Pain Management in the Emergency Department
Authors: Charles L. Emerman, MD, Chairman, Department of Emergency Medicine, The Cleveland Clinic Foundation, MetroHealth Medical Center, Case Western Reserve University, OH; Joseph Spenetta, MD, Anesthesiology Resident, The Cleveland Clinic Foundation, OH.
Peer Reviewers: Richard Wang, DO, FACEP, FACMT, Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA; William B. Ignatoff, MD, Emergency Physician, Carondelet Health Network, St. Joseph’s and St. Mary’s Hospitals, Tucson, AZ.
As Dr. Albert Schweitzer so aptly put it: "We must all die. But that I can save [a person] from days of torture, that is what I feel as my great and even new privilege. Pain is a more terrible lord of mankind than even death itself."
Pain is among the most common of human experiences, and is one of the most frequent reasons for which people seek medical care, many in the emergency department (ED). Pain is a major cause of partial or total disability in the United States1 and has astonishing economic implications in terms of health care utilization and lost wages. Pain exacts a tremendous physical, psychological, social, and vocational toll on the sufferer, and likewise may impact family, friends, and health care workers. Almost half of patients with chronic pain report considering suicide because of their pain.2
An area of intense clinical focus in the practice of emergency medicine, pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or both," and frequently is broken into two types — acute and chronic. Acute pain is a strong behavioral motivator undoubtedly conferring some survival advantage. This may lead to health care-seeking behavior, avoidance of further insult, recognition of internal disorder, or activation of the autonomic nervous system to maintain internal homeostasis. Acute pain usually has a readily identifiable cause and dissipates as the inciting stimulus resolves.
Chronic pain persists long after the inciting stimulus and frequently has no definable etiology. Chronic pain is poorly localized, difficult to quantify, may wax and wane, and is more difficult to treat than acute pain. Current theory on the genesis of chronic pain focuses on an apparently malfunctioning nervous system.3 Such malfunctions may occur as a result of direct nervous system involvement with a disease process (e.g., cancer infiltrating the spinal cord) or may be due to biochemical changes of neurons within the spinal cord in response to prolonged painful stimuli. A seemingly self-limited injury may result in production of a chronic pain state, sometimes as a result of incompletely treated acute pain.
Unrelieved pain may precipitate the stress response, leading to fluid retention, increases in blood pressure, arrhythmias, and increased myocardial oxygen requirements, all of which are associated with increased cardiac morbidity. Numerous studies have demonstrated that blockade of afferent impulses from the site of surgery prior to incision significantly reduces the levels of hormones associated with the stress response, reduces later pain, and decreases coagulability, thereby reducing risk for deep venous thrombosis (DVT) formation.4-6 Studies have demonstrated a decrease in immune system functioning in individuals enduring prolonged stress reactions.
Pain control has become an important issue in American medical practice, especially in emergency practice, and the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) has adopted specific guidelines for pain assessment and treatment. These standards affirm that all patients have the right to pain treatment. Physicians should assess and treat pain in every patient and reassess pain periodically during treatment. While such practices seem obvious, studies repeatedly have demonstrated that the single greatest barrier to adequate pain control in the United States is the failure of health care workers to recognize that pain exists. The JCAHO standards point out the large knowledge deficit that exists among both patients and physicians regarding pain control, suggesting that education should be offered to all.
With these issues in mind, the purpose of this review is to identify indications and strategies for pain control and follow-up pain management in patients encountered in the ED setting.— The Editor
Definition and Assessment
Patient report is the primary method of pain assessment in the ED, but it may be challenged by limited time, the presence of other conditions, mental impairment, and lack of a prior patient-physician relationship. Commonly, pain severity is assessed using a numeric scale from 0 to 10 or by having the patient place a mark along a 10-cm line that has its ends "anchored" with the terms "no pain" and "worst pain imaginable."7 Verbal descriptors such as mild, discomforting, distressing, horrible, and excruciating offer an alternative method. Purely visual pain scales, such as the Faces scale, particularly are useful for young children with limited verbal ability.
Although not as crucial for patients with acute pain in the ED, questions about the effect on the patient’s overall quality of life may be useful. Clinicians should recognize that characteristics including age, ethnicity, and gender also influence pain perception and reporting.8, 9 Certain subgroups of patients may believe that they should not inform health care workers when they are in pain.10 Elderly patients tend to report less pain in response to procedures such as catheter placement.11 Reports of pain that are incongruent with expectations may warrant an in-depth assessment, but may be experientially or culturally based. Heart rate, blood pressure, or patient grimacing are inconsistent signs of pain.
Characteristics of pain, such as location, severity, radiation, and qualitative descriptors (burning, gnawing, etc.), are part of a comprehensive pain assessment. Assessment should include any medications the patient has taken and whether they were successful. Pain that is episodically acute (such as sickle cell crisis pain) or chronic in nature always should prompt the physician to inquire whether the pain is identical to previous experiences. Assessment of pain in the elderly, children, and patients with cognitive deficits or language barriers can be difficult. In such cases, objective measurements, such as those described above, and information from the patient’s family may be useful.
The Pain Pathway
Numerous stimuli may trigger the firing of a pain nerve fiber (nociception), including mechanical, thermal, or chemical stimuli. Chemical mediators such as histamine, bradykinin, serotonin, and prostaglandins, however, play the greatest role. These substances are capable of triggering pain fiber depolarization, but more commonly function to reduce the subsequent stimuli necessary for depolarization to occur. The action of these chemicals may underlie cases of hypersensitivity, in which normally innocuous stimuli cause pain.
Nociceptive impulses are transmitted to the spinal cord by two distinct nerve fiber types, with so-called fast (sharp) pain traveling in A-delta fibers, and the slow (burning or diffuse) pain in smaller, unmyelinated C-fibers. Upon entering the spinal cord, most A-delta fibers cross to the opposite side and ascend to the brain stem. In contrast, many C-fibers synapse on groups of interneurons within the spinal cord before the impulses cross to the opposite side and ascend. These interneurons provide an important method of modifying the slower and more emotionally concerning pain traveling in C-fibers. Upon reaching the brain stem, pain fibers terminate in numerous areas, including the thalamus, hypothalamus, and reticular activating formation.
With an understanding of the pain pathway, physicians and other scientists have been able to develop numerous methods of modifying and alleviating pain by targeting specific points along the pain pathway. Often, this involves the use of medications, which frequently are broken into three broad groups: non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; opioids; and adjuvants. General characteristics of each class of drug, along with important specifics about selected representative medications from each class, will be presented below. This presentation is not intended to be comprehensive, but will instead focus on those with utility in the ED.
Aspirin. Aspirin-like compounds have been used for more than 2000 years. A related compound is contained in various types of tree bark, and the analgesic effects of the bark of the willow tree were known to the ancient Greeks. Salicylic acid was synthesized in the mid-1800s, and by the late 19th century, aspirin was being sold. Aspirin is approved for use as an over-the-counter drug in doses of 325-1000 mg, up to a total dose of 4 g per day. Its labeling limits use to 10 consecutive days for painful conditions without physician consultation. Aspirin is a mild to moderate analgesic. Aspirin works by blocking the cyclooxygenase (COX) system in a manner similar to other NSAIDs. In contrast to other NSAIDs, however, aspirin irreversibly blocks the COX enzyme. The analgesic effects of aspirin generally are thought to be from peripheral effects, although some studies also have found a central mechanism.12 In a dose of 650 mg, it has been found in dental pain studies to have equal analgesic effect to acetaminophen with codeine #3 or 5 mg of oxycodone. The addition of codeine to aspirin enhances aspirin’s analgesic effects. There is no additive analgesic effect when acetaminophen is added to aspirin.13 Maximal over-the-counter doses of aspirin, up to 1000 mg, have less analgesic effect than maximal doses of other NSAIDs, such as ibuprofen in doses of 600-800 mg. The most common side effects of aspirin are dyspepsia and gastrointestinal (GI) blood loss. Single-dose studies of aspirin have not found an increased incidence of GI side effects over placebo. Following repeated use, particularly in elderly patients, however, the risk for upper GI complications increases. Because renal function depends on prostaglandins, long-term use of high doses of aspirin, which is a prostaglandin inhibitor, can lead to an elevation in serum creatinine levels. Doses of aspirin greater than 2 g per day for more than 6-12 months lead to modest increases in creatinine in about 4% of patients.14 The patients most at risk for renal dysfunction include patients on diuretic therapy, patients with pre-existing renal disease, patients with congestive heart failure, and elderly patients. Aspirin should not be used in late pregnancy because of increased risk of hemorrhage. Aspirin use should be avoided in patients who also are drinking more than three alcoholic beverages per day, because of the increased risk of GI bleeding. Aspirin should be used with caution in patients who already take diuretics and antihypertensives. Aspirin also should be used with caution in patients on oral anticoagulants, lithium, methotrexate, metformin, sulfonylureas, and valproic acid.
Acetaminophen. The parent compound of acetaminophen, acetanilid, was discovered to have antipyretic properties when it was mistakenly given to a patient instead of naphthalene. The related compounds phenacetin and acetaminophen subsequently were found to have analgesic properties, although phenacetin was later withdrawn from use because of its association with nephropathy. Unlike aspirin, acetaminophen does not have significant anti-inflammatory action and has little effect on peripheral COX receptors.15 It does, however, block CNS COX receptors, which leads to its analgesic effect. Acetaminophen is approved for over-the-counter use of 325-1000 mg every 4-6 hours, up to a maximum of 4 g per day, with a 10-day limitation on use for acute pain without physician consultation. Acetaminophen has equivalent analgesic effects to aspirin on a milligram basis, with significant analgesic effect within 60 minutes and a duration of action of about four hours. The addition of caffeine to acetaminophen leads to greater analgesic effect, estimated to account for about 40% of the analgesic improvement.16 The analgesic effect also can be enhanced when acetaminophen is combined with opioids. Acetaminophen with codeine #3, for example, contains 300 mg of acetaminophen along with 30 mg of codeine, and provides equivalent analgesia to a single 600-mg dose of acetaminophen. The analgesic effect of acetaminophen is limited by the maximum doses that can be administered without toxic effects. Analgesia increases as the dose of acetaminophen is increased.
Unlike aspirin, acetaminophen has little GI side effect. In single-dose studies, the frequency of GI upset is similar to placebo. The hepatotoxicity of acetaminophen when taken in overdoses is well understood. Occasionally, however, children experience toxicity because of inadvertent overmedication by parents using the wrong preparation for their child’s age. High-dose, chronic acetominophen use may be associated with renal deterioration, although the relationship between the use of this agent and renal failure is much less clear than that between NSAIDs and renal failure, which is well-documented. Acetaminophen and NSAIDs also may cause an increased INR in patients receiving warfarin.17
Non-Steroidal Anti-inflammatory Drugs (NSAIDs). The NSAIDs are a diverse group of medications that share common properties. (See Table 1.) These drugs, similar to aspirin, act on the COX system by blocking the COX receptors. Unlike aspirin, the NSAIDs reversibly inhibit the enzyme. The COX receptors are composed of two types: the COX-1 receptor, which is present in a relatively constant amount; and the COX-2 receptor, which is synthesized in response to a variety of stimuli, primarily inflammatory in nature. COX-1 is present throughout the body and mediates homeostatic functions. It maintains gastric mucosal integrity, increases renal blood flow, supports platelet aggregation, and regulates vascular tone. The COX-2 enzymes synthesize prostanoids, which are involved in the inflammatory cascade, elevation of body temperature, and are part of the pain pathway. Prostanoids produced by the COX-2 enzymes decrease the pain-fiber firing threshold and sometimes trigger pain receptors peripherally, also exerting anti-pyretic and analgesic activity by inhibition of central COX. It is the inhibition of the COX-2 enzymes that provides the analgesic effects of the NSAIDs.
| Table 1. Commonly Used NSAIDs and Over-the-Counter Medications | |||||
| Drug Name | Usual
Adult Oral Dose (mg) |
Usual Dose Interval (hrs) |
Pediatric Dose (mg/kg) |
Maximal
Daily Dose (mg/day) |
Other Comments |
| Aspirin | |||||
| 325-1000 | 4-6 | 10-15 q 4-6 | 4000 | Not for use in children younger than 12 with possible viral illness due to Reye's syndrome. | |
| Acetaminophen | |||||
| 500-1000 | 4-6 | 10-15 q 4-6 | 4000 | Significant liver toxicity in over dose. May increase INR in patients taking warfarin. | |
| Choline Magnesium Trisalicylate | |||||
| 1000-1500 | 12 | 25 bid | 2000-3000 | No effect on platelet function. Avoid in children younger than 12 with possible viral illness. | |
| Ibuprofen | |||||
| 200-800 | 6 | 10 q 6-8 | 2400-3200 | Relatively infrequent GI side effects. | |
| Naproxen | |||||
| 250-500 | 6-12 | 5 bid | 750-1250 | May be beneficial for headaches or migraines. | |
| Ketoprofen | |||||
| 12.5-50 | 6-8 | Not recommended |
300 | Slightly increased GI side effects. | |
| Flurbiprofen | |||||
| 50-100 | Bid-tid | Not recommended |
300 | Potent anti-inflammatory properties. | |
| Oxaprozin | |||||
| 1200 | 24 | Not recommended |
1800 | Onset delayed for 3-6 hours. | |
| Sulindac | |||||
| 150-200 | Bid | Not recommended |
400 | Prodrug with decreased GI side effects. | |
| Etodolac | |||||
| 200-400 | 6-12 | Not recommended |
1000 | Balanced COX-1/COX-2 with decreased GI side effects. | |
| Indomethacin | |||||
| 25-50 | 8-12 | Not recommended |
100 | Limit use to 2 weeks if possible. | |
| Ketorolac | |||||
| 30 mg IV/IM | 6 | None | 120, except 150 first day | Efficacy similar to 4 mg morphine. Not for use for more than 5 days. | |
| Piroxicam | |||||
| 20 | 24 | Not recommended |
20 | About half of patients intolerant of GI effects. | |
| Nabumetone | |||||
| 500-1000 | 12 | Not recommended |
2000 | Low incidence of GI effects. | |
| Celecoxib | |||||
| 100-200 | 12-24 | Not recommended |
400 | Primarily COX-2 inhibitor. | |
| Rofecoxib | |||||
| 12.5-50 | 24 | Not recommended |
50 | Primarily COX-2 inhibitor. Increased incidence of cardiac events in VIGOR trial. | |
|
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| Key: INR = International normalized ratio; GI = Gastrointestinal | |||||
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NSAIDs are the most frequently used medications for pain outside the perioperative period, and all share three similar properties; they are analgesics, antipyretics, and anti-inflammatories. NSAIDs may be combined with narcotics, allowing lower doses and thereby decreasing the opioid side effects of narcotics. NSAIDs differ from narcotic analgesics in that they have a ceiling effect, in which additional dose increases do not increase efficacy, and they do not cause physical or psychological dependence.
All NSAIDs are rapidly absorbed following oral ingestion and tend to be highly protein-bound. They undergo extensive hepatic biotransformation, followed by renal excretion.
The degree of toxicity varies greatly among the different agents, but the most common side effects are GI, including ulcer formation and perforation. GI irritation is caused by decreased production of mucus and local irritant effects of the medications. Patients at highest risk for GI complications are those older than age 60, those with a previous history of GI events, and those using concomitant corticosteroids.18 These effects also appear to be dose- and duration-related.19 Medications such as proton pump inhibitors, H-2 blockers, and misoprostol can decrease the likelihood of significant GI occurrences and may be useful in patients falling into any of the above categories. NSAIDs are used safely in many patients with or without these medications. Short-term use is associated with little risk, and patients on long-term therapy should be monitored by their primary care physician. Less severe GI effects include nausea, vomiting, abdominal pain, diarrhea, and gastritis. Patients with inflammatory bowel disease may suffer exacerbation of their disease following NSAID administration. The incidence of GI events is related to the relative selectivity for the COX-1 and COX-2 enzymes.
NSAIDs also adversely affect renal function, occasionally causing acute renal failure. This is seen most commonly in individuals with poor renal reserve or in conditions with underlying renal hypoperfusion, such as hypovolemia, but such effects in patients with normal renal function are minimal. As a class, NSAID use may lead to hyponatremia and hyperkalemia in susceptible individuals. Patients predisposed to kidney disease, such as those with diabetes mellitus, congestive heart failure, and autoimmune disorders, and those taking nephrotoxic drugs, may have a deterioration in renal function when taking NSAIDs. NSAIDs also may increase blood pressure and decrease the effectiveness of anti-hypertensives.
NSAIDs exert several effects on the hematopoietic and vascular homeostasis systems. These drugs inhibit platelet aggregation and prolong bleeding time. Rarely, agranulocytosis, leukopenia, and thrombocytopenia may occur, but they are reversible when the medication is discontinued. Dermatologic effects, including toxic epidermal necrolysis and Stevens Johnson Syndrome, occasionally are seen.
NSAIDs may cause transient increases in liver function enzymes, and there have been rare reports of drug-induced hepatitis. Patients with a history of true aspirin allergy (asthma, rhinitis, and nasal polyps) may have partial cross-reactivity with NSAIDs. NSAIDs may interact with other medications, including phenytoin, sodium valproate, the sulfonylureas, and digoxin, leading to increased levels of these other medications.
One of the first of the NSAIDs introduced was indomethacin, an indoleacetic acid derivative. Indomethacin is a potent anti-inflammatory agent that also is uricosuric. Unfortunately, many patients are intolerant of indomethacin, and its use should be limited to 10 days to two weeks. Sulindac, another drug in the same class, is not active, but its metabolite is a potent COX inhibitor. Because it requires metabolism for effect, it has less GI toxicity compared to indomethacin and may be used for longer periods of time. There are occasional reports of hepatitis with sulindac.20 Etodolac is a balanced COX-1/COX-2 inhibitor, leading to a decreased incidence of GI side effects.21 Nabumetone is in a separate drug class, but is another prodrug with an active metabolite. It also is a good choice for long-term therapy because of a decreased incidence of GI effect.22 The propionic acid derivatives include ibuprofen, the most widely used of the NSAIDs aside from aspirin.
Ibuprofen is approved for over-the-counter use in doses of 200 mg, but greater analgesic effect is achieved by the prescription dose of up to 800 mg three times per day. Naprosyn has the advantage of a greater CNS uptake compared to ibuprofen, and it may be useful in patients with headaches and migraines, although it does have greater GI and CNS side effects compared to ibuprofen. Fenoprofen and ketoprofen are not potent analgesics but are good anti-inflammatory agents. Oxaprozin has a delayed onset of effect; however, it also has a long half-life and is available as a once-a-day preparation.
Phenylbutazone is a member of the pyrazole derivatives and is a potent analgesic and anti-inflammatory agent. It has a number of side effects, including hepatitis and bone marrow suppression, leading to recommendations to limit its use. Oxyphenbutazone is a phenylbutazone metabolite that has somewhat fewer side effects.
Tolmetin has good analgesic and anti-inflammatory properties, but its use occasionally leads to hypertension and edema. Diclo-fenac is a similar drug that is a more balanced COX-1/COX-2 inhibitor, leading to a lower incidence of GI side effects. Occasionally, patients get transient elevations of the liver enzymes.20 Ketorolac is another member of this class of NSAIDs with potent analgesic properties. A single dose of ketorolac is thought to be equivalent to approximately 4 mg of morphine sulfate but with a longer duration of action, lasting 6-8 hours. Long-term use is not recommended because of GI side effects and bleeding. The current recommendations are to limit its use to five days. Piroxicam is primarily a COX-1 inhibitor, and many patients are unable to tolerate its adverse GI effects. It does have a long half-life, allowing for once-a-day dosing.
COX-2 Inhibitors. The COX enzyme system was demonstrated in the early 1990s to include both a constitutive enzyme labeled COX-1 and an inducible enzyme labeled COX-2.23 An amino acid difference between the two enzymes leaves the COX-2 enzyme available for specific binding that is not available for COX-1 re-ceptors. The COX-2 inhibitors take advantage of this difference, such that they can reversibly bind the COX-2 enzymes with limited effect on COX-1 enzymes. The COX-2 inhibitors do have some COX-1 activity; however, their COX-1 activity is some orders of magnitude lower than that of the non-selective NSAIDS. The COX-2 inhibitors do not impair platelet function and are not associated with the significant GI side effects identified with the non-selective NSAIDs. Both the selective and non-selective NSAIDs share some renal side effects because both COX-1 and COX-2 receptors are present in the kidneys.
Two large-scale trials have evaluated the safety and efficacy of the approved COX-2 inhibitors, celecoxib and rofecoxib. The Celecoxib Long-term Arthritis Safety Study (CLASS) evaluated the incidence of symptomatic upper GI ulcers in patients taking celecoxib vs. patients taking the non-selective agents ibuprofen or diclofenac for rheumatoid or osteoarthritis.24 Prior to this study, other phase 2 and phase 3 clinical trials had found an overall incidence of significant ulcer complications in fewer than 2% of patients treated with celecoxib. In the CLASS trial, about 8000 patients were studied at a dose of celecoxib of 800 mg per day against patients treated with either 75 mg bid diclofenac or 800 mg tid for ibuprofen. Significantly, about 10% of the patients were older than 75, 8% of patients had a prior history of peptic ulcer disease, 20% of patients also were taking aspirin, and 40% of patients had a history of cardiovascular disease. Overall, fewer patients in the celecoxib arm of the study were withdrawn because of adverse effects, compared to patients treated with the non-selective agents. The risk of upper GI ulcer complications was half that of patients taking the non-selective agents, and the rate of symptomatic ulcers was not quite half that of the patients taking the non-selective agents. The decrease in GI complications was greatest in those patients who were not taking concomitant aspirin therapy.
The Vioxx Gastrointestinal Outcomes Research (VIGOR) study compared 50 mg per day of rofecoxib to 500 mg bid of naproxen in patients with rheumatoid arthritis.25 About 30% of patients withdrew from each arm of the study. As was the case with the CLASS trial, rofecoxib was found to decrease significantly the clinically important GI effects by about 55-60%. The incidence of acute myocardial infarction was significantly higher in the rofecoxib-treated group compared to the naproxen-treated group in the VIGOR trial. In the VIGOR study investigators noted that 4% of their patients met Food and Drug Administration criteria for the use of aspirin for secondary cardiovascular prophylaxis although they were not on low-dose aspirin. They noted that these patients accounted for about 40% of the patients who had myocardial infarctions, and that the others in the group did not have a significantly different rate of myocardial infarction than the patients in the naproxen-treated group. In the CLASS trial, however, there was no difference in myocardial infarction risk among patients who were not taking aspirin.
There is only limited data directly comparing celecoxib and rofecoxib. A recent study compared patients receiving either celecoxib 200 mg or rofecoxib 25 mg once a day for six weeks.26 These were patients older than age 65 who also were taking anti-hypertensive agents. Out of the 810 patients, the rofecoxib-treated patients were almost twice as likely to experience edema. Systolic blood pressure was increased in more rofecoxib-treated patients compared to celecoxib-treated patients. Although the COX-2-specific agents have significant GI protective effect, they share some of the same renal effects with the non-selective agents. It does appear, however, that there are differences between the agents, which may need to be taken into account for at-risk patients.
Opioids. Natural or synthetic derivatives of opium have been used for pain relief for centuries. Opium itself contains two significant analgesics, morphine and codeine, although codeine requires metabolism to morphine for effect. All other opioids in current use are synthetic or semi-synthetic drugs with morphine-like effects. Various opioids are available; however, none have analgesic properties superior to morphine. Opioids vary in terms of duration of action, liquid solubility, and relative potency. Any opioid, given in a large enough dose, can yield substantial analgesia limited only by the occurrence of side effects. As opposed to other drugs used for pain relief, opioids have no ceiling to their effect. Increasing the dosage leads to increased analgesia, ultimately resulting in general anesthesia.
Opioids relieve pain by acting on various opioid receptors in the brain and spinal cord.27 These opioid receptors also are found distributed throughout the body on peripheral nerves, pulmonary sites, the GI tract, and the bladder. The recognized opioid receptors include the mu receptor, which is distributed throughout the body and is responsible for some of the side effects, including nausea, constipation, and respiratory depressions.28 The delta receptor only has been described to have analgesic effects, while the kappa receptor leads to miosis, spinal analgesia, hallucinations, and delirium. In addition to the effect of exogenous narcotic administration, these opioid receptors also are acted on by endogenous opioids. Other receptors, including the sigma receptor, have been described as possibly having CNS effects. Opioids are divided into pure agonists that stimulate opioid receptors, antagonists that block the stimulation of the receptors, and mixed agonists/antagonists that stimulate some opioid receptors while blocking others.
Opioids vary in terms of potency, and commonly are compared against a standard 10-mg dose of morphine.29 These comparisons are based on single-dose studies and may vary for an individual patient depending on prior exposure to opioids, patient age, and renal function. Many of the opioids have active metabolites and the duration of their action will vary depending on renal function.30 In addition, some drugs, such as meperidine, have toxic metabolites that limit their use in situations in which patients must receive repeated doses.31
All opioids share a similar range of side effects. They can cause respiratory depression as a result of action on the brain stem. This may lead to a decrease in the respiratory rate, although it also may affect tidal volume, respiratory rhythm, and the ability to maintain a competent airway, with resulting intermittent obstructive apnea. As a result, monitoring of respiratory rate alone may be an inadequate measure of impending respiratory failure. Because respiratory depression usually is accompanied by increasing sedation, the respiratory rate should be monitored in conjunction with the depth of sedation. Patients reaching a deeper level of sedation may need additional supervision with cardiac monitoring and pulse oximetry. Concomitant use of other sedatives may accelerate the risk of respiratory depression. Careful titration and use of smaller than usual doses will minimize the risk of respiratory depression when combination therapy is administered. It should be remembered that the sedative effects of narcotics are antagonized by pain and external stimulation. A patient may have adequate alertness and respiratory effort while staff is with the patient. Once a painful stimulus is removed and the patient is left alone, however, more significant sedation may occur.
Opioids stimulate the chemoreceptor trigger zone, leading to activation of the brain stem portions responsible for emesis. In addition, there is increased sensitivity to the vestibular system so that opioids exaggerate the nausea and vomiting that occur from head movement. The occurrence of GI upset may be more prominent in an individual patient with one opioid compared to another. In addition, other factors, including as anxiety, pain, and the interval since the last meal, may affect the occurrence of vomiting, so that a patient may be able to tolerate a particular opioid on one occasion yet develop recurrent vomiting when exposed to the same opioid under other circumstances. Any number of antiemetic drugs can be given to treat medication-induced nausea and vomiting. These include the dopaminergic antagonists such as metoclopramide or prochlorperazine. Additionally, many antihistamines, including diphenhydramine and hydroxyzine, have antiemetic properties, particularly when nausea is induced by movement. Scopolamine patches have little use in the acute management of pain in the ED, although they may be a consideration when treating patients longer term with oral agents. Serotonin antagonists, such as ondansetron, also may be an effective, although more costly, option.32
Opioids have a variety of effects on the CNS in addition to sedation. Euphoria, of course, is the goal of recreational drug seekers; however, dysphoria and hallucinations also occur.33 Most opioids cause miosis, although certain opioids, such as meperidine, have atropine-like activity and may lead to mydriasis.
Opioids lead to venodilation, which can cause significant hypotension possibly secondary to histamine release.34 This also may be used to therapeutic effect, however, such as in the treatment of congestive heart failure. Elderly patients, patients who are dehydrated, or patients who are receiving other vasodilating medications may have a more profound response with significant hypotension. Opioids can lead to bradycardia, although meperidine may lead to tachycardia due to its atropine-like effects.
Opioids impair gastric motility, leading to delayed gastric emptying. In addition, there is impairment of bowel motility that leads to constipation. Opioids may increase biliary tract pressure. In addition, urinary retention may occur because of bladder outlet spasm and inhibition of the voiding reflex.
Most opioids have the capacity to cause histamine release. This may lead to venodilation, skin flushing, and pruritus. These effects either may be seen locally at the site of injection or may be generalized. They do not reflect a true allergy, but rather are known side effects of the drugs. Pruritus may be caused by central CNS stimulation. In the absence of other signs, such as bronchospasm, rash, or angioedema, these should not be attributed to allergic reaction. Pruritus is more common with certain opioids, including morphine, than it is with meperidine. This side effect may be treated either with antihistamines or with naloxone.35
Opioids can be administered via a variety of routes, including oral, subcutaneous, intramuscular, intravenous, rectal, transdermal, and transmucosal.36 The choice of route will depend on the urgency of the situation, availability of intravenous access, patient convenience, patient preference, and staff availability. The use of each of these administration routes will lead to varying onset of activity and duration of action. For example, transdermal administration of narcotics may lead to a prolonged effect lasting up to 24 hours, while in the case of oral administration a variety of factors may affect bioavailability. Because opioids undergo extensive first-pass liver metabolism, routes of administration that bypass the portal system, such as sublingual, may have a greater initial affect at a given dose compared to oral administration.37
Both intramuscular and subcutaneous routes of administration are effective.38 Except in the case of patients with profound hypoperfusion, subcutaneous administration is as effective as intramuscular administration, with the advantage of somewhat less patient discomfort. This is, of course, common knowledge among street users who "skin-pop" when they cannot obtain intravenous access. In the past, nursing units utilized butterfly needles placed subcutaneously for intermittent administration of narcotics. This had the advantage of avoiding repeated intramuscular injections while providing a route of access that could be used repeatedly for up to three days. These are not common considerations for the ED where intramuscular administration often is used. The time to reach adequate effect after intramuscular administration of most opioids is within 20-30 minutes. Patients who have inadequate analgesia should receive an additional bolus of medication, but there is not a fixed interval that must pass before narcotics can be re-administered to a patient. A patient who remains awake and in pain may receive repeated boluses, with monitoring for analgesic effect, sedation, and respiratory depression. This requires repeated evaluation for inadequate analgesia. Several studies have shown that patients receive less than 25% of their prescribed pain medication in spite of ongoing pain.39 Older patients are more likely to receive inadequate analgesia.40
Intravenous administration leads to a much more rapid onset of effect. The interval to onset will vary depending on the lipid solubility of the opioid. Morphine is not particularly lipid-soluble, and thus has a somewhat delayed onset of action compared to fentanyl, which is much more lipid-soluble. Even so, the effects of morphine should be seen within 15 minutes. Patients with inadequate analgesia should receive repeated administration. For opioids with a more rapid onset of action, such as meperidine, the dosing interval may be shortened even further. As noted previously, there is no ceiling effect to opioid administration. The dose is limited only by the occurrence of side effects. An exception may be meperidine; cumulative doses greater than 600 mg per day may lead to the accumulation of toxic metabolites with subsequent development of CNS hyperactivity and seizures.41
Intermittent intravenous administration of opioids also may be given using patient-controlled analgesia devices. These are infusion pumps that are computer-controlled, allowing the clinician to vary the dose, dosing interval, and maximum amount of opioids that can be administered within a given interval.42 These are not commonly used in the ED, but patients may have experience with them from inpatient use. In the ED observation unit, their use may be considered for patients with painful conditions that are expected to be persistent, such as sickle cell crisis.43
Opioids also can be administered via transmucosal routes, and a variety of opioids are available for nasal administration, including butorphanol, fentanyl, and meperidine. Fentanyl also is available in a pediatric formulation, commonly referred to as a lollipop.44 This may be useful for analgesia and sedation of children prior to performance of painful procedures. Opioids are absorbed through the rectal mucosa; however this route of administration is not used commonly.
Many opioids are available as both immediate-release and controlled-release preparations. This onset of effect will vary depending on gastric motility. Because orally absorbed opioids undergo extensive hepatic metabolism, oral dose requirements are greater than intravenous doses for comparable analgesic effect. Oral administration of immediate-release opioids will have significant effect within one hour, but controlled-release preparations may not have significant effect before 3-4 hours. Oral opioids frequently are packaged in combination with non-opioid analgesics such as aspirin or acetaminophen.45 These combination products, however, limit the amount of opioid that can be administered, based on the limits of the non-opioid component.
The dose of opioid required may vary widely among patients. Typically, opioids are dosed on a milligram per kilogram basis, although there is little evidence that analgesic requirements are actually weight-related. Data from studies of patient-controlled analgesia devices show that daily narcotic requirements are age-based, with elderly patients requiring (or self-administering) lower total doses of opioids than younger patients. At a given age, however, opioid requirements vary by a factor of five, even at the same weight.46 Nevertheless, common dosing schemes use weight-based recommendations for children and small adults. The "typical" dose of morphine required for adequate analgesia is 10 mg, based on studies performed approximately 50 years ago. Equi-analgesic doses of other opioids for both intravenous and oral dosing also are available in common references. (See Table 2.) Clinicians may choose to begin with somewhat smaller doses out of concern for respiratory depression, although, again, if adequate analgesia is not achieved within a short period of time, then repeat doses should be administered.
| Table 2. Equivalent Doses of Common Opioids: Typical Starting Doses | ||||
| Drug Name | Adult Oral Dose |
Adult Parenteral |
Oral Pediatric |
Parenteral Pediatric |
| Morphine | ||||
| 30-60 mg q 3-4 hours |
10 mg | 0.3 mg/kg | 0.1 mg/kg | |
| Codeine | ||||
| 130 mg q 3-4 hours |
75 mg | 1 mg/kg | Not recommended |
|
| Hydromorphone | ||||
| 7.5 mg q 3-4 hours |
1.5 mg | 0.06 mg/kg | N/A | |
| Levorphanol | ||||
| 4 mg q 6-8 hours |
2 mg | 0.04 mg/kg | 0.02 mg/kg | |
| Meperidine | ||||
| 300 mg q 2-3 hours |
100 mg | Not recommended |
0.75 mg/kg | |
| Methadone | ||||
| 20 mg q 6-8 hours |
10 mg | 0.2 mg/kg | 0.1 mg/kg | |
| Oxycodone | ||||
| 30 mg q 3-4 hours |
N/A | 0.2 mg/kg | N/A | |
| Oxymorphone | ||||
| N/A | 1 mg q 3-4 hours |
N/A | Not recommended |
|
| Buprenorphine | ||||
| N/A | 0.3 mg q 6-8 hours |
N/A | 0.004 mg/kg | |
| Butorphanol | ||||
| N/A | 2 mg q 3-4 hours |
N/A | Not recommended |
|
| Nalbuphine | ||||
| N/A | 10 mg q 3-4 hours |
N/A | 0.1 mg/kg | |
|
|
||||
| From Acute Pain Management in Adults — U.S. Department of Health and Human Services, AHCPR Publication 92-0019. These represent typical starting doses. Individual adjustments may be necessary. N/A = Not available. | ||||
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Larger doses may be necessary for patients on chronic opioids for pain management or for recreational drug abusers. Long-term opioid use may lead to tolerance to various opioids in some patients, although this clearly is not a routine phenomenon.47 Patients who are tolerant to one opioid may be either completely or incompletely tolerant to other opioids. This has led to some recommendations that patients on chronic opioid therapy be rotated among various opioids. Patients on chronic therapy or chronic opioid abusers may develop a physical dependence. This may lead to withdrawal symptoms when either pure antagonists or mixed agonists antagonists are administered. Withdrawal also may occur when patients have malfunction of an opioid-containing epidural pump. The withdrawal syndrome is characterized by anxiety, hypertension, tachycardia, abdominal distress, diaphoresis, and piloerection. Because the occurrence of withdrawal symptoms cannot be predicted in patients on chronic opioid therapy, pure opioids, rather than mixed agonists/antagonists, should be used for acute management. The amount of increase over typical dosages is difficult to predict. Again, the best approach is the initial administration of a pure opioid with rapid titration to effect.
Morphine is the opioid against which other opioids are compared. Morphine is extensively metabolized in the liver, but the active metabolite morphine-6-glucuronide primarily is excreted renally.30 Morphine is readily absorbed from the GI tract. It is available in both rapid and sustained-release preparations.
Codeine is found in opium, along with morphine, although at much lower concentrations. Codeine is metabolized to morphine, which probably accounts for its therapeutic effect. The metabolism to morphine involves a specific enzyme of the P450 system, which is lacking in approximately 10% of caucasians. Patients deficient in this enzyme will receive no relief from codeine formulations. Codeine is a widely prescribed, although modest-potency, opioid. It has the advantage of high oral bioavailability and can be used safely in pregnant patients and those with renal insufficiency.
Oxycodone is available either alone or in combination with other agents. It is metabolized to agents with very limited analgesic properties. Oral oxycodone has 10 times the analgesic effect of codeine.48 The sustained release preparation of oxycodone recently has come into favor among recreational drug users and there have been extensive media reports about diversion of slow-release oxycodone prescriptions.
Meperidine was formulated originally as an atropine-like analog and has anticholinergic side effects. Normeperidine, the active metabolite meperidine, leads to CNS excitability with anxiety, twitching, myoclonus, and seizures. When it occurs, normeperidine toxicity is treated symptomatically, and naloxone does not reverse the effects of normeperidine. Methadone has a long half-life, with some effects thought to occur because of action on the N-methyl-D-aspartate receptors. As such, it may be very useful for the treatment of neuropathic pain.
Propoxyphene commonly is administered in conjunction with other non-opioid analgesics. Propoxyphene has weak analgesic properties and is about equivalent to aspirin. Occasionally, its use is associated with hallucinations and confusion, particularly in the elderly.49
Oxymorphone has a very rapid onset of effect, with a duration of around four hours. Oxymorphone has been reported to cause less histamine release than morphine.50 Hydromorphone is about six times as potent as morphine. It is absorbed readily from subcutaneous tissue, leading to popularity among drug addicts.51 Hydromorphone lacks active metabolites and may be useful in renal failure patients.
Fentanyl is a highly lipid-soluble opioid with rapid onset of effect.52 The duration of action increases with repeated administration. Rapid administration may lead to muscular rigidity or laryngospasm. It does not have active metabolites and can be used in renal failure.
Buprenorphine is an agonist/antagonist opioid that is highly lipid-soluble. It has excellent intramuscular absorption and a duration of action of around eight hours. It reportedly is less subject to abuse because of a lowered propensity to induce euphoria. Pentazocine is an agonist/antagonist, and was a common drug of abuse in the 1960s and 1970s. In combination with an antihistamine, it was known by the street name of "Ts" and "Blues." It has a higher incidence of dysphoric effects than many other narcotics.53 Butorphanol is available both as an intravenous and an intranasal preparation. Increasing doses does not lead to increasing likelihood of respiratory depression when using the intranasal preparation.54 The onset of analgesia after nasal instillation is about 15 minutes.
Tramadol. Tramadol has two mechanisms of action that make it an attractive option for patients with significant pain.55 As is the case with codeine, tramadol is converted by the cytochrome P450 system to an active opioid. Unlike codeine, however, tramadol has a separate mechanism of action inhibiting norepinephrine and serotonin reuptake. As such, codeine will be ineffective in Caucasians who are deficient in the CYP2D6 enzyme, while tramadol will still be effective, although, perhaps, at somewhat decreased potency. Because of its dual mechanism of action, tramadol is effective in a variety of pain mechanisms, including treatment of moderate to severe neuropathic pain.56 The mechanism of action of tramadol differs from NSAIDs, and the two drugs can be combined for enhanced analgesic effects. Patients occasionally may complain of nausea, dizziness, vomiting, diaphoresis, and somnolence. Unlike the NSAIDs, tramadol does not lead to significant GI toxicity, renal impairment, or platelet inhibition. Occasional seizures may occur, particularly in epileptics or in patients who are taking other epileptogenic drugs.57 The incidence of side effects can be minimized by beginning treatment in the evening at a low dose and then increasing as tolerated. Although tramadol has opioid-like effects, it has low abuse potential and is not a controlled drug.
Adjuvants. Adjuvant medications are a heterogeneous group of pharmaceuticals that act at a variety of sites along the pain pathway. Unlike NSAIDs and narcotics that are useful for most types of pain, adjuvants primarily are used for neuropathic pain or to augment other analgesics. Several of the most frequently used groups are discussed below.
Capsaicin. Capsaicin is available as a topical product and may be useful for neuropathy of various causes.58 It leads to a burning sensation, which may limit compliance even at low concentrations. Higher concentrations sometimes are used in combination with regional anesthesia or opioid sedation.59
Skeletal Muscle Relaxants. The skeletal muscle relaxants are a diverse group of drugs whose mechanisms of action are not understood completely. (See Insert: Click here.) They are believed to inhibit the spinal reflexes responsible for muscular spasm, which may contribute to and prolong the pain state. Some have suggested that their effects occur by causing sedation, with a subsequent decrease in descending nervous tone and spasm, but this has not been proven. In general, they have no direct effect on skeletal muscle.
Skeletal muscle relaxants have been studied extensively, and recent meta-analysis of these studies indicate that such medications are effective in the management of certain forms of acute pain, most notably acute low back pain.60, 61 These medications are not more effective than NSAIDs or acetaminophen; however, efficacy is increased when skeletal muscle relaxants are combined with an NSAID pain reliever. The lack of evidence for the benefit of long-term skeletal muscle relaxant use, combined with their potential for abuse, suggests that courses of the drugs exceeding several weeks are not appropriate for most patients.
Most skeletal muscle relaxants have good oral bioavailability and rapidly reach therapeutic concentrations. These medications are hepatically metabolized with subsequent renal excretion, and should be used with caution in patients with hepatic or renal dysfunction. Sedation is the most frequent side effect, and these medications should be used cautiously when other CNS depressants are likely to be used. Other side effects involve the CNS, including confusion, hallucinations, agitation, blurred vision, and dizziness. Nausea, vomiting, and abdominal pain are relatively common GI side effects.
Tizanidine shares its mechanism of action with clonidine in that both are centrally acting alpha-2-agonists, and have found utility in pain management. Tizanidine is effective in treating spasticity due to upper motor neuron lesions and in the management of acute low back pain.62 There is limited data that suggest that combining tizanidine with lower doses of NSAIDs may decrease the incidence of GI complications. Common tizanidine side effects include drowsiness, dizziness, and dry mouth. Tizanidine may cause significant hemodynamic effects, including bradycardia and hypotension, and has been associated with transient liver enzyme elevation.
Although there is some controversy, studies show that clonidine may have a role in chronic pain management.63 Clonidine has analgesic properties superior to ibuprofen and codeine and enhances the efficacy of opioids.64,65 Transdermal clonidine has been demonstrated to be effective in reducing discomfort from diabetic neuropathy.66 When used for pain management, clonidine is given either by transdermal patch (changed once per week) or by oral administration starting at 0.1 mg twice per day.
Antidepressants. Antidepressants, primarily the tricyclic antidepressant (TCA) medications, probably are the most extensively studied adjunctive medications in pain management. These medications have proven efficacy in the management of neuropathic pain due to diabetes and post-herpetic neuralgia and frequently are used for other types of neuropathic pain. Evidence also supports the use of TCAs in tension- and migraine-type headaches, but the drugs have demonstrated little efficacy in the management of low back pain unless a neuropathic component is present.67,68 Their primary mechanism of action is believed to occur by inhibition of norepinephrine and serotonin reuptake, both of which are important neurotransmitters within the spinal cord. The analgesic effects of TCAs appear to be separate from their effects on mood.69
While TCAs are useful in neuropathic pain syndromes, they are associated with numerous side effects that frequently limit use. The most concerning adverse reactions typically involve the cardiovascular system and include orthostatic hypotension, tachycardia, conduction abnormalities, and arrhythmias. It may be prudent to evaluate an EKG for QT prolongation before initiating TCAs. Other common side effects are primarily anticholinergic in nature and include dry mouth, urinary retention, and visual changes, with sedation also quite common. They are contraindicated in people with glaucoma and should be used with caution in patients with urinary retention. They are associated with impotence and may cause changes in appetite. These medications should not be used within two weeks of cessation of monamine oxidase inhibitor (MAOI) therapy.
Because TCAs have numerous side effects and frequently are tolerated poorly by patients, the newer selective serotonin reuptake inhibitor (SSRI) class of antidepressants has been studied for use in neuropathic pain. While there have been a few trials demonstrating their efficacy, the results have tended to be disappointing,68 likely due to their relative selectivity for only serotonergic reuptake inhibition. Newer related medications, such as venlafaxine, that act on both serotonergic and adrenergic systems without the side effects associated with tricyclics, show promise, but further studies are needed.
Amitriptyline is the prototypical TCA for neuropathic pain, but it is associated with the most adverse effects. In neuropathic pain, a dose of 25-mg is used to start, with subsequent increases by 25 mg every three days until the appearance of side effects or until a dose in the range of 100-150 mg per day is achieved. Elderly patients should be started at 10 mg daily with 10-mg increment increases every three days as tolerated. Patients should be informed that complete pain relief is unlikely when using these medications, and relief may take several weeks. As with all antidepressants, abrupt cessation should be avoided.
Anticonvulsants. Anticonvulsant medications frequently are used for the management of neuropathic pain. Most are believed to act by decreasing spontaneous firing of fibers within nerves while allowing normal impulse propagation. Previously, their use was limited by a significant number of side effects, but newer anticonvulsants, such as gabapentin, offer similar efficacy to other anticonvulsants and have a relatively benign side effect profile. Their utility in the ED likely resides in the treatment of specific pain conditions such as trigeminal neuralgia, post-herpetic neuralgia, headache, and complex regional pain syndromes. They also are useful in peripheral neuropathy, especially when TCAs are tolerated poorly or are contraindicated. There is little convincing evidence supporting efficacy of one anticonvulsant over another.
Carbamazepine is the only anticonvulsant approved by the FDA for neuropathic pain management, and it is useful in diabetic neuropathy and trigeminal neuralgia.70 The initial dosing is 100 mg bid-qid, with increases of 100 mg/day every 3-7 days to a maximal maintenance dose of 1200 mg/day, or until the appearance of side effects. It has been suggested that some patients with exacerbations of trigeminal neuralgia may require doses higher than 1200 mg/day on occasion.71 Carbamazepine interacts with numerous other drugs and has side effects that include leukopenia and, rarely, aplastic anemia, so serum drug levels and blood counts should be checked. Other side effects involve the CNS and include sedation, ataxia, fatigue, vertigo, and blurred vision. Nausea, vomiting, and rash also are common and appear to be dose-related.
Gabapentin is perhaps the most widely used anticonvulsant for treating neuropathic pain in the United States, and is considered the first-line anticonvulsant by many pain specialists. It has demonstrated efficacy in painful diabetic neuropathy and post-herpetic neuralgia.72,73 There is preliminary data suggesting utility in other painful conditions. The recommended dosing is 300 mg/day with subsequent increases of 300 mg/day up to total doses of 3600 mg/day, which generally are well-tolerated. The commonly reported side effects include dizziness, ataxia, fatigue, and somnolence. Dosage modification is necessary for renal impairment; however, the drug is not hepatically metabolized, hence no changes are necessary in those with liver disease.
Phenytoin is known to be effective in treating neuropathic pain, but drug interactions and side effects have limited its use. Its availability in parenteral form previously made it appealing for use by emergency physicians for patients with severe and frequent trigeminal neuralgia, but fosphenytoin has a more rapid onset of action.74 Fosphenytoin is the prodrug of phenytoin, but intravenous administration of fosphenytoin is associated with fewer adverse events such as pain, itching, and hypotension. Fosphenytoin rapidly is converted to phenytoin by the body.75 Parenteral administration of phenytoin also is useful during acute flares of other chronic neuropathic pain conditions.76 The common side effects include nystagmus, ataxia, slurred speech, decreased coordination, confusion, and GI upset. Phenytoin is metabolized extensively by the liver and, as such, individuals with liver impairment are more likely to develop toxicity.
Valproic acid has efficacy in migraine prophylaxis and may be useful for acute migraine treatment at doses of 300-mg IV, but this has yet to be demonstrated in large placebo-controlled studies.77,78 There is also some evidence of efficacy in trigeminal neuralgia, but it is not a first-line treatment. As with most other anticonvulsants, its use in chronic pain has been limited by side effects and toxicity. Nausea, vomiting, dizziness, tremor, malaise, somnolence, headache, hair loss, and GI complaints may occur. Valproic acid is associated with potentially serious liver toxicity, including elevated liver enzymes and hepatic failure, especially in younger patients, and its use in patients with known liver disease is contraindicated. Valproic acid and its derivatives affect numerous other drugs’ metabolism, and plasma concentrations should be followed.
Other Adjuvant Medications. Recently, a topical lidocaine patch has been approved and has found utility in pain management. The lidocaine patch has been shown to be effective in treating post-herpetic neuralgia79,80 as well as pain associated with minor cutaneous surgical procedures.81 The patches are available in 5% strength by prescription and up to three patches may be placed over the affected area and left in place for 12 hours.
Implanted Analgesia Devices. Epidural or intrathecal implanted pumps are not placed in the ED; however, emergency physicians may be called upon to assess patients with ineffective or malfunctioning equipment. Epidural catheters are placed between the dural and the spinal ligaments and vertebral bodies. This space contains the nerve roots, so that epidural catheters allow the administration of anesthetic or analgesic drugs directly to the nerves as they exit the spinal canal. Intrathecal catheters are placed in the subarachnoid space, in which case the medication is mixed with cerebrospinal fluid (CSF). Because the intrathecal CSF space is continuous with the upper spinal cord, and with CSF bathing the brain, intrathecal administration generally is reserved for spinal anesthesia at the time of surgery.
Epidural catheters may contain either local anesthetics or opioids. Opioids injected into the epidural space may be absorbed into the systemic circulation, particularly for highly lipid-soluble opioids. Local anesthetics also may be used for epidural analgesia, and occasionally clonidine is added to the solution to improve efficacy.
There is some risk of respiratory depression from epidural analgesia.82 The highly lipid-soluble opioids may cause early respiratory depression; however, for ambulatory patients the lipid-soluble opioids are less likely to be a cause of respiratory depression, because they are rapidly absorbed and also rapidly cleared from the CSF. As is the case with systemic administration of opioids, epidural administration of opioids can lead to a similar spectrum of side effects, including sedation, nausea, urinary retention, constipation, and pruritus. Local anesthetics cause a range of side effects similar to systemic administration of local anesthetics, including the potential for precipitation of seizures. Hypotension can occur due to sympathetic block; however, given the low concentrations generally used for ambulatory management, this is an unlikely occurrence. Nausea and vomiting are less common with epidural administration of local anesthetics than with opioids. Motor and sensory blocks are rare side effects. Urinary retention is an uncommon but occasional side effect. Occasionally, opioids and local anesthetics are combined to minimize the adverse effects of either agent when used alone in larger doses.
The emergency physician may see patients for complications of epidural analgesia. Dural puncture is an undesired side effect of the placement of epidural catheter. It occurs in 1% or less of patients, and headache occurs following dural puncture in a variable percentage of patients. Post-dural headaches generally are seen soon after catheter placement and typically are bilateral or occipital, increased with straining, and are associated with nausea and vomiting. The treatment consists of fluids and analgesia. An intravenous infusion of 1 g of caffeine may be useful. The anesthesiologist who placed the epidural catheter may wish to place a "blood patch" to seal the CSF leak.83 Epidural hema-tomas are rare complications of catheter placement. The incidence is somewhat increased in patients who are receiving concomitant anticoagulants, including the low molecular weight heparins.84 These patients may present with neurological deficits such as motor weakness or incontinence. Infections, fortunately, are rare, but may present with increasing back pain, tenderness, fever, or signs of local infection. Patients most at risk for epidural space infection include patients who are otherwise immunocompromised, including transplant patients, cancer patients, patients on chronic high-dose steroid therapy, alcoholics, or diabetics.
More commonly, patients will present with signs of system malfunction. Epidural catheters may migrate out of the epidural space. Migration out of the epidural space will lead to ineffective analgesia. Migration into the intrathecal space raises the possibility of higher level blocks with concomitant respiratory impairment. Patients may notice that they have a decrease in effectiveness of analgesia or, in the case of local anesthetic administration, they may notice that areas of decreased sensation have now changed. In addition, effective analgesia may be terminated by kinking of the catheter or a pump malfunction. As is the case with systemic administration of opioids, rescue therapy may be necessary for side effects, including antiemetics for nausea or vomiting, naloxone or antihistamines for pruritus, a decrease in dosage for patients with excessive sedation, or co-administration of small doses of naloxone for urinary retention.
Special Considerations
Acute pain. The patient in acute pain is the most frequently encountered patient in the ED and is the easiest to treat. While determining the cause of the pain and initiating treatment are obvious priorities, the assessment and treatment of pain should begin as early as is feasible. The most frequently employed medications for acute pain are opioids and NSAIDs, which may be combined to minimize the opioid dose. Patients in moderate to severe acute pain should be treated with short-acting opioids or ketorolac. Pain should be reassessed at regular intervals, and additional analgesics given as necessary. The determining factor in analgesic response should be patient report rather than arbitrary doses.
Discharge medications should include adequate analgesics to cover the patient for the expected length of pain or until he or she can be seen by another physician. Patients should be instructed to take NSAIDs on a regular schedule when pain is likely to be constant or if inflammation is present, and it should be stressed that these medications are not solely for pain relief but to reduce inflammation as well. Likewise, opioids should be taken on a regular basis to avoid recurrence of pain. It should be stressed to patients that they will receive more complete pain relief if they take such medications at regular dosing intervals rather than waiting until pain is severe.
Chronic Pain. Not all chronic pain can be completely relieved, and the primary goal is improvement in comfort. The clinician should keep in mind that exacerbation of chronic pain can be due to the development of tolerance, progression of disease (as in the case of a cancer patient), an unrelated problem, or the development of a complication of the underlying disease.
These patients often have seen numerous physicians previously, tried many medications without success, and sometimes are viewed as demanding or manipulative. Most come to the ED with an idea of what will work, and it often is helpful to ask these patients directly what will help them. While the emergency physician may not be in a position to manage all aspects of a chronic pain patient’s disorder, patients should expect to have their complaints taken seriously and to have real treatment options offered.
Most patients with chronic pain already will be taking several medications for their pain. It is important to elicit all medications that the patient is taking, as it is not uncommon for such patients to utilize non-prescribed medications from family or friends. The use of illicit drugs also is not uncommon. Frequently these patients can be managed with a short course of analgesics in the same manner as the patient with acute pain, and if they are not already involved with a pain specialist, referrals may be provided. Communication with the patient’s primary care physician may be helpful.
Patients who are receiving chronic opiate therapy may exhibit signs of tolerance to their medications over time, and such signs should trigger notification of their pain physician that dosages may need to be increased. There is no ceiling effect for opioid analgesics, and as such, these patients may benefit from additional opioids, a change in analgesic regimen, or the addition of adjunctive agents. The development of tolerance may be agent-specific and a switch to a different opioid may be effective.
Patients on long-term opiates may benefit from a short course of NSAIDs, if they are not already taking them, as well as adjuvants such as skeletal muscle relaxants. Medications that are mixed opioid receptor agonist/antagonists should be avoided because of the possibility of precipitating a withdrawal reaction. There have been occasional reports that tramadol can precipitate opioid withdrawal. Clonidine may be helpful as an adjunctive agent for patients on substantial doses of oral opioids.
Pain Control in Children. Pain assessment sometimes is difficult in children, especially in the very young or in those with other impairments. For infants and very young children, observation of reflexive behaviors, such as withdrawal and crying, are important, whereas somewhat older children may engage in running away, hitting or biting, rubbing painful areas, or widening their eyes. At the age of 5 or 6 years, children often are able to rate pain. Children may be hesitant to report pain for fear of receiving treatments that are briefly painful. It may be helpful to enlist the parents’ help in assessing the degree of the child’s discomfort.
The treatment of children in acute pain is similar to that for adults, with opioids and NSAIDs being most useful. Short-acting opioids such as fentanyl and morphine are good choices for initial parenteral therapy. The judicious use of small doses of anxiolytics may be helpful in some pediatric patients, keeping in mind that they may potentiate the sedation caused by opioids.
Home-going medications should include adequate analgesics, but consideration must be made for the patient’s age and tolerability of pills. Many NSAIDs are not recommended for children, although some, such as ibuprofen, are available in suspension form. Some opioids, such as codeine and hydromorphone, are available as elixirs. Morphine and some other opioids may be given as rectal suppositories. Nasal stadol is an attractive alternative for children with intermittent, moderate pain. The physician should instruct caregivers as to acceptable over-the-counter medications to combine with prescriptions given.
Pain Control in the Elderly. Pain control in the elderly may be complicated by numerous factors. These patients typically have underlying concomitant problems, and assessment is sometimes complicated by hearing or visual impairment. The elderly are more likely to develop chronic pain syndromes such as trigeminal neuralgia, post-herpetic neuralgia, and temporal arteritis. Clinicians should be aware of minimization of pain by the elderly, either as an attempt at denial or to avoid consequences such as nursing home placement. Hepatic or renal impairment may complicate drug dosing.
The first-line drug for mild to moderate pain in older people is acetaminophen because of its relatively benign side effect profile. NSAIDs with relatively less GI toxicity, such as ibuprofen or etodolac, may be preferred. The COX-2 inhibitors rofecoxib and celecoxib should be used for patients with a history of NSAID intolerance or risk factors for GI side effects. As noted above, there may be benefits to celecoxib over rofecoxib. The elderly may benefit from starting at a lower dose than that used with younger adults.
Pain unresponsive to initial non-opioid therapy, or pain that is moderate to severe at presentation, warrants the use of an opioid. Generally, short-acting pure agonists are preferred as parenteral therapy. Oral therapy may include codeine, tramadol, hydromorphone, or transmucosal fentanyl. Tramadol, hydromorphone, and fentanyl all lack active metabolites and are useful in patients with impaired renal function. Opioids are likely to cause constipation in older patients, and stool softeners should be used. Codeine is known to be relatively more constipating, and patients should be counseled about diet and fluid intake when it is used. Elderly patients are more likely to experience dysphoria, delirium, and respiratory depression even at reduced dosages of opioids. This is a particular problem when propoxyphene is used in the elderly.
Because of the nature of many of their pain complaints, the elderly may benefit most from adjuvant medications. Unfortunately, many of the severe side effects associated with such agents are more pronounced in the elderly. Skeletal muscle relaxants and anticonvulsants can provide significant pain reduction when used judiciously, and these medications frequently offer opioid sparing effects. As previously mentioned, these medications may interact with others synergistically, leading to profound sedation. TCAs may potentiate the anticholinergic effects of other medications with similar action. The first-line anticonvulsant in elderly patients should be gabapentin, unless specific contraindications are present. Initial dosing is 100 mg tid with subsequent increases of 300 mg per day every 3-5 days thereafter.
Conclusion
All patients should expect to have their pain managed when presenting to the ED. (See Table 3.) Pain should be assessed in all patients, and a more in-depth assessment performed when pain is reported. The single scale pain severity indexes offer a relatively easy way to rapidly assess patients. The long-term consequences of inadequate pain control make it clear that pain is not a benign process. There are a variety of options for the initial treatment of acute pain and the long-term treatment of chronic pain. Referral to a pain center may be necessary for some patients with complex problems.
| Table 3. Approach to Pain Management in the Emergency Department | |
| General Principles | |
| 1. | The extent of pain should be assessed and a pain history obtained when appropriate. |
| 2. | Analgesia should be given as early as feasible. |
| 3. | Patients should be questioned about home pain treatment, and ED treatment should take into account success or failure with prior analgesic use. |
| 4. | Children and other patients with limited communication skills still feel pain, and care should be taken to assess their pain. |
| 5. | A reasonable dose of analgesics should be chosen based on the patient's age, size, and coincident medical problems. Dosing should be repeated if initially ineffective and then repeated if pain recurs. |
| 6. | While emotional and psychological factors may influence pain perception, rarely is a complaint of pain purely psychiatric in origin. |
| 7. | Opioids are the most effective method of pain control for moderate to severe pain and are exceptionally safe when simple precautions are taken. |
| 8. | Treatment is based on the patient’s perception of pain, except under limited circumstances.85 |
| 9. | The risk of iatrogenic addiction to narcotic medications when treating acute pain for short intervals is extremely low. |
| 10. | Adjuvant medications should be considered in patients with neuropathic pain or where adequate doses of narcotics are ineffective. |
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