Acute Pain
Analgesic Goals
1. E.T. is a 36-year-old woman recovering from the surgical repair of a left tibia fracture following a motor vehicle accident. She is otherwise healthy, with no other medical conditions. Her medication history reveals no drug allergies or history of recreational drug use, and occasional use of oral ibuprofen 400 mg every 6 hours as needed for menstrual cramps. Postoperatively, E.T. received acetaminophen 325 mg with codeine 30 mg, two tablets orally every 3 hours for pain; however, this analgesic regimen was inadequate for controlling her pain. After extensive complaints, E.T.'s analgesic medication was replaced with two tablets of hydrocodone 5 mg with acetaminophen 500 mg every 4 hours. Despite these changes, E.T. continues to complain of pain. Vital signs indicate the following: respiratory rate, 24 breaths/minute; heart rate, 110 beats/minute; blood pressure (BP), 140/85 mmHg. She rates the intensity of her pain as 8 on a 10-point scale. What is your assessment of E.T.'s pain and what are reasonable analgesia goals for E.T.?
The current analgesic regimen has not provided E.T. with adequate pain relief based on her pain evaluation rating of 8 on a 10-point scale. Physiologic responses to pain include autonomic findings, such as increased respirations, heart rate, and BP. The apparent analgesic failure in E.T. can be attributed to several factors. First, the choice of medication may not be effective for her level of pain, or she may simply require more analgesics than anticipated. Standard analgesic dosage recommendations are only conservative estimates of average initial doses. Ultimately, analgesic dosing must be tailored to the specific needs of the patient. Patients with compromised metabolic function may need smaller doses, whereas patients with extensive injuries may require larger doses. Acute pain always should be aggressively treated.
After an initial analgesic has been administered, the patient should be assessed frequently, and doses should be adjusted quickly in response to inadequate pain control or excessive sedation. The dose of an analgesic should be modified before a patient feels the need to express significant discomfort from pain. E.T.'s complaints of significant pain intensity may also be influenced by anxiety that commonly accompanies inadequate pain relief. E.T.'s possible anxiety over the current surgical outcome could intensify her pain because pain and anxiety are reinforcing phenomena. For most patients, pain is synonymous with injury. When an injury has been repaired and the patient continues to experience pain, the patient's anxiety and fear can intensify pain sensations. The use of pain distress scales, as shown in Figure 8-3, may be more useful for evaluating pain in patients with significant anxiety.24 The use of distraction or relaxation techniques can also help make E.T. more comfortable.
The goal for managing acute pain is to keep the patient as comfortable as possible while minimizing possible untoward adverse effects from the analgesic. It is important for the clinician to discuss the pain management plan with the patient, establish goals of therapy, address patient concerns, and evaluate patient understanding. Use of pain rating scales, as shown in Figure 8-2, should be reviewed with the patient, and a pain rating goal that is acceptable to the patient should be determined. The importance of factual reporting should be emphasized to the patient. This helps eliminate behaviors of stoicism or exaggeration.24 Appropriate goals for E.T. would be a pain rating of <4 of 10-point scale, a return of vital signs toward her baseline values, and reduced anxiety. Only appropriate analgesic selection, careful follow-up evaluations, and rational analgesic dosage adjustments can accomplish these goals.
Combination Analgesics
2. Is the choice of acetaminophen with hydrocodone appropriate for E.T.?
Acetaminophen and opioid analgesics provide pain relief by different mechanisms of action and it is reasonable to use both for their additive or synergistic effects when managing pain. Acetaminophen with hydrocodone is a fixed-dose combination, however, and these combination drug formulations decrease dosing flexibility and frequently lead to unintended toxic side effects. The combination of acetaminophen 500 mg and hydrocodone 5 mg given two tablets every 4 hours can result in the patient receiving 6 g of acetaminophen in a 24-hour period. Chronic administration of acetaminophen in doses exceeding 5 g/day has been associated with hepatic enzyme changes. Short-term use of 6 g of acetaminophen daily for a few days in patients without risk factors (e.g., alcoholism, malnutrition, concurrent administration of hepatic-enzyme inducers) is usually safe.55 If patients need to use acetaminophen-containing combination analgesics frequently throughout the day, then it is important to consider products that contain lower amounts of acetaminophen. Several NSAIDs also have been associated with hepatotoxicity.56 Acetaminophen and NSAIDs should be avoided in patients who have severe liver disease, as evidenced by elevated liver transaminases, a low serum albumin, or a prolonged prothrombin time. If acetaminophen is to be used at all in patients with impaired hepatic function, doses must be limited to <2 to 3 g/24 hours.
E.T. should have been initiated on a more potent analgesic to control her pain. Analgesic combinations of acetaminophen with either codeine 30 mg or hydrocodone 5 mg are effective for mild to moderate pain (e.g., 5 on a 10-point scale), but these combinations are less than adequate for moderately severe to severe pain, unless the opioid dose is increased. Because E.T.'s pain has not been successfully controlled with either acetaminophen with codeine or acetaminophen with hydrocodone, it would be reasonable to start her on oral morphine 30 mg every 4 hours. If she is unable to tolerate oral medications following surgery, then morphine 4 mg IV every 2 to 3 hours can be used instead. Although the use of IM administration is often prescribed, many clinicians discourage the use of this route because of erratic or unpredictable absorption with some opiates and additional pain caused from the injection itself.
After initiation of morphine, E.T. should be evaluated in a few hours for pain relief and adverse effects. The dose or dosing interval should be adjusted if either is found to be inadequate. Sometimes, changing to an alternative opiate may be indicated if analgesia is still inadequate or unwanted side effects are experienced. Until an individual's response to a particular opioid is known, it is wise for the clinician to formulate a back-up plan with an alternative opiate regimen.
An NSAID such as ibuprofen or naproxen also may be used adjunctively for E.T.'s pain. Although an NSAID alone usually is inadequate for controlling moderate to severe pain, they have additive analgesic effects when combined with opiates. In E.T., the prescriber should also consider the risk of bleeding after surgical intervention owing to the antiplatelet effect of NSAIDs. The cyclooxygenase-2 (COX-2) NSAIDs appear to have minimal antiplatelet effects, and may be considered if surgery or trauma presents a high risk of bleeding.
Equianalgesic Dosing of Opioid Analgesics
3. How should E.T.'s hydrocodone dose be converted to oral morphine?
Hydrocodone 20 mg orally is approximately equal to morphine 30 mg (Table 8-3). Therefore, 10 mg of hydrocodone as originally ordered for E.T. is equal to an oral morphine dose of approximately 15 mg, or 5 mg of morphine by injection. This dose of morphine would likely be inadequate for E.T. because her pain is not controlled by this equivalent dose. Thus, E.T. should be started on oral morphine 30 mg every 4 hours around-the-clock for the first 24 hours, then changed to as-needed dosing afterward. Inflammation caused by trauma often peaks around 48 to 72 hours following the inciting event, so pain is expected to decrease dramatically after this period.
Managing Side Effects of Opioid Analgesics
4. E.T. complains of itching after three doses of morphine, but shows no sign of rash. What can be done to alleviate the problem?
Opioid analgesics infrequently cause pruritic rashes due to true allergic-type reactions. In contrast, when administered parentally they commonly stimulate local histamine release from mast cells and cause a local wheal, burning, itching, and erythema at the site of injection. Similarly, systemic release of histamine after both oral and parenteral administration of opioids can produce either localized or generalized flushing and itching. Although histamine related reactions occur frequently and may be confused with an allergic reaction, true opioid allergies are infrequent. When they do occur, they are IgE-dependent.57 Coadministration of diphenhydramine (Benadryl) or hydroxyzine (Vistaril) prevents histamine-induced itching and also provides antianxiety effects that may add to morphine's analgesic benefit.
Chemically, there are three distinct structural categories of opioids: the phenanthrenes (morphine, codeine, hydrocodone, hydromorphone, dihydrocodeine, oxycodone, oxymorphone, levorphanol, nalbuphine, butorphanol, dezocine, and dihydrocodeine), the phenylpiperidines (meperidine, fentanyl, alfentanil, sufentanil, and remifentanil), and the phenylheptanones or diphenylheptanes (methadone, levomethadyl, and the weak analgesic, propoxyphene). Allergic reactions may cross-manifest within the same chemical structural class, but are less likely between classes. Thus, in patients with true allergic reactions, treatment can be instituted with a product from one of the other chemical groups. For example, if E.T. was allergic to morphine, she could be switched to fentanyl.
5. What other adverse effects from morphine should be monitored for in E.T.? What preventive measures should be considered?
The most common side effects reported with the use of opioid analgesics are nausea, vomiting, itching, and constipation. These are expected untoward opioid effects and, with some care, they can be managed or minimized. These first three symptoms of nausea, vomiting, and itching can all be minimized by antihistamines, such as diphenhydramine or hydroxyzine 25 to 50 mg orally every 6 hours as needed. If drowsiness from the antihistamine is excessive when used in combination with the opioid, a nonsedating antihistamine such as fexofenadine can be substituted. Persistent and more problematic symptoms may require switching to an alternative opioid analgesic.
The best method for treating opioid-induced constipation is prevention. Postsurgical patients are especially susceptible to this effect because their GI motility is already slowed from decreased physical activity and from anesthetic agents received during surgery. Morphine and other opioids suppress the propulsive peristaltic action of the colon, increase colonic and anal sphincter tone, and reduce the reflex relaxation response to rectal distention. These actions, combined with decreased normal sensory stimuli for defecation because of their CNS-depressant actions, contribute to opioid-induced constipation. Stool softeners are effective in keeping the bowel contents moist, but do not stimulate bowel peristaltic propulsion. Only the stimulant laxatives and prokinetic agents can increase bowel propulsive activity. When opioid analgesics are initiated, a stimulant laxative plus stool softener should also be given. E.T. will be receiving morphine orally around the clock and would probably benefit from two tablets of senna 8.6 mg daily in combination with docusate sodium 200 mg twice daily. If constipation persists, osmotic laxatives, such as lactulose or sodium phosphate enema, may be added to draw water into the lumen of the bowel, which would cause distention and peristalsis.
Postoperative ileus frequently is exacerbated by opioid analgesics, but opioids rarely produce ileus or bowel obstruction alone without other underlying physiologic causes. Oral naloxone 0.4 to 1.2 mg every 6 hours has been used with some success in preventing opioid-induced constipation. Unlike parenteral naloxone, oral naloxone is poorly absorbed systemically (25%) and, therefore, will not interfere with analgesic effect unless doses are high.58,59 An oral naloxone formulation is not yet commercially available, but the parenteral preparation can be administered orally if needed. The oral naloxone requirement rarely exceeds 2.4 mg every 6 hours. At higher dosages, systemic antagonist effects can occur, resulting in decreased analgesia in addition to the local intestinal effects. Other opioid antagonists, such as methylnaltrexone, are currently being investigated and may provide an alternative to oral naloxone.60
6. On the third day of her morphine treatment, E.T. appears agitated. Could her agitation be attributed to her morphine?
Although opioids are CNS depressants, they can cause CNS excitation, especially if the patient receives large doses for a prolonged period. Anxiety, agitation, irritability, motor restlessness, tremors, involuntary twitching, and myoclonic seizures have been associated with meperidine, morphine, and hydromorphone, but not methadone, although methadone may rarely cause myoclonus. For meperidine and morphine, the CNS toxicity correlates to accumulation of their active metabolites, normeperidine and morphine-6-glucuronide, respectively. Because both of these metabolites are cleared renally, patients with renal insufficiency are at greatest risk, but toxicity can also occur when high doses are administered frequently in patients with normal renal function.59,61 With meperidine, the problem is compounded by the 17-hour half-life of normeperidine. In patients with normal renal function, avoiding doses in excess of 60 mg/hour of meperidine, 100 mg/hour of morphine, or 40 mg/hour of hydromorphone minimizes CNS toxicity.
The treatment of opioid-induced CNS irritability should include discontinuation of the opioid analgesic and treatment with a benzodiazepine. Myoclonic seizures resulting from meperidine administration are sometimes preceded by involuntary twitching in the extremities and can be averted by discontinuing the meperidine. Seizures induced by meperidine are resistant to naloxone, but respond to anticonvulsants such as phenytoin or diazepam. Because E.T. has normal renal function and her morphine dose is not excessive, it is unlikely that she is suffering from morphine-induced CNS effects. It is more likely that she is starting to recover from her surgery and is anxious from her environment. Nevertheless, it may be time to start reducing her morphine dose if her pain is well controlled.
Ketorolac
7. Could parenteral ketorolac (Toradol) be given to E.T. instead of the morphine?
For patients such as E.T. with acute severe pain, an opioid such as oral or parenteral morphine or hydromorphone should be the first-line agent for pain management. As E.T.'s pain severity decreases, however, an NSAID may be considered for treating mild to moderate pain.
Because it is the only available injectable NSAID in the United States, ketorolac is sometimes used as an alternative to opioids. Although ketorolac is indicated for the short-term management of moderate to severe pain, it should not be substituted for appropriate opioid analgesics for the management of acute postoperative pain.62,63 Ketorolac is most beneficial in postoperative pain if it is used in combination with the opioids instead of as monotherapy. Parenteral formulations of NSAIDs are no more effective than oral formulations given in equivalent doses (e.g., ibuprofen 600 mg orally every 6 hours is equally as effective as 15 to 30 mg parenteral ketorolac).64 Ketorolac also has been associated with several cases of serious postsurgical bleeding. Although ketorolac could be effective in relieving E.T.'s pain, it is no more effective than morphine. Patients receiving ketorolac should be monitored for typical NSAID side effects, especially postsurgical bleeding.
The NSAIDs cause sodium retention and can also block prostaglandin-induced vasodilation in patients with compromised renal blood flow. Thus, NSAIDs should be used with caution in patients with heart failure, hypovolemia, dehydration or any other conditions that compromise renal blood flow and increase the risk of developing renal toxicity.
Nonsteroidal Anti-Inflammatory Drug Selection
8. Two days later, E.T. is ready to be discharged from the hospital. Although her pain is much improved, she still has mild to moderate intermittent pain. The pain management team is planning to send her home with an NSAID to treat her pain. Is any one NSAID analgesic superior to the others?
P.8p15
In all probability, all NSAIDs, not just those with an approved indication for the treatment of mild to moderate pain, have analgesic properties. The superiority of any particular NSAID for a particular patient cannot be predicted, and no one NSAID has been demonstrated to have superior analgesia over any other. Nevertheless, patients who fail to benefit from one NSAID can respond to a different NSAID. Therefore, an NSAID should be selected based on the patient's previous history of response, efficacy, safety, and cost. Ibuprofen and other proprionic acids have a long history of safety and are available as less costly generic products. (See Chapter 43, Rheumatic Disorders, for a more detailed discussion of the clinical use of NSAIDs.)
When selecting one of these agents, the clinician must be aware of the considerable risk of systemic side effects. Although GI side effects are the most common, NSAIDs have caused undesirable nervous system, otic, ocular, hematologic, renal, hepatic, and cardiovascular adverse effects.
Several large randomized, controlled trials prompted the U.S. Food and Drug Administration (FDA) in 2004 to withdraw rofecoxib, a selective COX-2 inhibitor, from the market because of increased cardiovascular risk associated with a prolonged period of use. At the same time, questions were also raised about the safety of nonselective NSAIDs. When compared with the selective COX-2 inhibitor, celecoxib, naproxen was linked to increased risk for cardiovascular events after approximately 3 years of therapy. This emerging knowledge, on a previously unrecognized problem, prompted the FDA to emphasize a warning for all NSAIDs regarding an increased risk for cardiovascular events. Until further data are available, these drugs should be initiated at the lowest effective dose for the shortest period of time.65
9. If E.T. had a history of asthma, would an NSAID be safe to use?
Aspirin and essentially all other NSAIDs can induce bronchospasm and other allergic manifestations in patients with a history of asthma, allergic rhinitis, and nasal polyps. An asthma history alone is not a reason to withhold an NSAID. If, however, a patient describes an asthma-like response (shortness or breath, wheezing, cough, laryngospasm) following aspirin or other NSAID ingestion, no drugs from this class should be used in the future.
The risk of using aspirin or other NSAID in patients with chronic bronchitis, emphysema, or in asthmatics without nasal polyps or history of drug-induced bronchospasm is less clear. If E.T. had a history of asthma, then an NSAID should be used cautiously.64,66 Acetaminophen does not induce bronchospasm and is safe to give to patients with obstructive airways disease, including a history of NSAID induced asthma.
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