation and evaluate the stability and proper storage of the medication. • The pharmacist should also monitor for adverse effects secondary to drug therapy. This may include providing pharmacologic and nonpharmacologic recommendations for the treatment of the adverse effects. An example would be recommending an appropriate bowel regimen to avoid opioidinduced constipation. • The pharmacist should also provide patient education regarding the proper administration of a specific drug regimen. • The pharmacist should also provide patient education regarding lifestyle modifications that may impact specific drug regimens and/or comorbid disease states. 1. Steeds CE. The anatomy and physiology of pain. Surgery 2013;31:49–53. 2. Fink WA. The pathophysiology of acute pain. Emerg Med Clin North Am 2005;23:277–284. 3. Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: an update. J Clin Gastroenterol 2005;39:709–716. 4. Li L, Shen J, Bala MM, et al. Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies. BMJ 2014;348:g2366. 5. Etienne D, Reda Y. Statins and their role in acute pancreatitis: case report and literature review. World J Gastrointest Pharmacol Ther 2014;5:191–195. 6.American Diabetes Association. Standards of Medical Care in Diabetes–2016. Diabetes Care 2016;39(S1):S1–S112. 7. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, 6th ed. Glenview, IL, American Pain Society, 2008. 8. Ghelardini C, Di Cesare Mannelli L, Bianchi E. The pharmacological basis of opioids. Clin Cases Miner Bone Metab 2015;12:219–221. 9. Prommer EE. Pharmacological Management of Cancer-Related Pain. Cancer Control 2015;22:412–425. 10. Thompson DR. Narcotic analgesic effects on the sphincter of Oddi: a review of the data and therapeutic implications in treating pancreatitis. Am J Gastroenterol 2001;96:1266–1272. 11. Spiegel B. Meperidine or morphine in acute pancreatitis? Am Fam Physician 2001;64:219–220. Copyright © 2017 by McGraw-Hill Education. All rights reserved. Acute Pain Management • The pharmacist can assist with monitoring for the effectiveness of the medication regimen based on patient self-reports of pain, using an appropriate pain instrument. The pharmacist should also monitor the amount of scheduled or “as-needed” medications requested by the patient to determine if the appropriate dose has been prescribed and make recommendations for changes, if appropriate, to the prescriber based on this information. REFERENCES CHAPTER 71 factors, patient-specific factors, formulary considerations (inpatient and outpatient), and cost concerns.