1585CHAPTER 132 Sedation and Analgesia monitor was not able to reduce this low incidence of awareness, the level of anesthesia between the groups was very similar This study was severely underpowered[.]
CHAPTER 132 Sedation and Analgesia assessment of sedation could be beneficial The Bispectral Index (BIS) is a processed electroencephalogram (EEG) monitor that measures the hypnotic effects of anesthetics and sedatives It is an empirical, statistically derived measurement that has been validated as a measure of hypnosis in adults in the operating room and ICU17 as well as in children in the PICU.18 It does not measure the concentration of a particular drug.19 The BIS monitor reports a single number from to 100 that represents an integrated measure of cerebral electrical activity A number of 100 on the BIS score indicates that the patient is fully awake, whereas a number less than 40 suggests a deep hypnotic effect A BIS value of less than 60 in surgical patients was not associated with a recall of intraoperative events.20 The use of the BIS monitor in adult surgical patients and in older pediatric patients has been shown to reduce anesthesia requirements and result in a shorter recovery time In critically ill adults, the BIS score has shown good correlation with various sedation scores.21 One of the main shortcomings of clinical sedation scoring systems is their inability to assess depth of sedation in patients receiving neuromuscular blocking agents (NMBAs) Patients who receive NMBAs in the operating room or in the PICU are at increased risk of awareness during anesthesia.22 Clinical signs may not reliably assess adequacy of anesthesia or sedation in the PICU patient since alterations in heart rate, blood pressure, perfusion, and pupillary responses can occur due a variety of other reasons.23 A study using BIS monitoring in pediatric patients receiving NMBAs found that the PICU bedside nurse’s assessment detected only 8% of patients at risk for awareness and recall (BIS 80; Fig 132.1).24 An important aspect of sedation monitoring is the level of stimulus The BIS monitor will estimate the degree of hypnosis at a point in time in the context of the balance between sedation, analgesia, and stimulation It cannot predict what will happen if this balance is changed Although the BIS monitor is used in many institutions, the question of whether its use can prevent awareness under anesthesia is still being debated A study of 2000 adults whose anesthesia was titrated to a BIS score of lower than 60 or by the end-tidal inhalational concentration of the anesthetic agent to at least 0.7 minimum alveolar concentration (MAC) found two cases of awareness in each group.25 The BIS score was greater than 60 in one case of awareness Although the BIS ACCURACY OF NURSE ASSESSMENT 100.0 % correct 80.0 1585 monitor was not able to reduce this low incidence of awareness, the level of anesthesia between the groups was very similar This study was severely underpowered to show any benefit.25 However, the combination of end-tidal monitoring and BIS monitoring may help to reduce intraoperative awareness Another potential concern with using the BIS monitor is its relevance or reliability for the pediatric patient Research thus far does not show a correlation with the myriad of sedation scoring systems used in the PICU Furthermore, the lack of continuous sedation assessment by these scoring systems, as is possible with BIS monitoring, makes comparison difficult It also is unclear whether the EEG analysis algorithms used in the BIS monitor are applicable to the pediatric brain This issue needs further evaluation before BIS monitoring can be considered standard in the PICU Pediatric-specific BIS probes are now available; its use for patients year and older appears to be appropriate.26 The possible inaccuracy of the BIS in younger children has been demonstrated in the operating room, where BIS values in younger children (age 1–12 years) tended to be higher (.60) than in older children receiving the same propofol, remifentanil-based anesthetic.27 In this study, there was no recovery benefit to a BIS-driven anesthetic compared with a standard dose-based, clinical signs–driven anesthetic In fact, the younger children took longer to wake up due to high doses of sedation agents received in an effort to keep the BIS score less than 60 Children with the BIS greater than 60 appeared to be appropriately anesthetized; thus, the concept that the BIS score must be less than 60 to ensure adequate anesthesia in younger children may not be correct.27 This may correlate with the need to select a different BIS end point in the PICU In a recent study in the neonatal population, the BIS score correlated well with deep sedation but was unable to differentiate between no sedation and light sedation.26 This may be related to a generally slower background cerebral activity in neonates as compared with older children and adults Finally, the BIS monitor is less reliable when used with certain hypnotic agents, such as ketamine, dexmedetomidine, nitrous oxide, xenon, and opiates Its accuracy is decreased by patient movement, the use of high-frequency oscillatory ventilation, underlying seizures, or any form of brain injury Other processed EEG sedation assessment monitors are now available The SNAP II monitor28 uses a different spectrum of EEG frequency analysis, but little has been reported with the SNAP II monitoring in pediatric patients In the PICU, SNAP II was found not to correlate well (r 0.18) with the sedation depth of intubated children The mean SNAP index changed only between 58 and 68 over a sedation score reflecting deep to light sedation.29 60.0 Opioids and Analgesia in the Pediatric Intensive Care Unit 40.0 20.0 0.0 BIS 80 BIS score Incorrect • Fig 132.1 Nurse Bispectral index Correct sedation assessment of the paralyzed patient. BIS, Sedation in the PICU is most commonly achieved with a mixture of opioids and benzodiazepines (BZDs) Although many synthetic and naturally occurring opioids exist, morphine is considered the agent against which others are compared The primary source of morphine is opium obtained from the opium poppy (Papaver somniferum), which also produces alkaloids such as codeine, thebaine, papaverine, and noscapine Opiates are substances derived from opium; the term opioid also describes substances derived from opiates (e.g., oxycodone) but includes substances that are created synthetically and have properties that are 1586 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit TABLE 132.2 Opiate Receptors Receptor m d Endogenous Ligand Agonist Antagonists b-Endorphin Morphine Naloxone Endomorphin Fentanyl Naltrexone Leu-enkephalin DPDPE Naloxone Met-enkephalin k Nociceptin Dynorphin Naltrindole Buprenorphine Naloxone — — DPDPE, [D-Pen2,D-Pen5]enkephalin—synthetic opiate peptide, selective d-receptor agonist acid sequence for met-enkephalin The main precursor is proenkephalin A, which contains four copies of met-enkephalin and one copy of leu-enkephalin The met-enkephalin sequence also gives opioid activity to a number of other larger peptides Proenkephalin B (prodynorphin) gives rise to the dynorphin series and contains three leu-enkephalin sequences Local application of these endogenous substances to the brain provides effects that are similar to those of opiates They arguably not function as analgesics in basal states because the administration of naloxone does not cause pain in the normal state They are released during periods of sustained pain, stress, or activity to modulate physiologic pathways, including those involved with pain Therefore, they are probably important to the physiologic condition of the patient in the ICU Specific Opioid Agonists similar to those of opiates (e.g., fentanyl and methadone) The terms often are used interchangeably because the pharmacologic effects fall into the same category Opioids are agonists at various opioid receptors, for which several endogenous ligands exist There are three major classes of receptors: mu (m), kappa (k), and delta (d; Table 132.2) Opioid receptors possess the same general structure: an extracellular N-terminal region, seven transmembrane domains, and an intracellular C-terminal tail structure Subtypes of each receptor (e.g., m1, m2) exist, as less well-characterized opioid receptors, such as nociceptin Most of the therapeutic and adverse effects can be accounted for by agonist activity at the m-receptor, which is responsible for analgesia, respiratory depression, pupillary constriction, and euphoria At the cellular level, m-receptor activation through a coupled G protein inhibits adenylate cyclase, resulting in inhibition of voltage-gated calcium entry channels and activation of potassium channels This results in a loss of potassium from the neuron, causing hyperpolarization and depression of excitability in the nervous system Associated effects on cholinergic, adrenergic, serotonergic, and dopaminergic neurotransmitter systems are seen within the central nervous system (CNS) These receptors are found at multiple sites along pain pathways, including the spinal cord, midbrain, thalamus, and cortex At the spinal cord level, pain reflexes (nociceptive) are depressed by receptors in the substantia gelatinosa, which are mostly presynaptic and inhibit the release of substance P from C-fiber nerve terminals and account for the effectiveness of opioids administered intrathecally and epidurally In the midbrain, the analgesic effect is mediated in the periaqueductal gray matter through ascending fibers and descending fibers that modulate the function of the dorsal horn Acetylcholine, g-aminobutyric acid (GABA), norepinephrine, and serotonin also are involved in these pain-modulating pathways Peripheral opioid receptors also exist and can be expressed in response to inflammation.30 The intraarticular injection of morphine produces analgesia following arthroscopy through activation of opioid receptors located on white blood cells.31 The endogenous ligands for the opioid receptors are the enkephalins, endorphins, and dynorphins They have a morphinelike effect that can be specifically antagonized by the m-receptor antagonist naloxone The endomorphins have potent analgesic and gastrointestinal (GI) effects At the cellular level, they activate G proteins ([35S] GTP g-S binding) and inhibit calcium currents.32 Pro-opiomelanocortin is the precursor for b-endorphin (as well as adrenocorticotropic hormone and melanocyte-stimulating hormone) b-Endorphin, itself very active, also includes the amino Morphine Morphine is an opiate, its primary therapeutic actions being sedation and analgesia; anxiolysis and euphoria also may occur These four therapeutic effects may be exploited to the benefit of the patient These actions are mediated through the periaqueductal gray matter, ventromedial medulla, and spinal reduction of nociceptive reflexes occurs all over the body, even below a completely transected spinal cord In addition to increasing the sensory threshold for pain, morphine may decrease the hurting aspect (or unpleasantness) of pain A patient given morphine may say something such as “I have just as much pain, but it doesn’t distress me as much.” It blunts most types and intensities of pain, although some forms of neuropathic pain are relatively resistant The resulting analgesia may be potent enough to abolish diagnostic symptoms and signs The sedative effects reduce higher cortical function, cause difficulty in concentration, and cause a sense of drowsiness and dream-filled sleep Higher doses will cause a state of unconsciousness or coma The rate of respiration is reduced, with a resultant fall in minute ventilation despite an accompanying increase in depth of breathing This effect is associated with a decreased responsiveness to carbon dioxide (CO2) and is additive to the decreased CO2 response seen during sleep In some circumstances, respiratory drive may be limited to hypoxic stimulation of the carotid chemoreceptors; this is the most serious dose-related adverse effect of morphine It can occur at doses used clinically for analgesia In general, all opiates produce the same degree of respiratory depression when given in equipotent doses and for any given level of analgesia Opioids not have anticonvulsant properties, whereas meperidine (and its metabolite normeperidine) may lower the seizure threshold Another CNS effect of morphine is pupillary constriction due to a central effect on the oculomotor nucleus Nausea results from stimulation of the chemotrigger zone However, opioids also depress the vomiting center; thus, the final effect is unpredictable Nausea and vomiting are much more frequent in ambulatory patients than in patients confined to a hospital bed Morphine can modify stress-related endocrine responses It decreases the release of several hormones, including adrenocorticotropic hormone, antidiuretic hormone, prolactin, growth hormone, and epinephrine The neuroendocrine stress response that is normally seen with trauma and surgery may be blunted Itching may be caused by histamine release, but it also may be due to opiate receptor activation in the spinal cord.33 CHAPTER 132 Sedation and Analgesia Morphine’s effects on smooth muscle cause constipation It reduces the intestinal propulsion activity through its central and peripheral effects The central effects may be mediated by the vagus nerve The direct smooth muscle relaxation and the increased local cholinergic transmission can be partly reversed by naloxone This decreased motility is the basis of several over-the-counter antidiarrheal preparations, including diphenoxylate, a m-agonist that does not cross the blood-brain barrier and thus acts as a peripheral opioid agonist Morphine causes an increase in biliary tract tone, which may cause biliary colic as well as increased tone in the bladder detrusor muscle and vesical sphincter Urinary retention is common with opioids, occurring in 55% of children receiving spinally administered opioid and 20% receiving intravenous (IV) opioid.34 Morphine has been studied extensively in term and preterm neonates Glucuronidation is present in term babies and in many preterm ones The half-life of morphine, however, is hours in children, 6.5 hours in term neonates, and hours in the preterm child because of reduced clearance Volume of distribution does not vary with age.35 Morphine causes histamine release and can cause peripheral vasodilation Infused at analgesic doses, it has little effect on the cardiovascular system, but skin flushing is not uncommon with rapid IV administration The histaminereleasing potential should be considered in patients with asthma, especially during an acute exacerbation, and in patients with unstable cardiovascular systems for whom safer alternatives exist, such as fentanyl Dosing recommendations in the ICU include a bolus dose of 0.05 to 0.10 mg/kg and an infusion of 10 to 50 mg/kg per hour Fifty percent of these doses should be used if the patient is younger than months of age All opiates are weak bases and are moderately ionized at pH 7.4 Oral morphine is effective but undergoes hepatic first-pass metabolism, which is variable among patients The oral dose for acute pain is to times the IV dose, whereas in long-term use the oral dose is 1.5 to 2.5 times the IV dose Morphine is metabolized to morphine-3-glucuronide (M3G) and M6G in the liver M3G is the major metabolite and has little morphine-like activity, although there is some suggestion that M3G may be associated with an antinociceptive effect, accounting for failure of analgesia during long-term use.36 In contrast, M6G is many times more potent than morphine itself Morphine undergoes significant first-pass hepatic metabolism, whereby after a single parenteral dose, only morphine is initially active After a single dose by mouth (PO), both morphine and M6G are active With long-term oral use, M6G accumulates until its analgesic effect is greater than that of morphine A similar effect can be anticipated with long-term morphine infusion in the patient in the PICU The kidney excretes the glucuronides, together with only a small amount of free morphine Ninety percent of total urinary excretion occurs within 24 hours Tolerance, defined as an increase in the dose required to create the same response, is a potential problem with all opiates Tolerance is mainly limited to the depressant actions of morphine, including analgesia, respiratory depression, anxiolysis, and drowsiness Tolerance of morphine’s inhibition of bowel motility and pupillary constriction is minimal The mechanism of tolerance appears to involve the degree and duration of both m- and kreceptor occupancy It appears more rapidly after continuous infusion, and cross-tolerance to other opiates is common, although anecdotal evidence suggests that a dose reduction may be possible when opioids are switched because cross-tolerance sometimes 1587 appears incomplete.37 Receptor downregulation also may occur as well as altered metabolism with an increased M3G/M6G ratio Simultaneous blockade of N-methyl-d-aspartate receptors is effective in reducing the development of tolerance.38 Clinical tolerance appears uncommon with an exposure of less than days However, after prolonged administration, doses 10 to 20 times that which would cause respiratory arrest in naïve patients may be tolerated Meperidine Meperidine has one-tenth the potency of morphine Compared with other common opioids, meperidine has more CNS excitatory effects, including tremors, muscle spasm, myoclonus, psychiatric changes, and seizures These effects may be due to a central serotoninergic effect.39 It is metabolized by the liver to normeperidine, which is twice as toxic as meperidine and has a longer half-life (15 hours) Normeperidine accumulation is enhanced in patients with an induced cytochrome P450 system Meperidine has a shorter duration of action (2–3 hours) and has a more rapid onset because of its increased lipid solubility compared with morphine Meperidine is unique among opioids because of its local anesthetic properties, which are capable of providing surgical spinal analgesia.40 A small dose (0.125–0.250 mg/kg) of meperidine may be used to treat postoperative shivering Fentanyl Fentanyl is one of the most commonly used opiates in the ICU It is a synthetic derivative of meperidine without many of its unwanted side effects It is a potent m-agonist and is 100 times more potent than morphine It has a rapid onset and cessation because of its high lipid solubility (Fig 132.2) Fentanyl may be administered by several routes, including IV, intramuscular (IM), transmucosal,41 and subcutaneous (SC) when venous access is inadequate Fentanyl may be given intranasally as an alternative to the transmucosal route It has been used for premedication, sedation, and for the treatment of hypercyanotic spells in tetralogy of Fallot.42 There is also a 12.5-mg transdermal patch available for children designed to release 12.5 mg/h of fentanyl for approximately days.43 It is indicated for children with chronic pain syndromes; however, improved efficacy, compared with standard oral alternatives, has not been established Due to the different kinetics of fentanyl in children, it may take longer to achieve the steady state in the skin depot, and the patch may not last for a full 72 hours The patch must be removed if the patient undergoes magnetic resonance imaging (MRI) since patches contain metal and may cause burns to the skin Withdrawal from the fentanyl patch may be delayed owing to availability of skin depot reserves Unfortunately, an increasing number of patients are now being admitted to the PICU owing to fentanyl overdose as a result of chewing, smoking, or extracting fentanyl from the patch.44 A 12.5-mg fentanyl patch contains over mg total of fentanyl Skeletal muscle rigidity after rapid administration of fentanyl is well described in the literature but can also occur with other synthetic opiates It is mediated through the CNS and is an idiopathic response usually associated with a large bolus dose (5 mg/kg) It improves with the administration of NMBAs and is reversible with naloxone Fentanyl has limited cardiovascular effects; moderate bradycardia is the most common Fentanyl does not cause histamine release Dosing in the ICU is either by bolus (1–2 mg/kg) or 1588 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit After a single bolus, sufentanil has kinetics similar to that of fentanyl, with a short duration of clinical effect of approximately 30 minutes However, with prolonged use, sufentanil accumulates less and is associated with a more rapid recovery after infusion because of its smaller volume of distribution and similar clearance When the patient is receiving high doses of fentanyl, sufentanil can be useful to conserve infusion volume 200 100 50 Fentanyl ng/g tissue 20 Fat Alfentanil 10 Muscle Plasma 0.5 0.2 0.1 15 30 60 120 180 Minutes after injection 240 • Fig 132.2 Initial fentanyl redistribution infusion (1–4 mg/kg per hour with higher doses required as tolerance develops) The short duration of effect of a single dose of fentanyl is not due to metabolism but rather to rapid redistribution Maximum brain concentration after a bolus is achieved within 90 seconds Then, because of rapid redistribution, the plasma level falls by 50% in 30 minutes The result is a clinical duration of effect of a single dose of approximately 30 minutes Fentanyl then accumulates in fat, where it is stored and slowly released with a longer elimination half-life of about hours (longer than morphine) Marked respiratory depression occurs within 120 seconds, and a single dose of mg/kg will cause apnea in 50% of patients Fentanyl is metabolized by the liver to norfentanyl and hydroxyfentanyl derivatives, both of which are thought to be inactive In the operating room, high-dose fentanyl is commonly used for cardiac anesthesia and for anesthetization of other unstable patients A loading dose of 50 mg/kg, followed by 0.5 mg/kg per minute, will occupy all opioid receptors and produce a state of anesthesia Many cases of awareness with patients under anesthesia have been documented, however, even when these high doses of fentanyl are used Sufentanil Sufentanil is another synthetic opiate with actions and therapeutic effects similar to those of fentanyl It is to 10 times more potent than fentanyl and is the most potent opioid in clinical practice, posing a high risk of apnea with bolus administration Dosing recommendations include a bolus of 0.2 to 0.4 mg/kg or an infusion of 0.2 to 1.0 mg/kg per hour Alfentanil is another synthetic opiate with a rapid onset It is five times less potent than fentanyl Although it is less lipid soluble than fentanyl because of its low pKa (negative logarithm of the acid ionization constant), a higher percentage of the drug is present in the active un-ionized form, which results in a rapid onset Because of its low volume of distribution, alfentanil has a short elimination half-life, which results in a short duration of action (5–10 minutes) Dosing regimens include boluses of to 10 mg/kg if there is spontaneous respiration or 20 to 50 mg/kg if the patient is mechanically ventilated Alfentanil is a useful agent for preventing hypertension or increased intracranial pressure (ICP) responses to intubation As with all synthetic opiates, there is a risk of muscle rigidity with higher dosing Infusion dosing is typically 0.2 to 1.0 mg/kg per minute for patients receiving mechanical ventilation Postinfusion recovery is quicker with alfentanil than with fentanyl Alfentanyl is safe to use in patients with hepatic or renal failure Remifentanil Remifentanil is one of the newest synthetic opiates in clinical practice It was designed to be metabolized by plasma esterases for a short half-life It is a potent m-agonist with mild k and d effects It is substantially more potent than fentanyl Remifentanil is supplied as a white lyophilized powder that contains glycine and should not be used for epidural or spinal analgesia The metabolism is by nonspecific esterases not affected by pseudocholinesterase deficiency The metabolite, a weak m-agonist, is excreted by the kidney The kinetics of remifentanil is different from those of most opiates used in the ICU It has a short half-life that is owing to metabolism rather than to redistribution Therefore, remifentanil has what is known as a context-sensitive half-life The elimination half-life for remifentanil is about minutes With an infusion of remifentanil, the half-life does not increase but rather remains constant With opiates such as fentanyl and alfentanil, the clinical effect half-life increases with time until it reflects the elimination half-life of between and hours (Fig 132.3) The kinetics reported for neonates is similar to those reported for adults The continuous infusion rate depends on the degree of sedation/analgesia required (0.1–0.5 mg/kg per minute for sedation; 0.75–2.00 mg/kg per minute for balanced anesthesia; mg/ kg per minute for loss of consciousness) Remifentanil has effects on the cardiovascular system that are similar to those of fentanyl Remifentanil causes a mild bradycardia and a slight decrease in blood pressure,45 which may be prevented with glycopyrrolate No histamine release occurs Remifentanil is a potent respiratory depressant For spontaneous respiration, a low continuous infusion dose (without a bolus) should be used (0.1 mg/kg per minute) Sedation can be effectively managed by continuous infusion without the need for a bolus because of the short half-life An increase or decrease of infusion rate is rapidly reflected by a change in the degree of sedation, which is important to note Most other opiate CHAPTER 132 Sedation and Analgesia phenotype In these patients, a therapeutic dose of codeine that is rapidly converted to morphine can result in respiratory depression and death, especially following postoperative tonsillectomy in patients with a history of obstructed sleep apnea.50 This complication appears to be very rare in adults Codeine now carries a black box warning, and its use in children is discouraged.51 Time required for a 50% reduction in effect site concentration (min) 300 Fentanyl Alfentanil Sufentanil G187084 250 200 1589 150 Hydromorphone 100 50 0 100 200 Duration of infusion (min) 300 • Fig 132.3 Context-sensitive half-life sedatives require bolus dosing to achieve a rapid change in effect This type of dosing is neither appropriate nor needed for remifentanil Remifentanil has the usual opiate adverse effects; however, because of the short half-life, these clinical effects are brief Remifentanil may prove to be a safe and effective choice for PICU sedation in patients with severe renal or hepatic disease However, the potential exists for glycine accumulation in patients with renal failure It is an option for those who require overnight ventilation or for patients in whom a rapid awakening may be required for neurologic assessment Remifentanil has been shown to reduce cerebral oxygen use and reduce cerebral blood flow (CBF) if the CO2 is maintained in a normal range Remifentanil is currently an expensive option and should not be considered for every patient Because of its short duration, the postoperative patient may need an alternative analgesic after extubation Rapid development of opiate tolerance with remifentanil has been described in healthy volunteers46 and in the ICU setting This rapid tolerance has also been described in postoperative scoliosis patients.47 However, the increased morphine requirements described probably reflect the initial postoperative need to achieve an adequate morphine blood level rather than any acute tolerance Codeine Codeine has a chemical structure similar to that of morphine It has been used as an oral medication for cough suppression or mild to moderate pain relief However, codeine itself has no analgesic effect; it is a prodrug that must be metabolized to morphine to promote analgesia Between 10% to 20% of patients lack a metabolic pathway to convert codeine to morphine, which results in unpredictable effects and inadequate analgesia Dosing is 0.5 to 1.0 mg/kg Constipation is a major adverse effect, and some patients report having a vague, peculiar, or unpleasant feeling when they take codeine Codeine can be habit forming It can be given orally, IM, or rectally Rapid IV use may result in cardiovascular collapse Rectally administered codeine has been shown to have as rapid an onset as IM codeine, but it yields lower peak levels in children.48 Codeine has been the analgesic of choice by neurosurgeons because of the belief that pupillary signs are maintained with use of this drug Morphine has been shown to be a more effective analgesic in patients with head injuries, however.49 Approximately 1% to 2% of children have a duplication of the CYP2D6 allele that results in an ultrarapid-metabolizer Hydromorphone is a hydrogenated ketone of morphine It is seven times as potent as morphine, with a similar onset and duration of action It causes less histamine release than morphine and may be used in patients who report pruritus due to morphine Like morphine, hydromorphone undergoes hepatic metabolism However, no active metabolites are dependent on renal excretion; thus, it may be an effective alternative in patients with renal insufficiency or failure Tramadol Tramadol is an opiate analgesic Its action is due to the metabolite O-desmethyltramadol, which relieves pain by binding to opiate receptors and by inhibiting the reuptake in the CNS and spinal cord of norepinephrine and serotonin, two pain-modifying neurotransmitters Tramadol does not have antiinflammatory effects Its use is indicated in cases of moderate to severe pain.52 Even though it is a narcotic-like agent, the FDA only recently classified tramadol as a controlled substance Tramadol is now classified as a schedule IV medication, reflecting concerns about tolerance, habituation, abuse potential, and withdrawal syndrome.53 Dosage (not FDA approved for patients ,16 years) is an initial oral administration of to mg/kg every hours and should not exceed mg/kg per day An IV preparation is available outside of the United States Patients with a creatinine clearance less than 30 mL/ should not receive more than one dose every 12 hours, with a maximum dose of mg/kg per day The dose for patients with cirrhosis or hepatic dysfunction is mg/kg every 12 hours Patients undergoing dialysis can receive their dose on the day of dialysis because only 7% of the drug is removed by the process The adverse effects of tramadol most often involve the CNS and GI tract Patients may become dependent on tramadol Abuse is possible; thus, it should not be dispensed to opiate-dependent patients Seizures have been seen in patients receiving high single oral doses of 10 mg/kg This danger is even greater in patients with epilepsy and in anyone taking monoamine oxidase inhibitors or neuroleptic agents that lower the seizure threshold Respiratory depression may occur if the recommended dosage is consistently exceeded or if another centrally acting depressant drug (e.g., alcohol) or an anesthetic is given concurrently Because of the possibility of withdrawal symptoms, patients should not abruptly discontinue use of tramadol Tramadol is not a useful drug for sedative action Similar to codeine, it is metabolized by the CYP2D6 enzyme complex.48 Patients who are ultra-rapid metabolizers have an increased risk of respiratory depression and death due to high levels of the active metabolite O-desmethyltramadol A black box warning akin to that for codeine is now in effect for tramadol Current recommendations include the use of acetaminophen alternating with ibuprofen for initial analgesia treatment; oxycodone and hydrocodone can be considered when opiates are required Pharmacokinetics for relevant opiates are shown in Table 132.3 Table 132.4 provides conversion doses for some commonly used oral opiates A summary of IV doses of various opiates is provided in Table 132.5 ... morphine may say something such as “I have just as much pain, but it doesn’t distress me as much.” It blunts most types and intensities of pain, although some forms of neuropathic pain are relatively... with a resultant fall in minute ventilation despite an accompanying increase in depth of breathing This effect is associated with a decreased responsiveness to carbon dioxide (CO2) and is additive... resulting in inhibition of voltage-gated calcium entry channels and activation of potassium channels This results in a loss of potassium from the neuron, causing hyperpolarization and depression of