Emergency Medicine Clinics of North America Volume 18 • Number 4 • November 2000 Copyright © 2000 W. B. Saunders Company PHARMACOLOGIC ADVANCES IN EMERGENCY MEDICINE PHARMACOLOGY OF EMERGENCY DEPARTMENT PAIN MANAGEMENT AND CONSCIOUS SEDATION Paul Blackburn 1 DO, FACOEP, FACEP Robert Vissers 2 MD, FRCPC, FACEP 1 Department of Emergency Medicine, Maricopa Medical Center, Phoenix, Arizona (PB) 2 Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (RV) Address reprint requests to Paul Blackburn, DO, FACOEP, FACEP Department of Emergency Medicine Maricopa Medical Center 2601 East Roosevelt Phoenix, AZ 85008

PAIN MANAGEMENT Appropriate treatment of pain and anxiety is a major portion of the practice of emergency medicine. Nearly all studies to date have demonstrated that physicians are poor at adequately treating pain. The usual reasons cited for this inadequate administration of analgesics are concerns of adverse affects such as respiratory depression with higher dosages, and addiction with prolonged treatment courses. The term oligoanalgesia was coined to describe the underutilization of analgesics to treat pain, a practice reported to occur in a significant proportion of emergency department (ED) patients, particularly in pediatric patients and patients of different ethnicities.[17] [51] [73] [74] [86] [89] [90] [98] Of note, oligoanalgesia is now more than a purely clinical concern. In 1999, the Oregon Board of Medical Examiners disciplined a physician for

failing to treat adequately the pain of several of his patients, marking the first time a medical board in the United States has taken action for failing to provide adequate pain relief to patients.[82] Routes of Administration Oral The major advantage of oral administration is ease of delivery. The efficacy of agents delivered orally depends on several variables: gastrointestinal absorption, hepatic metabolism, lipophilicity, pH sensitivity, and solubility. Adverse effects can include aspiration and emesis.[71] Rectal Generally well tolerated, the rectal route avoids the pain of parenteral administration, the risk of aspiration, and results in less residual unabsorbed drug than the oral route.[71] Inhalation Nitrous oxide is the only practical inhalable sedative/analgesic for ED use and has been proved safe and effective. Most newer units have scavenging equipment built in, avoiding the need for special ventilation requirements.[71] Intravenous Medications delivered intravenously have the most rapid onset and allow for precise titration to effect. The requirement of vascular access is a disadvantage. Intramuscular The advantage of medication by injection is ensuring drug delivery without requirement of vascular access. Disadvantages include pain on injection(s), delayed action, and the possibility of erratic absorption. TYPES OF MEDICATIONS There are three major classes of analgesic medications available: opioids, nonopioids (including aspirin, acetaminophen, and other nonsteroidal antiinflammatory drugs [NSAIDs], and a third category of medications not normally considered analgesics, that either act

as adjuvants when combined with opioid or nonopioid medications, or that have intrinsic analgesic activity with some types of pain. Opioids Opioids are considered the drugs of choice for severe pain, although in some instances NSAIDs can be as effective.[48] Opioids are classified as full agonists, partial agonists, or mixed agonistantagonists. Morphine, meperidine, hydromorphone, oxymorphone, methadone, levorphanol, fentanyl, and oxycodone are used for more severe pain. Morphine and the other full agonists, unlike NSAIDs, generally have no ceiling for analgesic effectiveness except that imposed by adverse reactions. Propoxyphene, pentazocine, and oral codeine and its congeners in usual doses are no more effective when taken alone than is aspirin or acetaminophen, and usually are prescribed in combination with these drugs to treat moderate or moderately severe pain.[5] Adverse Effects Respiratory depression is the most important adverse effect of opioids. Most patients develop tolerance to the respiratory effects, but addition of other medications such as sedative-hypnotics (as in conscious sedation), general anesthetics, phenothiazines, or tricyclic antidepressants can increase the risk. In addition, those patients with an underlying pulmonary condition can experience decreased respiratory drive or apnea with "usual" doses of opioids, including the mixed agonist/antagonists. The most common adverse effects are sedation, lightheadedness, nausea and vomiting, and constipation. Sedation can be addressed by decreasing the dose while concomitantly increasing the frequency of administration, by using opioids with shorter half-lives, or by administering small doses of dextroamphetamine or methylphenidate in the morning and early afternoon.[13] Constipation is addressed by the use of stool stimulants or stool softeners. Transdermal fentanyl can cause fewer adverse effects than sustained-relief oral morphine.[65] Tolerance Tolerance to the analgesic effects of opioids is common with chronic administration and is noted by the patient as decreasing duration of action and effectiveness of the medication. Tolerance to most adverse affects, such as respiratory and central nervous system (CNS) depression, nausea, and sedation develops as well.

Tolerance to the constipating effect does not occur. Delaying or avoiding tolerance can occur by combining opioids with nonopioid analgesics and administering lower doses. Cross-tolerance of all full agonists occurs but is not complete. One therefore can attempt to regain pain control by switching to a different opioid and beginning dosing at approximately one half the equianalgesic dose.[5] Dependence Clinically significant physical dependence develops after several weeks of therapy with larger doses of full agonist opioids, although it can be detected within a few days of therapy initiation if an antagonist is administered. If the patient becomes dependent, abstinence symptoms occur if the medication is discontinued suddenly or an antagonist is administered. Patients taking opioids for acute pain or chronic cancer pain only rarely experience euphoria and only very rarely develop physical dependence or mood-altering effects.[5] Choice of Opioid All of the full agonist opioids are equally capable of relieving acute pain if the dose is adjusted appropriately. The higher doses of codeine and meperidine that would be equianalgesic, however, would lead to unacceptable adverse events.[5] Full Agonists Morphine. Morphine is considered the standard of comparison for strong parenteral analgesics. It also can be administered orally or rectally.[10] Orally administered morphine is well absorbed but is subjected to extensive first-pass metabolism in the liver. Sustained-release oral preparations have a longer duration of action.[94] Morphine has no greater dependence liability than any other equally effective doses of full agonist. The dosage is 0.1 to 0.2 mg/kg intravenously (IV) intramuscularly (IM) or subcutaneously (SC). The onset of action after IM injection is 20 to 60 minutes, with a duration of action of 4 to 5 hours. Meperidine. Meperidine is a synthetic narcotic analgesic that can be administered orally or parenterally. If given IM or SC meperidine is irritating to tissues, incompletely and erratically absorbed, and

shorter acting than morphine. Meperidine is metabolized to normeperidine. Normeperidine's 15- to 20-hour half-life far exceeds that of meperidine, and accumulation occurs, particularly with large repeated doses or decreased renal function. Normeperidine can cause dysphoria, irritability, tremors, myoclonus, and seizures. Patients given meperidine who are concomitantly taking monoamine oxidase (MAO) inhibitors or medications with MAO properties can develop severe encephalopathy that can be fatal.[6] Meperidine therefore, should be used only for short-term treatment of acute pain and should not be prescribed in high or repeated doses. The usual dose is 1.0 to 2.0 mg/kg IV or IM. The onset of action following IM injection is 15 to 30 minutes, with a duration of 3 to 4 hours. Fentanyl. Fentanyl is the opioid most commonly used to provide analgesia during procedural sedation (see definition later in this article) in the ED.[45] [66] A synthetic opioid related to the phenylpiperidine family, it is very lipid soluble, leading to a much more rapid onset and higher potency than morphine.[24] When given parenterally, onset of analgesia can be in as short a time as 90 seconds. In equivalent doses, fentanyl is approximately 100 times as potent as morphine and 1,000 times more potent than meperidine.[24] [49] It is eliminated primarily by the liver and has an elimination half-life of 3 hours, which is slightly longer than morphine. Its high degree of lipid solubility leads to rapid redistribution into tissues from the CNS however, and serum, giving it a much shorter duration of action. Its volume of distribution is about 4 L/kg. Fentanyl's clinical effects in the acute setting are approximately 30 minutes.[24] Continuous infusion of fentanyl can lead to prolonged duration of effects once tissue sites are saturated; however, this is rarely an issue the emergency setting. As all other opiods, fentanyl, does not reliably produce sedation or unconsciousness and should not be considered a true anesthetic. It causes a dose-dependent depression of ventilation by decreasing the responsiveness to the stimulatory effects of carbon dioxide.[24] [66] The respiratory depression seen with fentanyl is less than that with either morphine or meperidine.[5] Fentanyl produces minimal hemodynamic effects, and because of this is a popular agent during cardiac anesthesia.[24] [66] Histamine release is minimal compared with other narcotics.[24] The recommended dose for both adults

and children is 2 to 4 mug/kg titrated in IV doses of 0.5 to 1 mug/kg given slowly every 3 to 5 minutes.[24] [66] [71] The metabolism of fentanyl in infants is prolonged, leading to a recommendation of using one third the normal dose in this age group.[71] Caution must be used because of the microgram dosing of fentanyl, and when fentanyl is used in conjunction with benzodiazepines, because the risk of severe respiratory depression.[71] Sedation is inconsistent, and most patients maintain awareness at these doses. Fentanyl is therefore commonly combined with a sedating agent such as midazolam or propofol during procedural sedation.[24] [71] When compared directly with midazolam for sedation in children, midazolam was the drug of preference in the majority of patients.[72] Oral transmucosal fentanyl citrate has been used successfully in children when IV access is not feasible.[66] [71] [75] This "lollipop" preparation is formulated in a dose of 10 to 15 mug/kg.[75] Direct absorption into the systemic circulation avoids first-pass metabolism and produces effects in 12 to 30 minutes. Although the onset is relatively rapid, titration is difficult using this route of administration and carries with it the same risks of respiratory depression.[66] [75] Transdermal fentanyl patches can be used for painful conditions requiring longer periods of analgesia. Respiratory compromise and apnea have been associated with fentanyl use during procedural sedation in the ED, but it is relatively rare and usually transient.[24] Maximal respiratory depression occurs 5 minutes after administration, is dose dependent, and is most common when combined with a sedating agent. In a study of 841 patients receiving fentanyl in the ED, only 6 experienced respiratory depression, 4 of whom had associated ethanol levels in excess of 160 mg/dL.[24] Chest wall and glottic rigidity have been reported with high-dose fentanyl, resulting in the inability to ventilate the patient.[66] [71] [84] This complication tends to occur at much higher doses than used in the ED and with rapid infusion and has not been reported in the emergency medicine literature.[66] [71] [84] Rigidity can be reversed only partially with naloxone and patients can require paralysis and intubation for ventilatory support.[49] [71] [84] Fentanyl is also associated with nausea, vomiting, and mild facial pruritis. Hypotension is uncommon but can occur, particularly when ethanol is present.[24]

Other Short-acting Opioids Alfentanyl is a fentanyl derivative that is approximately one fifth as potent as fentanyl.[59] [66] Despite a lower lipid solubility, alfentanyl remains nonionized at physiologic pH and therefore has a very rapid onset of action of between 45 and 60 seconds.[61] Because of its higher clearance rate and lower volume of distribution, it has a slightly shorter duration of action (30-40 minutes) and does not suffer accumulative effects from repeat dosing or drips.[59] [66] The total IV dose is usually 5 to 20 mug/kg, titrated in 2.5 to 5 mug/kg doses administered slowly over 5 minutes. Remifentanil and rapifentanil are both piperidine derivatives of fentanyl, with pharmacologic effects similar to other short-acting opioids. Their onset is similar to alfentanyl, but their duration of clinical action appears to be much shorter (approximately 8-15 min).[49] Mirfentanil is a short-acting agent from a new class of opioids that are structurally related to fentanyl, which have mixed agonist and antagonist effects at the mu receptor. It appears to have respiratory-sparing effects within the normal analgesic range, but few studies have been performed and its clinical utility is yet to be determined.[49] Codeine. Although it is one of the more popularly prescribed pain medications, any efficacy of codeine in relieving pain described as more than mild to moderate must be questioned. A meta-analysis of 24 randomized, controlled studies comparing acetaminophen alone with acetaminophen with codeine 60 mg found only a 5% difference in added benefit.[30] The usual dosage is 0.5 mg/kg up to 15 to 60 mg orally (PO) or IM every 4 to 6 hours as needed. Hydrocodone and Oxycodone. Semisynthetic analogues of codeine, these agents both are more potent than codeine, with oxycodone slightly more potent that hydrocodone. Both are available in liquid formulation. Hydromorphone. Hydromorphone is a potent analgesic that has excellent bioavailability when given PO, and it also comes in a suppository preparation. Owing to its high solubility, large doses can be

administered parenterally in small quantities of fluid. There may be a particular role for hydromorphone in sickle cell disease.[64] The dosage of hydromorphone is 1 to 4 mg IM/SC/IV every 4 to 6 hours, 2 mg to 4 mg orally every 4 to 6 hours, or 3 mg rectally every 6 to 8 hours. Methadone and Levorphanol. Methadone and levorphanol are administered PO and are occasionally used to relieve pain in cancer patients who have become tolerant to morphine.[69] One must monitor these patients carefully, particularly if they are elderly or debilitated, because the long half-lives of the drugs (methadone: 24-36 h, levorphanol: 1216 h) can lead to accumulation and CNS depression.[5] Tramadol. Tramadol is an opioid agonist that also blocks reuptake of norepinephrine and serotonin. It is marketed for treatment of moderate to moderately severe pain.[3] It appears to be as effective as combinations of aspirin or acetaminophen with codeine or propoxyphene.[55] Because seizures have been reported in patients taking tramadol, patients with a history of seizures, or those concomitantly taking antidepressants, MAO inhibitors, or antipsychotic medications, could be at risk.[5] Tramadol is not free from the psychic or physical dependence properties of other opioids. Partial Agonists and Mixed Agonist/Antagonists This subset of opioids consists of synthesized medications designed to provide analgesia with less potential for respiratory depression and abuse. The medications produce both agonist and antagonist effects, varying by medication, as a consequence of which class of opiate receptor is stimulated and to what degree. Although the primary advantage to these medications is diminished respiratory depression compared with full opioids, they also produce less biliary spasm and appear to have diminished abuse potential.[64] All have an analgesic ceiling that is approximately equal to that of moderate narcotic doses. All are capable of precipitating withdrawal in patients physically dependent on full agonists. All can lead to dependence but are less likely to do so than full agonists.[5] Pentazocine.

Introduced in 1967, pentazocine was the first agent in this class. Side effects have limited the effectiveness of this medication, with up to 7% experiencing a psychomimetic reaction that can include hallucinations (visual or auditory), disorientation, dysphoria, and feelings of depersonalization or panic reactions. Subsequent to a period of parenteral abuse popularity in the 1970s, the manufacturer combined pentazocine with 0.5 mg naloxone in its tablets (Talwin NX). As naloxone is not absorbed by the gut, oral pentazocine remains effective.[64] Pentazocine is the only agent in this class that can be administered orally and is only available in combination products.[5] The dose of parenteral pentazocine is 30 mg IV/IM every 3 to 4 hours. The oral dose is 1 tablet (pentazocine 50 mg + naloxone 0.5 mg) every 3 to 4 hours. There are few, if any, indications for which pentazocine offers any clinical advantage for production of analgesia. Nalbuphine. The advantages of nalbuphine are the ceiling on respiratory depression, no demonstrated cardiovascular effects, and an incidence of psychomimetic reactions that is considerably less than that of pentazocine. There appears to be low potential for abuse. The half-life of the drug is 3.5 hours, but the effects of metabolism in the face of renal or hepatic disease are unknown. Of interest, nalbuphine is not subject to regulation under the Controlled Substance Act. This could be of benefit to EMS systems that do not use opioids because of difficulties of maintaining or regulating distribution of controlled substances. Nalbuphine has been demonstrated safe and effective in the prehospital environment.[22] [64] [83] The usual dosage is 10 mg to 20 mg IV/IM/SC every 3 to 6 hours. Butorphanol. A synthetic opioid, butorphanol has properties similar to nalbuphine, with the significant difference that butorphanol increases systemic and pulmonary artery pressures. Because of the increase in cardiac afterload, butorphanol is not recommended in myocardial infarction or states of decreased cardiac function. Sedation is the most common side effect. The incidence of psychomimetic side effects is much lower than that of pentazocine. The half-life is about 3 hours, and both hepatic and renal excretion contribute to drug elimination.[64] The usual dosage is 1.5 mg to 2.0 mg IV or 1 to 4 mg IM every 3 to 4 hours. Of note, butorphanol

is available in a nasal spray. Intranasal administration results in rapid absorption that can be self-administered by the patient.[64] Each nasal application delivers approximately 1 mg of drug and can be administered every 3 to 4 hours. The analgesic effect of nasal administration is comparable to IM injection. Drug dependence and abuse have become a serious problem with use of butorphanol nasal spray for treatment of migraine, however.[5] Buprenorphine. Buprenorphine is a semisynthetic opioid agent with similar qualities to the other agonist/antagonist agents. It is well absorbed PO and sublingually but this preparation is not available in the United States at this time. Although it has a half-life of 2 to 3 hours, the duration of analgesia is much longer because of strong binding at the opiate receptor. Whether there is a total ceiling on respiratory depression in humans in unknown. Opioid antagonists do not completely reverse its actions.[64] Buprenorphine has essentially no psychomimetic effects.[5] The usual dose is 0.3 to 0.6 mg IV/IM every 6 to 8 hours. Dezocine. Dezocine is a synthetic opioid agonist/antagonist with analgesic potency, onset, and duration of action in the relief of postoperative pain comparable to that morphine. It is not currently available in the United States. Dezocine is rapidly and completely absorbed following IM injection. Following a 10-mg infusion over 5 minutes, the average half-life is 2.4 hours. One must give cautiously in reduced dosages in those patients with hepatic or renal dysfunction. It is not recommended for those under 18 years of age because safety in this age group has not been established. Dezocine contains sodium metabisulfite, a sulfite that could cause allergic reactions, including anaphylaxis and life-threatening or less severe asthma episodes in certain susceptible patients. Dezocine and morphine produce similar degrees of respiratory depression when given in the usual analgesic doses, they but share the ceiling effect with other agonist/antagonists in animals and healthy human volunteers. The usual dose of dezocine is 2.5 to 10 mg IV every 2 to 4 hours or 5 to 20 mg IM every 3 to 6 hours. SC administration is not recommended (see Table 1 (Table Not Available) for a full list of opioid analgesic agents).[8] TABLE 1 -- OPIOID ANALGESICS (Not Available)

From Opioid analgesics. Med Lett 40:84, 1998; with permission. Nonopioids: Aspirin, Acetaminophen, and NSAIDs Aspirin, acetaminophen, and NSAIDs all reach a maximal analgesic effect with increasing doses. Aspirin and acetaminophen reach their maximal analgesic efficacy at dosages of approximately 650 mg to 1300 mg. The ceiling efficacy for NSAIDs is higher, with a longer duration of action. There does not appear to be a tolerance to the effects of nonopioid analgesics. There is no potential for abuse, and physical dependence has not been reported.[5] Adverse Effects Aspirin. Aspirin can lead to salycilism and inhibits platelet function for the 8 to 10-day lifetime of the platelet. Aspirin is contraindicated in children with febrile illnesses owing to an association with Reye's syndrome. Acetaminophen. Large overdosages of acetaminophen can cause hepatic injury that is serious or even fatal. In addition, alcoholic patients and those who are fasting and concurrently taking cytochrome P 450 enzymeinducing drugs can develop hepatic injury with ingestion of even high therapeutic doses.[4] NSAIDs. The adverse effects of aspirin and other NSAIDs are qualitatively similar. A single or few doses of NSAIDs causes few adverse effects, although precipitation of asthma or anaphylactoid reactions in aspirin-sensitive patients can occur. Elimination of the NSAID leads to return of platelet function, unlike aspirin. The organ systems most commonly affected by aspirin and NSAIDs are gastrointestinal (GI) and renal. With chronic administration, GI ulcer, bleeding, and perforation can occur without warning. It is estimated that NSAID GI effects account for 107,000 hospitalizations and 16,500 deaths annually in the United States.[79] Particularly at risk are those on higher dosages, with prolonged use, previous peptic ulcer, excessive alcohol intake, and advanced age.[5] Ibuprofen in doses less than 1600 mg/day can lead to fewer GI problems than other NSAIDs, including aspirin.[43]

A recent NSAID development involved the medications celecoxib and rofecoxib. NSAIDs inhibit cyclo-oxygenase (COX) isoforms 1 and 2, which catalyze prostaglandin synthesis. Cox-1 involves prostaglandins in the GI tract, whereas Cox-2 is induced at sites of inflammation throughout the body and mediates inflammation and pain. Both celecoxib and rofecoxib specifically inhibit Cox-2 while having no effect on Cox-1 activity. Celecoxib appears to be as effective as older NSAIDs in treating osteoarthritis and rheumatoid arthritis, and unlike older drugs did not increase the bleeding time.[7] A study of 1,149 rheumatoid arthritis patients randomized to celecoxib versus naproxen versus placebo resulted in a 4% incidence of endoscopically determined gastroduodenal ulcers in both the placebo and celecoxib groups, and with a 26% incidence with naproxen. The overall incidence of GI tract adverse events was 19% with placebo, 25% to 28% for celecoxib (three different dosages), and 31% with naproxen.[78] A combined analysis of eight trials of patients (N = 5,435) with osteoarthritis treated with rofecoxib was associated with a significantly lower incidence of GI tract bleeding than treatment with other NSAIDs (12-month cumulative incidence 1.3% vs. 1.8%; P = 0.46; rate per 100 patientyears 1.33 vs. 2.60; relative risk 0.51; 95% confidence interval 0.26-1.00). The cumulative incidence of GI adverse experiences was also lower with rofecoxib versus NSAIDs over 6 months (23.5% vs. 25.5%; P = 0.2), after which the incidence rates converged.[47] Neither celecoxib or rofecoxib is approved for use in patients less than 18 years of age. Renal failure is known to occur in those taking NSAIDs, and it is believed to be due to the decreased synthesis of renal vasodilator prostaglandins with subsequent decreased renal blood flow. Patients at particular risk are elderly as well as those with congestive heart failure, renal insufficiency, ascites, volume depletion, and diuretic therapy. Allergic interstitial nephritis and nephrotic syndrome, both usually reversible, have been known to occur.[5] Acetaminophen. Acetaminophen is a pure analgesic agent. It shares the antipyretic action of aspirin but not the anti-inflammatory properties.[71] Compared with aspirin, acetaminophen is as effective, similar in potency, and has an equianalgesic time-curve effect. The usual PO or rectal dose is 10 to 15 mg/kg administered every 4 hours as needed. Most adult patients can safely take 4 g/day of acetaminophen without problem.[5]

Aspirin. Aspirin has been shown to be effective in most types of pain, including cancer pain.[5] Aspirin acts through inhibition of prostaglandin production by blocking prostaglandin synthetase enzymes. The subsequently reduced inflammation produces analgesia. The usual PO or rectal dose is 10 to 15 mg/kg administered every 4 hours as needed. NSAIDs. NSAIDs also work through inhibition of prostaglandin development, leading to anti-inflammatory activity and subsequent analgesia. In acute pain, single full doses of NSAIDs are more effective than aspirin or acetaminophen. Some can equal the analgesic effect of oral narcotic preparations, or even usual doses of parenteral narcotics. This is not as well established for treatment of chronic pain.[5] Patients sometimes respond better to one NSAID than another. The usual oral dose of ibuprofen is 5 to 10 mg/kg and can be administered every 6 hours as needed. Ketorolac. Although an NSAID, ketorolac is reviewed separately as it is the only parenteral NSAID available for use in the United States; it can also be given PO. Additional parenteral NSAIDs are available in other countries, but adverse injection site reactions have limited their widespread use. Ketorolac is essentially nonirritating to tissues.[5] Ketorolac 30 mg IM or IV has been shown to be as effective as moderate doses of morphine or meperidine, with a slower onset and longer duration of action.[33] Three other studies demonstrated equal efficacy when ibuprofen 800 mg PO was compared with 60 mg ketorolac IM; two of the studies noted that speed of onset of analgesia was similar.[62] [92] [99] Care must be taken and the dose of ketorolac reduced in those over 65 years of age or weighing less than 50 kg, and in the face of even moderately elevated serum creatinine levels. In addition, bleeding can occur even with parenteral use, particularly when administered at higher dosages, in older patients, or for more than 5 days.[85] Use of ketorolac, parenteral or oral, should not exceed 5 days. It is contraindicated before and during surgery, and whenever even minimal bleeding cannot be tolerated, such as following plastic surgery.[5] Combinations.

Acetaminophen, aspirin, or NSAIDs combined with opioids leads to an additive analgesic effect.[5] The additive effect of the NSAID permits a lower dosage of the opioid (see Table 2 (Table Not Available) for a full list of acetaminophen and NSAID analgesics).[56] TABLE 2 -- ACETAMINOPHEN AND NSAID ANALGESICS (Not Available) From Opioid analgesics. Med Lett 40:84, 1998; with permission. Other Agents Nitrous Oxide A safe and effective sedative/analgesic, nitrous oxide has an onset of action of 3 to 5 minutes, with a duration of action of 3 to 5 minutes. The mechanism of action is not known but appears to blunt the reaction to pain rather than blocking the painful stimulus. The drug is transported unbound in physical solution, is not metabolized, and is eliminated unchanged by the lungs.[71] Nitrous oxide is self-administered as a 50/50 N2 O/O2 mixture. The patient holds a facemask in place, and, as sedation occurs, relaxation begins, leading to a release on the facemask's grip. As the mask loosens or falls aside, the flow of nitrous oxide stops. Nausea and vomiting occurs in 10% to 15% of patients.[58] Another concern is diffusional hypoxia in the recovery phase. As the nitrous oxide is washed out of the system through the lungs, it displaces oxygen in the alveoli and can cause hypoxia. This process can be avoided by providing supplemental oxygen throughout the recovery phase. Because of its 32 fold greater than air solubility coefficient, nitrous oxide preferentially enters areas of the body such as the gut and middle ear, possibly leading to overdistension. As such, contraindications to its usage would include conditions exacerbated by gas expansion, such as bowel obstruction, pneumothorax, severe lung disease, procedures using balloon-tipped catheters, and with middle ear effusions.[71] Other potential problems in the ED are potential for recreational abuse, possible environmental contamination if no scavenger system is available, and potential teratogenic effects with chronic exposure. Reduced concentrations of nitrous oxide should be used at higher altitudes to avoid hypoxia.[71] Corticosteroids

Corticosteroids are known to reduce inflammation through inhibition of prostaglandin synthesis, decrease edema by reducing capillary permeability, and reduce spontaneous discharge in injured nerve. Corticosteroids therefore can be of assistance in various pain syndromes of bone, visceral, or neuropathic etiology.[95] They are well absorbed orally and can be administered by IM, IV, and topical routes. Corticosteroids are over 90% protein bound. Some synthetic analogues such as cortisone and prednisone require activation in the liver and can be less effective in the face of hepatic dysfunction. Of interest, the plasma half-lives do not necessarily determine their observed duration of action. Adverse effects to both acute and chronic administration are numerous, with immediate and longterm toxicities too numerous to mention here. The optimal type and dosage of corticosteroid has not been established. Dexamethasone could be considered a good choice owing to its high potency, long duration of action, and minimal mineralocorticoid effect. A reasonable starting dosage is 10 mg twice a day, with tapering to the minimal effective dose.[95] Tricyclic antidepressants. Tricyclic antidepressants such as amitriptyline can be helpful in relieving neuropathic pain such as postherpetic neuralgia and diabetic neuropathy.[52] [53] Anticonvulsants. Neuropathic pain from postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, glossopharyngeal neuralgia, and neuralgias originating from trauma or cancer infiltration may be ameliorated by anticonvulsants such as carbamazepine, clonazepam, phenytoin, or gabapentin.[40] [57] [97] Benzodiazepines. There have been surprisingly few clinical studies of benzodiazepine use in patients with pain. Based on the scant literature and clinical experience, it seems unlikely at this time that there is any intrinsic analgesic activity. Benzodiazepines have gained widespread clinical acceptance as adjuvants in the management of certain specific pain states: pain associated with anxiety, muscle injury or spasm, and the lancinating pain due to nerve injury.[68] Caffeine.

Caffeine has no intrinsic analgesic properties. In doses of 65 mg to 200 mg, however, it has been shown to increase the analgesic effectiveness of acetaminophen, aspirin, and NSAIDs when used for the pain of headache, oral surgery, and postpartum.[54] Hydroxyzine. Hydroxyzine is commonly used in conjunction with parenteral opioids with the thought of adding to opioid efficacy while having a disproportionately small effect on respiratory drive. The antiemetic effect of hydroxyzine is beneficial in certain clinical situations. Others have questioned the practice citing lack of objective evidence, increased cost, relatively large doses of hydroxyzine needed for efficacy, with concomitant reduction in safety margin of drug administration.[34] Calcitonin. A prospective, double-blind, placebo-controlled study of 100 patients with nontraumatic osteoporotic vertebral compression fractures showed a dramatic decrease in spinal pain with administration of nasal salmon calcitonin, 200 IU, daily for 28 days.[50] CONSCIOUS SEDATION The term conscious sedation is commonly used to describe the process of providing analgesia, sedation, and amnesia for patients undergoing painful procedures, although its inconsistent definition has been described as misleading.[44] [60] [80] A more precise and therefore preferred term is procedural sedation and analgesia. In a recently published American College of Emergency Physicians' clinical policy, procedural sedation was defined as a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant procedures while maintaining cardiorespiratory function. Procedural sedation and analgesia is intended to result in a depressed level of consciousness but one that allows the patient to maintain airway control independently and continuously.[45]

Specifically excluded are patients receiving analgesia without sedation for pain control and patients receiving sedation for the sole purpose of behavioral control. Pharmacology of Procedural Sedation and Analgesia The ideal agent would provide somnolence, analgesia, anxiolysis, and amnesia rapidly and predictably fashion, without any adverse effects. Unfortunately, no single agent has all these properties. As a result, various mixtures of sedative-hypnotic, analgesic, neuroleptic, and dissociative agents have been used in an attempt to achieve the desired endpoint.[60] Because of this, the emergency physician must understand the primary pharmacologic actions of the various medications, and their relative contributions to the "cocktail" and anticipate potential interactions and side effects. The selection of particular agents used varies appropriately with different patients, procedures, and physicians. It is suggested that medications with relatively pure actions and limited side effect profiles be used. Recommendations for monitoring and documentation should be followed in order to minimize complications.[45] The preferred route of administration for agents used in procedural sedation is IV. Drugs given IV provide a rapid onset with more predictable results; it is also easier to repeat doses and titrate to clinical effect. Agents given PO, transmucosally, or IM are less predictable, onset is delayed and the sedation can be prolonged. A possible exception exists in children, in whom the difficulty of IV access could outweigh the disadvantages of other routes. OTHER TYPES OF MEDICATION Sedative Hypnotics Midazolam Midazolam is a benzodiazepine commonly used in the ED to provide sedation. It is also used in the treatment of generalized seizures and behavioral emergencies, and as an induction agent in rapid sequence intubation.[66] It is particularly popular in procedural sedation owing to its rapid onset and short duration of action.

Midazolam belongs to a new class of benzodiazepines, the imadodiazepines. The addition of an imidazole ring to the benzodiazepine nucleus has led its unique pharmacokinetic properties.[63] In an acidic environment midazolam is water soluble, allowing it to be packaged without diluents, thereby reducing venous irritation and possible dysrhythmias.[31] This also accounts for its rapid absorption from the GI tract. Onset of action is 15 minutes after oral administration, with peak effects within 30 to 90 minutes.[46] Approximately 50% of oral or rectal midazolam is lost to first-pass metabolism in the liver. The onset and duration of action for rectal and nasal administration is similar.[13] [41] IM midazolam is rapidly absorbed and highly bioavailable, with onset in 5 minute and peak effects within 15 to 30 min.[63] After IV infusion clinical effects can be seen in 2 to 3 minutes.[46] Once in a physiologic pH, midazolam becomes extremely lipophilic, resulting in rapid tissue uptake and distribution. The volume of distribution is 1 to 2.5 L/kg, and is greater in women than men, obese patients, pregnancy, and elderly patients.[31] [63] Midazolam crosses the placenta and carries a Food and Drug Administration (FDA) pregnancy category of D.[20] Midazolam undergoes hepatic metabolism by the cytochrome P450 oxidase system.[63] Cytochrome P450 inhibitors such as cimetidine can speed its onset of action and increase sedation.[32] The elimination half-life is only 1.5 to 3 hours and has an even shorter duration of action of 1 to 2 hours. Most excretion is through the kidneys.[16] Midazolam has been associated with prolonged sedation in patients with renal impairment. Midazolam has sedative, anxiolytic, muscle relaxant, and anticonvulsant properties.[66] In addition, its amnestic properties appear to be superior to other benzodiazepines.[27] Midazolam does not provide any analgesia.[102] Midazolam acts on the benzodiazepine receptors to potentiate the inhibitory action of the neurotransmitter gamma-aminobutyric acid (GABA).[63] By increasing the influx of chloride ions into the cell, GABA inhibits the ability to initiate an action potential.[31] Because of its rapid onset, short half-life, and amnestic properties, midazolam is the benzodiazepine commonly chosen for procedural sedation. When compared with diazepam, midazolam was

associated with a quicker onset and decreased patient recall, and there were fewer adverse reactions.[25] [27] [101] Midazolam can be given by intranasal, IM, sublingual, PO, intraosseous, or rectal routes.[66] Intravenous administration is recommended for conscious sedation using titrated doses.[63] [67] In healthy patients less than 60 years of age, the recommended initial dose is 1 mg (0.02-0.03 mg/kg) given slowly over 2 minutes.[63] [66] This dose may be repeated every 2 minutes while monitoring the level of sedation. A total of more than 5 mg (0.1 mg/kg) is rarely required.[63] [67] In elderly or chronically ill patients, and those with renal impairment, the dose should be reduced by at least one half. Oral midazolam at a dose of 0.2 mg/kg has been used successfully to sedate young children.[26] [66] Its bitter taste can be diminished by dilution in juice. Intranasal administration, while equally effective, has been associated with nasal burning and irritation.[14] [26] Midazolam has also been administered rectally in children at a dose of 0.45 mg/kg with variable results.[76] Midazolam can cause respiratory depression and death. Most cases have occurred in patients who were not monitored closely and when midazolam was used in combination with an opioid.[63] In a study in which volunteers received midazolam and fentanyl alone or in combination, respiratory depression occurred only when fentanyl was used.[11] [12] The combination of the agents caused the greatest degree of hypoventilation (90%) and apnea (50%), however, consistent with other reports, suggesting a synergistic interaction.[81] Respiratory depression associated with midazolam could be more common with rapid administration, and higher doses can cause hypotension.[66] Hiccups is a common reaction that usually resolves quickly and spontaneously.[27] Diazepam For several compelling reasons, midazolam has largely replaced diazepam as an agent for use in procedural sedation. Although diazepam can be an effective drug, midazolam has a quicker onset of sedation and patients recover more rapidly. Patients can be discharged sooner after sedation with midazolam compared with diazepam.[101] There is also greater reported amnesia and less burning pain on injection with midazolam.[27] [101] Methohexital

Methohexital sodium is an ultrashort-acting barbiturate introduced in the early 1960s as an induction and general anesthetic agent. Its brief duration of action soon led to outpatient use for short procedures and some more recent use in the ED.[103] Structurally similar to pentobarbital and thiopental, methohexital is about twice as potent as thiopental. Maximal brain uptake occurs within 30 seconds of IV administration. Methohexital is 70% to 80% plasma protein bound and has a smaller volume of distribution than the more lipid-soluble thiopental. Its half-life is 3 to 4 hours; however, its clinical effects are usually less than 10 minutes owing to the redistribution of the drug. Elimination is primarily through hepatic metabolism. Barbiturates have numerous sites of action in the central nervous system. They are uniquely capable of depressing the reticular activating system. As opposed to the other agents used in conscious sedation, methohexital induces a state of unconsciousness. Methohexital has a direct myocardial depressant effect and causes peripheral vasodilation; this can result in hypotension that is usually mild and transient owing compensatory increases in the heart rate. Barbiturates also depress medullary ventilatory centers and can cause hypoventilation and apnea. Respiratory reflexes are usually not depressed and can be heightened, potentially causing laryngospasm.[103] For procedural sedation in both adults and children, an IV dose of 0.75 to 1 mg/kg produces unconsciousness in less than 1 minute.[103] Most patients awaken and recover within 10 minutes. More subtle drug effects, such as impairment of driving skills, can be present for several hours. Although amnesia is often present, methohexital does not provide any analgesia and should be combined with an opioid if the procedure is likely to be painful. Because of its short duration, it has been recommended for use in short procedures such as bone or joint reduction.[19] Methohexital can cause hypotension and should be avoided in patients with hemodynamic compromise. The increased reactivity of the airways can cause hiccups, coughing, or rarely, laryngospasm. Hypoventilation and apnea can also occur, although is uncommon at the described doses.[103] There is no specific pharmacologic antagonist for barbiturates.

Chloral Hydrate Chloral hydrate is a sedative-hypnotic that has been particularly popular for use in the pediatric population.[18] It is usually given PO or rectally. Its onset is delayed up to 60 minutes, and the effects can be present for hours. These significant disadvantages make it unsatisfactory for ED use, particularly when much better agents are now available.[66] Associated aspiration, respiratory depression, and death have been reported.[66] Analgesics Opioids are used primarily to provide the analgesia in procedural sedation and analgesia. Although all these agents cause varying degrees of sedation, this effect is inconsistent, depending on the route and speed of administration and the agent used, and responses can vary greatly among individual patients. These agents are best considered as analgesics with the potential to supplement other primarily sedating drugs, such as the benzodiazepines. Although morphine and meperidine have both been used as analgesics in this setting, they have been largely replaced by shorter-acting opioids, particularly fentanyl. The role of opioids in pain control is discussed earlier. Other Agents Ketamine Ketamine has become a popular agent for use in pediatric sedation and analgesia in the past decade and has largely replaced chloral hydrate and sedation cocktails such as DPT.[29] [35] [37] A synthetic derivative of phencyclidine, it induces a dissociation between the cortical and limbic systems.[36] [71] This produces a trancelike, cataleptic state of sensory isolation, preventing the higher cortical centers from appreciating auditory, visual, or painful stimulation, providing a unique combination of amnesia, sedation, and analgesia.[36] Ketamine is highly lipid soluble and rapid cerebral uptake results in clinical effects within 1 minute when it is given IV. It is then redistributed to peripheral tissues and undergoes hepatic elimination. Clinical effects resolve approximately 15 minutes after a single IV injection. IM injection, the more common form of administration in the ED, results in a clinical onset of 5 minutes; effects are more prolonged and variable than with IV administration. Return of coherence and purposeful neuromuscular activity typically return in 30 to 120 minutes following an IM

dose.[29] [35] [36] Concurrent use of benzodiazepines and barbiturates can extend the half-life of ketamine, prolonging clinical recovery time by about 30%.[36] Ketamine possesses several clinical effects unique to the sedativehypnotics. Spontaneous respirations and airway muscular tone are preserved. Protective reflexes such as coughing and swallowing can even be exaggerated.[39] [84] Ketamine also acts as a bronchodilator through increased catecholamines and smooth muscle relaxation.[36] By inhibiting the reuptake of catecholamines, ketamine also has sympathomimetic effects on the cardiovascular system, causing mild to moderate increases in heart rate, blood pressure, and cardiac output. Salivary and tracheobronchial secretions can be stimulated. Skeletal muscle hypertonicity and rigidity are commonly seen and result in random movement of the head or extremities. Occasionally, this results in intense myoclonic jerking that appears to be a seizure but is not associated with EEG changes.[36] Hallucinatory phenomena while emerging from the dissociative state have been reported in up to 50% of adults but in fewer than 10% of children.[71] An IM dose of 4 to 5 mg/kg produces adequate sedation in most children.[35] Although there is less ED experience with IV ketamine, two recent studies suggest a dose of 1.5 mg/kg for sedation and analgesia in children.[29] [38] Interestingly, there was no difference in time to discharge when this is compared with the IM route, possibly owing to a higher use of midazolam in the IV group.[38] Benzodiazepines reduce the incidence of hallucinatory emergence reactions and should be considered if risk factors are present; these include age greater than 10 years, rapid IV administration, excessive noise or stimulation or a baseline of frequent dreaming.[71] Routine administration of benzodiazepines to children under the age of 10 years is of questionable benefit owing to the low incidence of emergence phenomena and the prolongation of recovery time.[39] Administration of a concurrent anticholinergic is recommended by some to reduce the hypersalivation seen with ketamine. Atropine 0.01 mg/kg (maximal total dose of 0.5 mg) and or glycopyrrolate 0.005 mg/kg (maximal total dose of 0.25 mg) can be combined with ketamine in a single IM injection.[36] [71]

Respiratory depression is extremely rare but has been reported with rapid IV push, in neonates, in patients with CNS injury, and when very high doses are used.[36] Laryngospasm, presumed to be secondary to the heightened gag reflex, is the most dangerous potential complication, but this occurs in fewer than 2% of cases in the doses described above and is usually transient, rarely requiring intubation.[36] [37] [39] Emesis and a transient hyperemic rash can occur after recovery. Propofol Propofol is an ultrashort-acting sedative-hypnotic unrelated to the benzodiazepines or barbiturates. An isopropylphenol, it is formulated as an aqueous emulsion in soybean oil and is almost completely insoluble in water.[66] [71] Conversely, its extremely high lipid solubility accounts for an onset of less than 60 seconds and duration of action of only 10 minutes.[87] [93] Despite a rather long elimination half-life (13-44 h), propofol redistributes rapidly out of the brain tissues, accounting for the very short clinical effects and quick recovery.[87] The pharmacokinetics are not altered by hepatic or renal disease, suggesting that elimination occurs through an extrahepatic metabolic pathway.[15] [93] The volume of distribution diminishes with age, therefore, children require higher initial doses and infusion rates, whereas the doses should be reduced in elderly patients.[93] Similar to other sedative-hypnotics, propofol produces a depression of the CNS and exerts its action through potentiation of GABA binding to its CNS receptor sites. It causes a decrease in cerebral metabolism and reduces intracranial pressure.[93] Propofol has no analgesic properties and minimal amnestic effects.[87] Propofol causes a dose-related respiratory depression similar to the barbiturates, but the period of apnea can be more prolonged.[93] [96] Propofol causes hypotension owing to a decrease in systemic vascular resistance and can have a negative inotropic effect, resulting in decreased cardiac output. This can occur to a greater degree than with benzodiazepines and barbiturates.[87] [96] Propofol quickly became the induction agent of choice in general anesthesia, primarily because of its rapid recovery rate with minimal associated residual effects. For similar reasons, it was soon used as an agent for outpatient procedures.[77] [96] Recently, some EDs have used propofol successfully as a sedating agent during

procedural sedation and analgesia, particularly for short procedures.[15] [87] [91] Although some reports have described higher doses, in the largest series of emergency patients reported, adequate onset of sedation was achieved with a bolus of 0.21 mg/kg in 20 adults (approximately 10% of the induction dose).[87] The patients were then maintained on a maintenance infusion of 3 to 6 mg/kg/h (50-100 mug/kg/min). It is recommended that doses be decreased by up to 50% in the elderly population. Larger doses are often required for children, and initial boluses of up to 1 mg/kg have been used with infusions of 50 to 150 mug/kg/minute.[15] [42] [66] Single boluses have been described as being effective for very short procedures such as temporomandibular joint reduction.[91] Because of burning at the IV site, lidocaine 0.5 mg/kg has been used to ameliorate this effect.[66] Fentanyl or alfentanyl is often used in combination to provide analgesia.[15] [77] [87] Respiratory depression and hypotension appear to be related to the rate of administration as well as the dose, so that the bolus should be given slowly over 1 to 2 minutes.[42] [93] Nausea and vomiting are rare following propofol administration, possibly owing to antiemetic properties.[87] Sedation Cocktails Several sedative/analgesic cocktails have been developed for use during painful procedures in children, primarily to avoid the difficulty of IV access in a child. Historically, the most popular "lytic" cocktail was DPT, which used a combination of IM meperidine, promethazine, and chlorpromazine. Prolonged sedation times, potential dystonic reactions, relatively high rates of sedation failure, and the advent of alternative agents argue against its continued use for pediatric sedation and analgesia in the ED.[14] [66] [70] [71] [88] PREVENTION OF DRUG-RELATED COMPLICATIONS Appropriate selection and dosing of medications with a good understanding of their pharmacologic actions can minimize complications. Appreciation of potential drug interactions is crucial. A written consent should be obtained before procedural sedation and analgesia is begun.[44] [45] A thorough evaluation of the patient, specifically including airway assessment and the patient's physiologic reserve, should be performed prior to the initiation of

procedural sedation and analgesia.[2] [44] [45] Recent food ingestion is not a contraindication but should be considered when choosing the level of sedation.[2] [45] A physician familiar with sedation and analgesia as well as advanced life support and airway management should be present in the ED for the procedure and the recovery period. Monitoring during Sedation and Analgesia Close monitoring of vital signs and the level of sedation has been recommended as an integral part of procedural sedation protocols in the ED.[1] [44] [45] [71] Pulse oximetry is widely used to reduce the risk the risk of unrecognized hypoxemia.[28] [45] There are no studies that have demonstrated that a detection of a decrease in the oxygen saturation in the absence of other clinical findings has an impact on patient care, and pulse oximetry monitoring should not be used as a substitute for frequent clinical assessments.[9] [45] The monitoring of end-tidal CO2 through noninvasive capnometry can detect early cases of inadequate ventilation before oxygen desaturation and has been suggested as a useful adjunct. This has not been adequately studied enough to recommend its routine use during procedural sedation, but it can be helpful in patients in whom ventilatory efforts cannot be visualized.[45] [100] SUMMARY The endpoints of sedation and analgesia have been more difficult than traditional physiologic parameters to measure adequately.[9] Several clinical scoring systems have been developed in an attempt to provide more consistent and objective assessments of sedation, but the few that have been validated are cumbersome to use in the clinical setting and cannot accurately determine subtle changes in the level of sedation.[9] [23] Recent developments in EEG monitoring, particularly one using bispectral (BIS) analysis of the EEG signal obtained through a noninvasive forehead "lead," are promising. BIS monitoring has been used as a reliable measure of depth of midazolam-induced sedation during general anesthesia.[23] Anesthesiologists have used this technology to prevent awareness during paralysis. One recently completed but as yet unpublished study in the ED demonstrated a high correlation with traditional sedation scales and found the device easy to use (UNC Hospitals Department of Emergency Medicine, personal

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