Cough Suppresants
Codeine
Hydrocodone
As an analgesic and antipyretic, acetaminophen inhibits cyclooxygenase (COX)
Has some minor drug interactions (eg, warfarin), it remains the safest analgesic medication compared to traditional NSAIDs and aspirin.
Acetaminophen overdose can result in irreversible hepatic necrosis. A hepatotoxic metabolite, generated by oxidative metabolism in the liver is responsible for hepatic necrosis. Therefore, the maximum daily dose should never exceed 4000 mg/day.
Particularly effective for headache and musculoskeletal pain.
2. NSAIDS (Cyclooxygenase Inhibitors)
COX inhibitors are absorbed well from the gastrointestinal tract and, with occasional use, have only minimal side effects. With chronic use, gastric irritation is a common side effect of aspirin and NSAIDs and is the problem that most frequently limits the dose that can be given. Gastric irritation is most severe with aspirin, which may cause erosion and ulceration of the gastric mucosa leading to bleeding or perforation. Because aspirin irreversibly acetylates platelet cyclooxygenase and thereby interferes with coagulation of the blood, gastrointestinal bleeding is a particular risk. Older age and history of gastrointestinal disease increase the risks of aspirin and NSAIDs. In addition to the well-known gastrointestinal toxicity of NSAIDs, nephrotoxicity is a significant problem for patients using these drugs on a chronic basis. Patients at risk for renal insufficiency, particularly those with significant contraction of their intravascular volume as occurs with chronic diuretic use or acute hypovolemia, should be monitored closely. NSAIDs can also increase blood pressure in some individuals. Long-term treatment with NSAIDs requires regular blood pressure monitoring and treatment if necessary. Although toxic to the liver when taken in high doses, acetaminophen rarely produces gastric irritation and does not interfere with platelet function.
The introduction of parenteral forms of NSAIDs, ketorolac anddiclofenac, extends the usefulness of this class of compounds in the management of acute severe pain. Both agents are sufficiently potent and rapid in onset to supplant opioids for many patients with acute severe headache and musculoskeletal pain.
There are two major classes of COX: COX-1 is constitutively expressed, and COX-2 is induced in the inflammatory state. COX-2–selective drugs have similar analgesic potency and produce less gastric irritation than the nonselective COX inhibitors. The use of COX-2–selective drugs does not appear to lower the risk of nephrotoxicity compared to nonselective NSAIDs. On the other hand, COX-2–selective drugs offer a significant benefit in the management of acute postoperative pain because they do not affect blood coagulation. Nonselective COX inhibitors are usually contraindicated postoperatively because they impair platelet-mediated blood clotting and are thus associated with increased bleeding at the operative site. COX-2 inhibitors, including celecoxib (Celebrex), are associated with increased cardiovascular risk. It appears that this is a class effect of NSAIDs, excluding aspirin. These drugs are contraindicated in patients in the immediate period after coronary artery bypass surgery and should be used with caution in elderly patients and those with a history of or significant risk factors for cardiovascular disease.
| Generic Name | Dose, mg | Interval | Comments | |||||
| Nonnarcotic analgesics: usual doses and intervals | ||||||||
| Acetaminophen | 650 PO | q4h | Side effects uncommon | |||||
| Ibuprofen | 400 PO | q4–6h | Available without prescription | |||||
| Naproxen | 250–500 PO | q12h | Delayed effects may be due to long half-life | |||||
| Fenoprofen | 200 PO | q4–6h | Contraindicated in renal disease | |||||
| Indomethacin | 25–50 PO | q8h | Gastrointestinal side effects common | |||||
| Ketorolac | 15–60 IM/IV | q4–6h | Available for parenteral use | |||||
| Celecoxib | 100–200 PO | q12–24h | Useful for arthritis | |||||
2. Nonsteroidal Anti-Inflammatory Drugs
NSAIDs have analgesic activity both peripherally and centrally. They are potent inhibitors of prostaglandin synthesis, which have effects on inflammation, pain receptors, and nerve conduction and may have central effects as well. There are two major NSAID-sensitive cyclooxygenase enzymes (COX-1 and COX-2) synthesized in a variety of organs. COX-1 is present in most organ systems and plays a role in normal organ function such as gastric mucosal blood flow and barrier function, renal blood flow, hepatic blood flow, and platelet aggregation. COX-2, normally present in lower concentrations, is an inducible enzyme in response to injury or inflammation. Selective inhibition of COX-2 gives rise to analgesic and anti-inflammatory activity with less organ toxicity compared to the nonselective inhibition of both enzymes. Clinical trials have found COX-2 inhibitors to be similarly effective to traditional NSAIDs in terms of peak pain relief and total pain relief and in reducing joint inflammation in patients with arthritis. Safety profiles of these agents have shown a 50% reduction of gastrointestinal (GI) injury when used alone, but little data are available to support additional GI injury with concomitant use of proton pump inhibitors or misoprostol. Thus, patients at risk of cardiovascular events who are taking a COX-2–specific NSAID should also consider low-dose aspirin to offset this effect. Unfortunately, the COX-2 drugs remain expensive and the cost-benefit ratio remains controversial.
Nonspecific inhibitors of COX enzymes (most older NSAIDs) are still appropriate for short-term use in inflammatory arthritic conditions such as gout, calcium pyrophosphate arthropathy, acute flares of rheumatoid arthritis, and other inflammatory rheumatic conditions. They have also been reported to relieve the pain of headache, menstrual cramps, and other mild-to-moderate pain syndromes. These drugs can be used alone for mild-to-moderate pain or in combination with opioids for more severe pain. They have the advantage of being nonhabit forming. Individual drugs in this class vary widely with respect to anti-inflammatory activity, potency, analgesic properties, metabolism, excretion, and side effect profiles. Moreover, failure of response to one NSAID may not predict the response to another. A disadvantage of NSAIDs (including COX-2–specific inhibitors) is that these all demonstrate a ceiling effect, that is, a level at which increase in dose results in no further increase in analgesia. A large number of NSAIDs are now available; however, there is no evidence to support a particular compound as the NSAID of choice. Several compounds are available over the counter without a prescription. Table 56-4 lists COX-2 and other selected NSAIDs for pain.
Parenteral NSAIDs: Ketorolac and diclofenac are sufficiently potent and rapid in onset to supplant opioids for many patients with acute severe pain.Narcotic analgesics in oral or parenteral form can be used for more severe pain. The opioid antagonist naloxone should be readily available when narcotics are used in high doses or in unstable pts. Opioids produce analgesia by actions in the CNS. They activate pain-inhibitory neurons and directly inhibit pain-transmission neurons. Most of the commercially available opioid analgesics act at the same opioid receptor (μ-receptor), differing mainly in potency, speed of onset, duration of action, and optimal route of administration. Some side effects are due to accumulation of nonopioid metabolites that are unique to individual drugs. One striking example of this is normeperidine, a metabolite of meperidine. At higher doses of meperidine, typically greater than 1 g/d, accumulation of normeperidine can produce hyperexcitability and seizures that are not reversible with naloxone. Normeperidine accumulation is increased in patients with renal failure.
Of all analgesics, they have the broadest range of efficacy and provide the most reliable and effective method for rapid pain relief. Although side effects are common, most are reversible: nausea, vomiting, pruritus, and constipation are the most frequent and bothersome side effects.
Respiratory depression is uncommon at standard analgesic doses, but can be life-threatening. Opioid-related side effects can be reversed rapidly with the narcotic antagonist naloxone.
Generic Name Parenteral Dose, mg PO Dose, mg Comments Narcotic analgesics: usual doses and intervals Codeine 30–60 q4h 30–60 q4h Nausea common Oxycodone — 5–10 q4–6h Usually available with acetaminophen or aspirin Morphine 5 q4h 30 q4h Morphine sustained release — 15–60 bid to tid Oral slow-release preparation Hydromorphone 1–2 q4h 2–4 q4h Shorter acting than morphine sulfate Levorphanol 2 q6–8h 4 q6–8h Longer acting than morphine sulfate; absorbed well PO Methadone 5–10 q6–8h 5–20 q6–8h Delayed sedation due to long half-life; therapy should not be initiated with >40 mg/d, and dose escalation should be made no more frequently than every 3 days Meperidine 50–100 q3–4h 300 q4h Poorly absorbed PO; normeperidine is a toxic metabolite; routine use of this agent is not recommended Butorphanol — 1–2 q4h Intranasal spray Fentanyl
Buprenorphine
Buprenorphine
25–100 μg/h
5–20 μg/h
0.3 q6–8h
— 72-h transdermal patch
7-day transdermal patch
Parenteral administration
Tramadol — 50–100 q4–6h Mixed opioid/adrenergic action Generic Name Uptake Blockade Sedative Potency Anticholinergic Potency Orthostatic Hypotension Cardiac Arrhythmia Average Dose, mg/d Range, mg/d 5-HT NE Antidepressantsa Doxepin ++ + High Moderate Moderate Less 200 75–400 Amitriptyline ++++ ++ High Highest Moderate Yes 150 25–300 Imipramine ++++ ++ Moderate Moderate High Yes 200 75–400 Nortriptyline +++ ++ Moderate Moderate Low Yes 100 40–150 Desipramine +++ ++++ Low Low Low Yes 150 50–300 Venlafaxine +++ ++ Low None None No 150 75–400 Duloxetine +++ +++ Low None None No 40 30–60 Generic Name PO Dose, mg Interval Generic Name PO Dose, mg Interval Anticonvulsants and antiarrhythmicsa Phenytoin 300 daily/qhs Clonazepam 1 q6h Carbamazepine 200–300 q6h Gabapentinb 600–1200 q8h Oxcarbazepine 300 bid Pregabalin 150–600 bid aAntidepressants, anticonvulsants, and antiarrhythmics have not been approved by the U.S. Food and Drug Administration (FDA) for the treatment of pain.
Opioid analgesics work by binding to receptors in the spinal cord and brain. They interfere with pain transmission (narcotics), or enhance descending modulation.
There are four types of opioid receptors: three classic families (delta, kappa, and mu, each with identified subtypes) and nociceptin, a receptor with significant structural homology. These receptors are found in the brain, spinal cord, and GI tract where their physiologic function is to interact with endogenous dynorphins, enkephalins, endomorphins, endorphins, and nociceptin. Opioid analgesics interact with these receptors in varying degrees, accounting for the difference in desired and adverse effects among the drugs in this class. Stimulation of the mu-1 (μ1) receptor produces supraspinal analgesia. Stimulation of the mu-2 (μ2) receptor results in euphoria, miosis, respiratory depression, and depressed GI motility. Stimulation of the delta (δ) receptor produces analgesia, but less than the μ1 receptor, and also exerts an antidepressant effect. Stimulation of the kappa (κ) receptor produces dysphoria, along with dissociation, delirium, and diuresis by inhibiting antidiuretic hormone release.
Anticonvulsants (gabapentin, carbamazepine) may be effective for aberrant pain sensations arising from peripheral nerve injury. or enhancing descending modulation (narcotics and antidepressants).
Pt-controlled analgesia (PCA) permits infusion of a baseline dose plus self-administered boluses (activated by press of a button) as needed to control pain.
OPIOID ANALGESICS
The most rapid pain relief is obtained by intravenous administration of opioids; relief with oral administration is significantly slower. Because of the potential for respiratory depression, patients with any form of respiratory compromise must be kept under close observation following opioid administration; an oxygen-saturation monitor may be useful, but only in a setting where the monitor is under constant surveillance. Opioid-induced respiratory depression is typically accompanied by sedation and a reduction in respiratory rate. A fall in oxygen saturation represents a critical level of respiratory depression and the need for immediate intervention to prevent life-threatening hypoxemia. Ventilatory assistance should be maintained until the opioid-induced respiratory depression has resolved. The opioid antagonist naloxone should be readily available whenever opioids are used at high doses or in patients with compromised pulmonary function. Opioid effects are dose-related, and there is great variability among patients in the doses that relieve pain and produce side effects. Synergistic respiratory depression is common when opioids are administered with other CNS depressants, most commonly the benzodiazepines. Because of this, initiation of therapy requires titration to optimal dose and interval. The most important principle is to provide adequate pain relief. This requires determining whether the drug has adequately relieved the pain and frequent reassessment to determine the optimal interval for dosing. The most common error made by physicians in managing severe pain with opioids is to prescribe an inadequate dose. Because many patients are reluctant to complain, this practice leads to needless suffering. In the absence of sedation at the expected time of peak effect, a physician should not hesitate to repeat the initial dose to achieve satisfactory pain relief.
An innovative approach to the problem of achieving adequate pain relief is the use of patient-controlled analgesia (PCA). PCA uses a microprocessor-controlled infusion device that can deliver a baseline continuous dose of an opioid drug as well as preprogrammed additional doses whenever the patient pushes a button. The patient can then titrate the dose to the optimal level. This approach is used most extensively for the management of postoperative pain, but there is no reason why it should not be used for any hospitalized patient with persistent severe pain. PCA is also used for short-term home care of patients with intractable pain, such as that caused by metastatic cancer.
It is important to understand that the PCA device delivers small, repeated doses to maintain pain relief; in patients with severe pain, the pain must first be brought under control with a loading dose before transitioning to the PCA device. The bolus dose of the drug (typically 1 mg of morphine, 0.2 mg of hydromorphone, or 10 μg of fentanyl) can then be delivered repeatedly as needed. To prevent overdosing, PCA devices are programmed with a lockout period after each demand dose is delivered (5–10 min) and a limit on the total dose delivered per hour. Although some have advocated the use of a simultaneous continuous or basal infusion of the PCA drug, this increases the risk of respiratory depression and has not been shown to increase the overall efficacy of the technique.
The availability of new routes of administration has extended the usefulness of opioid analgesics. Most important is the availability of spinal administration. Opioids can be infused through a spinal catheter placed either intrathecally or epidurally. By applying opioids directly to the spinal or epidural space adjacent to the spinal cord, regional analgesia can be obtained using relatively low total doses. Indeed, the dose required to produce effective localized analgesia when usingmorphine intrathecally (0.1–0.3 mg) is a fraction of that required to produce similar analgesia when administered intravenously (5–10 mg). In this way, side effects such as sedation, nausea, and respiratory depression can be minimized. This approach has been used extensively during labor and delivery and for postoperative pain relief following surgical procedures. Continuous intrathecal delivery via implanted spinal drug-delivery systems is now commonly used, particularly for the treatment of cancer-related pain that would require sedating doses for adequate pain control if given systemically. Opioids can also be given intranasally (butorphanol), rectally, and transdermally (fentanyl and buprenorphine), or through the oral mucosa (fentanyl), thus avoiding the discomfort of frequent injections in patients who cannot be given oral medication. The fentanyl and buprenorphinetransdermal patches have the advantage of providing fairly steady plasma levels, which maximizes patient comfort.
Recent additions to the armamentarium for treating opioid-induced side effects are the peripherally acting opioid antagonists alvimopan (Entereg) and methylnaltrexone (Rellistor). Alvimopan is available as an orally administered agent that is restricted to the intestinal lumen by limited absorption; methylnaltrexone is available in a subcutaneously administered form that has virtually no penetration into the CNS. Both agents act by binding to peripheral μ-receptors, thereby inhibiting or reversing the effects of opioids at these peripheral sites. The action of both agents is restricted to receptor sites outside of the CNS; thus, these drugs can reverse the adverse effects of opioid analgesics that are mediated through their peripheral receptors without reversing their analgesic effects. Alvimopan has proven effective in lowering the duration of persistent ileus following abdominal surgery in patients receiving opioid analgesics for postoperative pain control. Methylnaltrexone has proven effective for relief of opioid-induced constipation in patients taking opioid analgesics on a chronic basis.
Opioid and COX Inhibitor CombinationsWhen used in combination, opioids and COX inhibitors have additive effects. Because a lower dose of each can be used to achieve the same degree of pain relief and their side effects are nonadditive, such combinations are used to lower the severity of dose-related side effects. However, fixed-ratio combinations of an opioid with acetaminophen carry an important risk. Dose escalation as a result of increased severity of pain or decreased opioid effect as a result of tolerance may lead to ingestion of levels of acetaminophen that are toxic to the liver. Although acetaminophen-related hepatotoxicity is uncommon, it remains a significant cause for liver failure. Thus, many practitioners have moved away from the use of opioid-acetaminophen combination analgesics to avoid the risk of excessive acetaminophen exposure as the dose of the analgesic is escalated.
It is the physician’s responsibility to provide rapid and effective pain relief.
Measures to treat pain should occur in addition to, and at the same time as, treatment of the underlying illness or injury. It is not possible to generalize the extent and quality of pain control needed for a specific patient.
For example, pain is an indicator of ongoing cardiac ischemia, and the goal should be to eliminate all pain. On the other hand, a patient with a traumatic injury may choose to endure more pain out of personal or cultural beliefs. Physicians may limit analgesics in those with head injuries to perform serial neurologic examinations. Whenever possible, medications that act on specific sites that initiate the pain signal—a mechanistic approach—are preferred to agents such as opioids that mask pain, which is a symptomatic approach. Current migraine treatment is an excellent example of the mechanistic approach; preferred treatment includes a serotonin agonist (triptan)11 or adopamine antagonist (phenothiazine),12 rather than opiates.13,14
Treatment of acute pain should not be withheld for fear of facilitating drug misuse although it is recognized that pain and addiction are not mutually exclusive.1
Document the degree of pain on initial assessment.
ED pain assessment should determine duration, location, quality, severity, and exacerbating and relieving factors. The patient's subjective reporting of pain, not the physician's impression, is the basis for pain assessment and treatment. Because pain is dynamic and changes with time, periodic pain reassessment is needed.
The primary value of pain scales is their essential role in research enabling reproducible comparisons of interventions. Some studies have suggested that the use of pain scales may actually decrease the provision of analgesics. Given the subjectivity both of pain reporting and the provider's interpretation of such reporting, the use of simple descriptors such as "a little" or "an awful lot" is equally valid in the clinical setting. What is important is that the patient's subjective reporting should be the basis for assessment and management. For most, but not all, painful conditions, the goal is to control pain to the level the patient desires. Asking if the patient requires more analgesic may even be simpler and accomplish more than using any standardized pain evaluation tool.21,22
The purpose of pain scales is to quantitate pain severity, guide the selection and administration of an analgesic agent, and reassess the pain response to determine the need for repeated doses or more effective analgesics. Several self-report instruments are valid in patients with acute pain, and some require only a verbal response (Table 35-2). Each tool has advantages and specific limitations. ED personnel in any one location should use the same tool so information collected is standardized. A value assigned by a patient is not an absolute value but rather a reference point based on past personal experience.23
Pain Scales29A
| Scale | Method | Comments |
|---|---|---|
| Adjective rating scale (Figure 35-1) | Patient rates pain by choosing from an ordered list of pain descriptors, ranging from no pain to worst possible pain, with allowance for marks between discrete labels. | Easy to administer. |
| Visual analog scale (VAS) (Figure 35-2) | Patient places a mark that best describes pain intensity along a 10-cm linear scale marked at one end with a term such as no pain and at the other end with worst imaginable pain. | Pain intensity measured in millimeters from the no-pain end. A difference of 13 mm is the minimum clinically significant change noticeable by patients, whereas an average decrease of 30 mm appears to be the minimum acceptable change for pain control.* |
| Numeric rating scale (Figure 35-3) | The patient is asked to self-report pain on a scale of 0 to 10 with descriptors. | Can be used in patients with visual, speech, or manual dexterity difficulties by using upheld fingers. Not as discriminating as the VAS. |
| 5-Point global scale | Patient rates pain as: 0 = none 1 = a little 2 = some 3 = a lot 4 = worst possible |
A decrease of 1 point is a large change; scales with more choices allow monitoring of small changes in pain and may be more sensitive to changes. |
| Verbal quantitative scale | The patient is asked to self-report pain on a scale of 0 to 10 without descriptors. |
Pain scale: Adjective rating scale.
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Pain scale: Numeric rating scale.
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PAIN SCALE PERFORMANCE IN SPECIAL PATIENT POPULATIONS
The elderly often report pain differently from younger patients because of physiologic, psychological, and cultural changes associated with aging. Visual, hearing, motor, and cognitive impairments can be barriers to effective pain assessment. Using a numerical pain scale, the elderly may also experience a decrease in the minimum clinically significant noticeable difference in acute pain over time.24,25 Family members and caregivers are often able to judge nonverbal actions of the patient as representing pain or distress, so they should be used if available to help with pain assessment in the noncommunicating elderly patient.
Trauma patients and those with acute intoxication do not perform as well on pain scales.26 Women are more likely to express pain and to actively seek treatment for pain,27,28 yet there is a tendency to underestimate and undertreat pain in women. Ethnicity of both the patient and the physician has a bearing on different cultural concepts of pain and on the characteristics of culturally appropriate pain-related behaviors.7 Translators and family members should be asked to provide assistance. There is also interplay between the ethnicity of the patient and that of the physician.7 When there are language difficulties or cross-cultural differences, the visual analog scale is the preferred pain assessment tool because it is the least affected by these factors.
Specific measures to treat pain should occur in addition to, and at the same time as, treatment of the underlying illness or injury. It is not possible to generalize the extent and quality of pain control needed for a specific patient. For example, pain is an indicator of ongoing cardiac ischemia, and the goal should be to eliminate all pain. On the other hand, a patient with a traumatic injury may choose to endure more pain out of personal or cultural beliefs. Physicians may limit analgesics in those with head injuries to perform serial neurologic examinations. Whenever possible, medications that act on specific sites that initiate the pain signal—a mechanistic approach—are preferred to agents such as opioids that mask pain, which is a symptomatic approach. Current migraine treatment is an excellent example of the mechanistic approach; preferred treatment includes a serotonin agonist (triptan)11 or a dopamine antagonist (phenothiazine),12 rather than opiates.13,14
Psychological factors such as social support, hypnotic suggestion, excitement, or distraction can significantly modulate pain's intensity or unpleasantness.In some arguments put forth in physician-assisted suicide or euthanasia debates, pain has been used as an argument to permit terminally ill patients to end their lives.
When it is acute, pain is characteristically associated with behavioral arousal and a stress response consisting of increased blood pressure, heart rate, pupil diameter, and plasma cortisol levels. In addition, local muscle contraction (e.g., limb flexion, abdominal wall rigidity) is often present.
Additionally, the latter part of the definition allows for the possibility, as in chronic pain states, that the overt tissue damage may no longer be present.
When it is acute, pain is characteristically associated with behavioral arousal and a stress response consisting of increased blood pressure, heart rate, pupil diameter, and plasma cortisol levels. In addition, local muscle contraction (e.g., limb flexion, abdominal wall rigidity) is often present.
Psychological factors such as social support, hypnotic suggestion, excitement, or distraction can significantly modulate pain's intensity or unpleasantness.[8][9]
When a painful injury or pathology is resistant to treatment and persists, when pain persists after the injury or pathology has healed, and when medical science cannot identify the cause of pain, the task of medicine is to relieve suffering. Treatment approaches to long term pain include pharmacologic measures, such as analgesics, tricyclic antidepressants and anticonvulsants, interventional procedures, physical therapy, physical exercise, application of ice and/or heat, and psychological measures, such as biofeedback and cognitive behavioral therapy.
______________________________________________
Treatment approaches to long term pain include pharmacologic measures, such as analgesics, tricyclic antidepressants and anticonvulsants, interventional procedures, physical therapy, physical exercise, application of ice and/or heat, and psychological measures, such as biofeedback and cognitive behavioral therapy.
Sometimes, treating the underlying condition does not immediately relieve pain. Furthermore, some conditions are so painful that rapid and effective analgesia is essential (e.g., the postoperative state, burns, trauma, cancer, or sickle cell crisis).
Analgesic medications are a first line of treatment in these cases.
ASPIRIN, ACETAMINOPHEN, AND NONSTEROIDAL ANTI-INFLAMMATORY AGENTS (NSAIDs)All these compounds inhibit cyclooxygenase (COX), and, except for acetaminophen, all have anti-inflammatory actions, especially at higher dosages. They are particularly effective for mild to moderate headache and for pain of musculoskeletal origin.
Because they are effective for these common types of pain and are available without prescription, COX inhibitors are by far the most commonly used analgesics. They are absorbed well from the gastrointestinal tract and, with occasional use, have only minimal side effects. With chronic use, gastric irritation is a common side effect of aspirin and NSAIDs and is the problem that most frequently limits the dose that can be given. Gastric irritation is most severe with aspirin, which may cause erosion and ulceration of the gastric mucosa leading to bleeding or perforation. Because aspirin irreversibly acetylates platelet cyclooxygenase and thereby interferes with coagulation of the blood, gastrointestinal bleeding is a particular risk. Older age and history of gastrointestinal disease increase the risks of aspirin and NSAIDs. In addition to the well-known gastrointestinal toxicity of NSAIDs, nephrotoxicity is a significant problem for patients using these drugs on a chronic basis. Patients at risk for renal insufficiency, particularly those with significant contraction of their intravascular volume as occurs with chronic diuretic use or acute hypovolemia, should be monitored closely. NSAIDs can also increase blood pressure in some individuals. Long-term treatment with NSAIDs requires regular blood pressure monitoring and treatment if necessary. Although toxic to the liver when taken in high doses, acetaminophen rarely produces gastric irritation and does not interfere with platelet function.
The introduction of parenteral forms of NSAIDs, ketorolac anddiclofenac, extends the usefulness of this class of compounds in the management of acute severe pain. Both agents are sufficiently potent and rapid in onset to supplant opioids for many patients with acute severe headache and musculoskeletal pain.
There are two major classes of COX: COX-1 is constitutively expressed, and COX-2 is induced in the inflammatory state. COX-2–selective drugs have similar analgesic potency and produce less gastric irritation than the nonselective COX inhibitors. The use of COX-2–selective drugs does not appear to lower the risk of nephrotoxicity compared to nonselective NSAIDs. On the other hand, COX-2–selective drugs offer a significant benefit in the management of acute postoperative pain because they do not affect blood coagulation. Nonselective COX inhibitors are usually contraindicated postoperatively because they impair platelet-mediated blood clotting and are thus associated with increased bleeding at the operative site. COX-2 inhibitors, including celecoxib (Celebrex), are associated with increased cardiovascular risk. It appears that this is a class effect of NSAIDs, excluding aspirin. These drugs are contraindicated in patients in the immediate period after coronary artery bypass surgery and should be used with caution in elderly patients and those with a history of or significant risk factors for cardiovascular disease.
OPIOID ANALGESICSOpioids are the most potent pain-relieving drugs currently available. Of all analgesics, they have the broadest range of efficacy and provide the most reliable and effective method for rapid pain relief. Although side effects are common, most are reversible: nausea, vomiting, pruritus, and constipation are the most frequent and bothersome side effects. Respiratory depression is uncommon at standard analgesic doses, but can be life-threatening. Opioid-related side effects can be reversed rapidly with the narcotic antagonist naloxone. Many physicians, nurses, and patients have a certain trepidation about using opioids that is based on an exaggerated fear of addiction. In fact, there is a vanishingly small chance of patients becoming addicted to narcotics as a result of their appropriate medical use. The physician should not hesitate to use opioid analgesics in patients with acute severe pain. Table 18-1 lists the most commonly used opioid analgesics.
Opioids produce analgesia by actions in the CNS. They activate pain-inhibitory neurons and directly inhibit pain-transmission neurons. Most of the commercially available opioid analgesics act at the same opioid receptor (μ-receptor), differing mainly in potency, speed of onset, duration of action, and optimal route of administration. Some side effects are due to accumulation of nonopioid metabolites that are unique to individual drugs. One striking example of this is normeperidine, a metabolite of meperidine. At higher doses of meperidine, typically greater than 1 g/d, accumulation of normeperidine can produce hyperexcitability and seizures that are not reversible with naloxone. Normeperidine accumulation is increased in patients with renal failure.
The most rapid pain relief is obtained by intravenous administration of opioids; relief with oral administration is significantly slower. Because of the potential for respiratory depression, patients with any form of respiratory compromise must be kept under close observation following opioid administration; an oxygen-saturation monitor may be useful, but only in a setting where the monitor is under constant surveillance. Opioid-induced respiratory depression is typically accompanied by sedation and a reduction in respiratory rate. A fall in oxygen saturation represents a critical level of respiratory depression and the need for immediate intervention to prevent life-threatening hypoxemia. Ventilatory assistance should be maintained until the opioid-induced respiratory depression has resolved. The opioid antagonist naloxone should be readily available whenever opioids are used at high doses or in patients with compromised pulmonary function. Opioid effects are dose-related, and there is great variability among patients in the doses that relieve pain and produce side effects. Synergistic respiratory depression is common when opioids are administered with other CNS depressants, most commonly the benzodiazepines. Because of this, initiation of therapy requires titration to optimal dose and interval. The most important principle is to provide adequate pain relief. This requires determining whether the drug has adequately relieved the pain and frequent reassessment to determine the optimal interval for dosing. The most common error made by physicians in managing severe pain with opioids is to prescribe an inadequate dose. Because many patients are reluctant to complain, this practice leads to needless suffering. In the absence of sedation at the expected time of peak effect, a physician should not hesitate to repeat the initial dose to achieve satisfactory pain relief.
An innovative approach to the problem of achieving adequate pain relief is the use of patient-controlled analgesia (PCA). PCA uses a microprocessor-controlled infusion device that can deliver a baseline continuous dose of an opioid drug as well as preprogrammed additional doses whenever the patient pushes a button. The patient can then titrate the dose to the optimal level. This approach is used most extensively for the management of postoperative pain, but there is no reason why it should not be used for any hospitalized patient with persistent severe pain. PCA is also used for short-term home care of patients with intractable pain, such as that caused by metastatic cancer.
It is important to understand that the PCA device delivers small, repeated doses to maintain pain relief; in patients with severe pain, the pain must first be brought under control with a loading dose before transitioning to the PCA device. The bolus dose of the drug (typically 1 mg of morphine, 0.2 mg of hydromorphone, or 10 μg of fentanyl) can then be delivered repeatedly as needed. To prevent overdosing, PCA devices are programmed with a lockout period after each demand dose is delivered (5–10 min) and a limit on the total dose delivered per hour. Although some have advocated the use of a simultaneous continuous or basal infusion of the PCA drug, this increases the risk of respiratory depression and has not been shown to increase the overall efficacy of the technique.
The availability of new routes of administration has extended the usefulness of opioid analgesics. Most important is the availability of spinal administration. Opioids can be infused through a spinal catheter placed either intrathecally or epidurally. By applying opioids directly to the spinal or epidural space adjacent to the spinal cord, regional analgesia can be obtained using relatively low total doses. Indeed, the dose required to produce effective localized analgesia when usingmorphine intrathecally (0.1–0.3 mg) is a fraction of that required to produce similar analgesia when administered intravenously (5–10 mg). In this way, side effects such as sedation, nausea, and respiratory depression can be minimized. This approach has been used extensively during labor and delivery and for postoperative pain relief following surgical procedures. Continuous intrathecal delivery via implanted spinal drug-delivery systems is now commonly used, particularly for the treatment of cancer-related pain that would require sedating doses for adequate pain control if given systemically. Opioids can also be given intranasally (butorphanol), rectally, and transdermally (fentanyl and buprenorphine), or through the oral mucosa (fentanyl), thus avoiding the discomfort of frequent injections in patients who cannot be given oral medication. The fentanyl and buprenorphinetransdermal patches have the advantage of providing fairly steady plasma levels, which maximizes patient comfort.
Recent additions to the armamentarium for treating opioid-induced side effects are the peripherally acting opioid antagonists alvimopan (Entereg) and methylnaltrexone (Rellistor). Alvimopan is available as an orally administered agent that is restricted to the intestinal lumen by limited absorption; methylnaltrexone is available in a subcutaneously administered form that has virtually no penetration into the CNS. Both agents act by binding to peripheral μ-receptors, thereby inhibiting or reversing the effects of opioids at these peripheral sites. The action of both agents is restricted to receptor sites outside of the CNS; thus, these drugs can reverse the adverse effects of opioid analgesics that are mediated through their peripheral receptors without reversing their analgesic effects. Alvimopan has proven effective in lowering the duration of persistent ileus following abdominal surgery in patients receiving opioid analgesics for postoperative pain control. Methylnaltrexone has proven effective for relief of opioid-induced constipation in patients taking opioid analgesics on a chronic basis.
Opioid and COX Inhibitor CombinationsWhen used in combination, opioids and COX inhibitors have additive effects. Because a lower dose of each can be used to achieve the same degree of pain relief and their side effects are nonadditive, such combinations are used to lower the severity of dose-related side effects. However, fixed-ratio combinations of an opioid with acetaminophen carry an important risk. Dose escalation as a result of increased severity of pain or decreased opioid effect as a result of tolerance may lead to ingestion of levels of acetaminophen that are toxic to the liver. Although acetaminophen-related hepatotoxicity is uncommon, it remains a significant cause for liver failure. Thus, many practitioners have moved away from the use of opioid-acetaminophen combination analgesics to avoid the risk of excessive acetaminophen exposure as the dose of the analgesic is escalated.
TABLE 18-1 Drugs for Relief of Pain
| Generic Name | Dose, mg | Interval | Comments | |||||
| Nonnarcotic analgesics: usual doses and intervals | ||||||||
| Acetylsalicylic acid | 650 PO | q4h | Enteric-coated preparations available | |||||
| Acetaminophen | 650 PO | q4h | Side effects uncommon | |||||
| Ibuprofen | 400 PO | q4–6h | Available without prescription | |||||
| Naproxen | 250–500 PO | q12h | Delayed effects may be due to long half-life | |||||
| Fenoprofen | 200 PO | q4–6h | Contraindicated in renal disease | |||||
| Indomethacin | 25–50 PO | q8h | Gastrointestinal side effects common | |||||
| Ketorolac | 15–60 IM/IV | q4–6h | Available for parenteral use | |||||
| Celecoxib | 100–200 PO | q12–24h | Useful for arthritis | |||||
| Valdecoxib | 10–20 PO | q12–24h | Removed from U.S. market in 2005 | |||||
| Generic Name | Parenteral Dose, mg | PO Dose, mg | Comments | |||||
| Narcotic analgesics: usual doses and intervals | ||||||||
| Codeine | 30–60 q4h | 30–60 q4h | Nausea common | |||||
| Oxycodone | — | 5–10 q4–6h | Usually available with acetaminophen or aspirin | |||||
| Morphine | 5 q4h | 30 q4h | ||||||
| Morphine sustained release | — | 15–60 bid to tid | Oral slow-release preparation | |||||
| Hydromorphone | 1–2 q4h | 2–4 q4h | Shorter acting than morphine sulfate | |||||
| Levorphanol | 2 q6–8h | 4 q6–8h | Longer acting than morphine sulfate; absorbed well PO | |||||
| Methadone | 5–10 q6–8h | 5–20 q6–8h | Delayed sedation due to long half-life; therapy should not be initiated with >40 mg/d, and dose escalation should be made no more frequently than every 3 days | |||||
| Meperidine | 50–100 q3–4h | 300 q4h | Poorly absorbed PO; normeperidine is a toxic metabolite; routine use of this agent is not recommended | |||||
| Butorphanol | — | 1–2 q4h | Intranasal spray | |||||
Fentanyl Buprenorphine Buprenorphine |
25–100 μg/h 5–20 μg/h 0.3 q6–8h |
— | 72-h transdermal patch 7-day transdermal patch Parenteral administration |
|||||
| Tramadol | — | 50–100 q4–6h | Mixed opioid/adrenergic action | |||||
| Uptake Blockade | ||||||||
| Generic Name | 5-HT | NE | Sedative Potency | Anticholinergic Potency | Orthostatic Hypotension | Cardiac Arrhythmia | Ave. Dose, mg/d | Range, mg/d |
| Antidepressantsa | ||||||||
| Doxepin | ++ | + | High | Moderate | Moderate | Less | 200 | 75–400 |
| Amitriptyline | ++++ | ++ | High | Highest | Moderate | Yes | 150 | 25–300 |
| Imipramine | ++++ | ++ | Moderate | Moderate | High | Yes | 200 | 75–400 |
| Nortriptyline | +++ | ++ | Moderate | Moderate | Low | Yes | 100 | 40–150 |
| Desipramine | +++ | ++++ | Low | Low | Low | Yes | 150 | 50–300 |
| Venlafaxine | +++ | ++ | Low | None | None | No | 150 | 75–400 |
| Duloxetine | +++ | +++ | Low | None | None | No | 40 | 30–60 |
| Generic Name | PO Dose, mg | Interval | Generic Name | PO Dose, mg | Interval | |||
| Anticonvulsants and antiarrhythmicsa | ||||||||
| Phenytoin | 300 | daily/qhs | Clonazepam | 1 | q6h | |||
| Carbamazepine | 200–300 | q6h | Gabapentinb | 600–1200 | q8h | |||
| Oxcarbazepine | 300 | bid | Pregabalin | 150–600 | bid | |||
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ED pain assessment should determine duration, location, quality, severity, and exacerbating and relieving factors. The patient's subjective reporting of pain, not the physician's impression, is the basis for pain assessment and treatment. Because pain is dynamic and changes with time, periodic pain reassessment is needed.
The primary value of pain scales is their essential role in research enabling reproducible comparisons of interventions. Some studies have suggested that the use of pain scales may actually decrease the provision of analgesics. Given the subjectivity both of pain reporting and the provider's interpretation of such reporting, the use of simple descriptors such as "a little" or "an awful lot" is equally valid in the clinical setting. What is important is that the patient's subjective reporting should be the basis for assessment and management. For most, but not all, painful conditions, the goal is to control pain to the level the patient desires. Asking if the patient requires more analgesic may even be simpler and accomplish more than using any standardized pain evaluation tool.21,22
PAIN SCALES
The purpose of pain scales is to quantitate pain severity, guide the selection and administration of an analgesic agent, and reassess the pain response to determine the need for repeated doses or more effective analgesics. Several self-report instruments are valid in patients with acute pain, and some require only a verbal response (Table 35-2). Each tool has advantages and specific limitations. ED personnel in any one location should use the same tool so information collected is standardized. A value assigned by a patient is not an absolute value but rather a reference point based on past personal experience.23
Pain Scales29A
| Scale | Method | Comments |
|---|---|---|
| Adjective rating scale (Figure 35-1) | Patient rates pain by choosing from an ordered list of pain descriptors, ranging from no pain to worst possible pain, with allowance for marks between discrete labels. | Easy to administer. |
| Visual analog scale (VAS) (Figure 35-2) | Patient places a mark that best describes pain intensity along a 10-cm linear scale marked at one end with a term such as no pain and at the other end with worst imaginable pain. | Pain intensity measured in millimeters from the no-pain end. A difference of 13 mm is the minimum clinically significant change noticeable by patients, whereas an average decrease of 30 mm appears to be the minimum acceptable change for pain control.* |
| Numeric rating scale (Figure 35-3) | The patient is asked to self-report pain on a scale of 0 to 10 with descriptors. | Can be used in patients with visual, speech, or manual dexterity difficulties by using upheld fingers. Not as discriminating as the VAS. |
| 5-Point global scale | Patient rates pain as: 0 = none 1 = a little 2 = some 3 = a lot 4 = worst possible |
A decrease of 1 point is a large change; scales with more choices allow monitoring of small changes in pain and may be more sensitive to changes. |
| Verbal quantitative scale | The patient is asked to self-report pain on a scale of 0 to 10 without descriptors. |
Pain scale: Adjective rating scale.
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Pain scale: Numeric rating scale.
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PAIN SCALE PERFORMANCE IN SPECIAL PATIENT POPULATIONS
The elderly often report pain differently from younger patients because of physiologic, psychological, and cultural changes associated with aging. Visual, hearing, motor, and cognitive impairments can be barriers to effective pain assessment. Using a numerical pain scale, the elderly may also experience a decrease in the minimum clinically significant noticeable difference in acute pain over time.24,25 Family members and caregivers are often able to judge nonverbal actions of the patient as representing pain or distress, so they should be used if available to help with pain assessment in the noncommunicating elderly patient.
Trauma patients and those with acute intoxication do not perform as well on pain scales.26 Women are more likely to express pain and to actively seek treatment for pain,27,28 yet there is a tendency to underestimate and undertreat pain in women. Ethnicity of both the patient and the physician has a bearing on different cultural concepts of pain and on the characteristics of culturally appropriate pain-related behaviors.7 Translators and family members should be asked to provide assistance. There is also interplay between the ethnicity of the patient and that of the physician.7 When there are language difficulties or cross-cultural differences, the visual analog scale is the preferred pain assessment tool because it is the least affected by these factors.
Specific measures to treat pain should occur in addition to, and at the same time as, treatment of the underlying illness or injury. It is not possible to generalize the extent and quality of pain control needed for a specific patient. For example, pain is an indicator of ongoing cardiac ischemia, and the goal should be to eliminate all pain. On the other hand, a patient with a traumatic injury may choose to endure more pain out of personal or cultural beliefs. Physicians may limit analgesics in those with head injuries to perform serial neurologic examinations. Whenever possible, medications that act on specific sites that initiate the pain signal—a mechanistic approach—are preferred to agents such as opioids that mask pain, which is a symptomatic approach. Current migraine treatment is an excellent example of the mechanistic approach; preferred treatment includes a serotonin agonist (triptan)11 or a dopamine antagonist (phenothiazine),12 rather than opiates.13,14
Psychological factors such as social support, hypnotic suggestion, excitement, or distraction can significantly modulate pain's intensity or unpleasantness.In some arguments put forth in physician-assisted suicide or euthanasia debates, pain has been used as an argument to permit terminally ill patients to end their lives.