The anesthetic implications of illicit opioid abuse more

The Anesthetic Implications of Illicit Opioid Abuse Ethan O. Bryson, MD Mount Sinai Medical Center New York, New York Abuse of opioids has expanded greatly over the last several decades.1 Self-reported lifetime use of heroin was 1.5% in 2005, up from 1.2% 5 years earlier, and the nonmedical use of prescription opioids had increased from 8.6% to 13.4% over the same period.2 With the increasing availability of highly addictive prescription opioids in tablet form through the internet and other sources, the patient-addict no longer fits the classic stereotype of the down-and-out individual living on the outskirts of society.3 Heroin, once only the scourge of addicts willing to inject this agent intravenously, is now available in purity high enough to allow addicts to obtain a satisfactory ‘‘high’’ from simply snorting or smoking the drug. It has been estimated that between 3% and 16% of the general population has an addiction disorder,4 and opioid addiction now affects members of every social class and profession. When such patients require anesthetic services, they may present with increased tolerance, in withdrawal, or with any number of associated side-effects and complications. Opioid abusers are at increased risk for developing blood-borne viral infections such as human immunodeficiency virus (HIV), hepatitis C virus, and hepatitis B virus, either through the sharing of injection equipment or from unsafe sexual activities performed under the influence. All users are at risk for drug overdose, drug dependence, and many may also have associated mental health problems. ’ Types of Opioids Opioids are either naturally occurring agents that are found in their active form in nature, semisynthetic agents that are produced by REPRINTS: ETHAN O. BRYSON, MD, DEPARTMENT OF ANESTHESIOLOGY, MOUNT SINAI MEDICAL CENTER, NEW YORK, NY, E-MAIL: ETHAN.BRYSON@MOUNTSINAI.ORG INTERNATIONAL ANESTHESIOLOGY CLINICS Volume 49, Number 1, 67–78 r 2011, Lippincott Williams & Wilkins www.anesthesiaclinics.com | 67 68 ’ Bryson chemically altering the structure of the naturally occurring agents, or fully synthetic agents created in the laboratory in an attempt to produce agents with specific pharmacokinetic properties. All the clinically relevant opioids, regardless of origin, produce the same basic effects of analgesia, sedation, and respiratory depression, and share the same clinical features of intoxication. These actions are produced through the activation of the m, k, or d-opioid receptors found throughout the body. Naturally occurring opioids such as opium, morphine (MS-Contin, Oramorph SR, MSIR, Roxanol, Kadian, and RMS), and codeine are derived from the milky fluid that seeps from incisions in the unripe seedpod of the poppy plant, Papaver somniferum. Once processed, opium is broken down into its alkaloid constituents, the phenanthrenes (morphine, codeine, and thebaine) and the isoquinolines which have no significant central nervous system effects and are therefore not considered drugs of abuse. Semisynthetic agents such as heroin, hydromorphone (Dilaudid and Palladone), oxycodone (OxyContin, OxyIR, Percodan, and Percocet), and hydrocodone (Vicodin, Lortab, Lortab ASA, Vicoprofen, and Hycomine) are derived from natural-occurring opioids. Although similar in chemical structure and biochemical profile, synthetic opioids are not derived from the naturally occurring opioids and are produced entirely within the laboratory. Synthetic opioids include meperidine (Demerol, Mepergan, and Pethidine), dextropropoxyphene (Darvon), fentanyl (Sublimaze, Duragesic, and Actiq), alfentanil (Alfenta), sufentanil (Sufenta), carfentanil (Wildnil), pentazocine (Talwin and Talwin Nx), and butorphanol (Stadol, Stadol NS, Torbugesic, and Torbutrol). ’ Naturally Occurring Opioids Morphine is the principal constituent of opium and can be used directly or after conversion to codeine and other derivatives. Despite the significant potential for abuse, the legitimate medical use of morphine has increased significantly in recent years.5 Morphine remains one of the most effective agents for the relief of severe pain, especially cancerrelated pain and the pain of myocardial infarction, and is commonly used to treat chronic pain in opiate-tolerant patients. Morphine-based products are available in a variety of forms such as oral solutions, immediate and sustained-release tablets, capsules, suppositories, as well as the traditional injectable preparations. Codeine (O-methylmorphine) is used as a mild analgesic and an antitussive. Although codeine is found naturally within the poppy, commercial methylation of morphine is responsible for the majority of the clinically used product. Codeine is actually a prodrug and is not active itself. After ingestion, only 5% to 10% of codeine is converted to www.anesthesiaclinics.com Anesthetic Implications of Illicit Opioid Abuse ’ 69 morphine, with the remainder either free, conjugated to form codeine6-glucuronide, or converted to small amounts of norcodeine and hydromorphone. As such, its strength ranges from 8% to 12% of morphine. As it is very effective when administered orally and has a wide safety margin, codeine has been combined with a large number of other medications and marketed for the treatment of headache, nasal congestion, rhinorrhea, cough, hay fever, osteoarthritis, muscle spasm, and mild-to-moderate pain. ’ Semisynthetic Opioids Heroin was first synthesized from morphine in 1874 and initially used extensively as a pain remedy, although today it is considered to have no legitimate medical use and is listed as a schedule I agent. Heroin may vary in color from white to dark brown to black and consistency may vary from powder to sticky (black tar) to hard (coal) depending on the origin and the manufacturing process. As with most illicit substances produced in clandestine and unregulated facilities, heroin powder often contains impurities and additives. Generally, only a portion of the heroin sold on the street contains actual heroin, with the remainder consisting of any one or combination of the several agents used to ‘‘cut’’ pure heroin. Agents used to reduce the potency of heroin are known to include sugar, starch, acetaminophen, procaine, benzocaine, or quinine, but as there is no standardization across the industry, any agent could be used, including steroids6 or the banned b2-adrenergic agonist, clenbuterol.7 Recent attempts to increase the potency of heroin by adding a fully synthetic opioid such as fentanyl have been associated with overdose deaths.8 The documented use of adjuvants such as clenbuterol and fentanyl should remind the clinician that any patient who is suspected to have ingested heroin may likely have also ingested other agents with unknown sideeffects on the body. Anesthesiologists are facile with the management of patients under the influence of opioids; however, illicit opioid using patients should be treated cautiously. The wide range of cutting agents unwittingly administered along with heroin is responsible for a number of unanticipated problems encountered in the heroin-abusing patient, regardless of the route of administration. Historically, heroin has almost always been injected, but the recent availability of higher purity heroin has allowed a larger percentage of users to either snort or smoke heroin.9 This trend has reduced the prevalence of syringe-borne diseases, such as HIV and hepatitis, in noninjecting heroin users below that seen in the injecting population, but such infections are still significantly in excess of the nondrug using population.10 Hydromorphone is a semisynthetic opioid with analgesic potency 2 to 8 times that of morphine, but with a shorter half-life, greater www.anesthesiaclinics.com 70 ’ Bryson sedation, and more euphoric effects. As such, hydromorphone has a much higher abuse liability than morphine. It is available in a number of formulations including tablets, suppositories, oral solutions, and injectable solutions. Tablets are usually obtained through fraudulent prescriptions or theft and may be dissolved and injected in an attempt to increase the high experienced by the user. Oxycodone is a semisynthetic opioid derived from thebaine which is effective orally and marketed alone in controlled-release tablets, immediate-release capsules, or in combination products with aspirin or acetaminophen for the relief of pain. Abuse of oxycodone typically involves either oral ingestion of the intact preparation, or crushed extended release tablets that are either sniffed or dissolved in water and injected. Hydrocodone, another semisynthetic opioid derived from codeine, is typically prescribed as a cough suppressant in liquid formulations or as an analgesic tablet in combination with acetaminophen or aspirin. These products are the most frequently prescribed pharmaceutical opiates and are the commonest pharmaceutical drugs associated with diversion, abuse, and addiction.1 ’ Synthetic Opioids Meperidine was first synthesized in the 1930s, marketed as an analgesic with effects similar to morphine but with a shorter duration of action, and was the narcotic of choice during much of the 20th century because of a supposed relief of renal and biliary colic. Unfortunately, meperidine is not as effective as morphine and has the unique side-effects of delirium and seizures. Demerol interacts with monoamine oxidase inhibitors to cause serotonin syndrome and a single injection can cause seizures, coma, and death. As a result of this, it has been banned in Australia and is currently only in limited use now in the United States and many other countries. It is available in tablet, syrup, and injectable forms used for sedation and anxiolysis before anesthesia and for the relief of mild-to-moderate pain, particularly in obstetrics and postoperative situations. Meperidine is not as effective at relieving pain as other opioids but it does produce a generalized feeling of well being and has a considerable abuse liability. Many patients who have received meperidine report still experiencing pain but not minding much. On account of its morphine-like effects, multiple illicit attempts have been made to synthesize meperidine analogs for nonmedical uses. In an attempt to synthesize the meperidine analog, 1-methyl-4-phenyl-4-propionoxypiperidine, desmethylprodine for recreational use, the neurotoxic by-product 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine was produced. Addicts who ingested the 1-methyl-4-phenyl-4-propionoxypiperidine-1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine preparation developed an irreversible Parkinsonian-like syndrome because of the destruction of dopaminergic www.anesthesiaclinics.com Anesthetic Implications of Illicit Opioid Abuse ’ 71 neurons in the substantia nigra. As meperidine is highly addictive, has more side-effects, and is less effective as an analgesic than other opioids, it is primarily used as a second or third-line agent. Dextropropoxyphene was synthesized in 1957 and marketed as an oral agent with analgesic potency one-half to one-third that of codeine for relief of mild-to-moderate pain. This opioid is chemically similar to methadone, has been associated with a number of toxic side effects and is among the top 10 drugs reported by medical examiners in drug abuse deaths. Fentanyl was also synthesized in the late 1950s and marketed as an intravenous anesthetic agent. It has an analgesic potency of about 80 times that of morphine and an extremely high abuse potential. Three fentanyl analogs subsequently introduced into clinical practice are alfentanil, an ultra-short acting analgesic; sufentanil, an analgesic with a potency 5 to 10 times that of fentanyl typically used for surgeries with high opioid requirements; and carfentanil, an analog with an analgesic potency 10,000 times that of morphine primarily used for procedures involving extremely large animals. In addition to injectable preparations, fentanyl is available as a transdermal patch used in chronic pain management, and as a ‘‘lollypop’’ formulation of fentanyl citrate on a stick designed for transmucosal absorption. Illicit use of pharmaceutical fentanyl first appeared among members of the medical community primarily because this drug was not available on the street in quantities large enough to cause a problem until recently.11 However, even with increased availability, addiction to fentanyl remains a problem primarily within the community of healthcare professionals and others with access. Opioid addicts who are not healthcare professionals have reported a fear of toxicity or overdose and are less likely to abuse fentanyl than other opioids.12 The effects of these agents are indistinguishable from those of heroin, but these synthetic agents are hundreds of times more potent and much more likely to cause an unintended fatal overdose. Like heroin, fentanyl and fentanyl analogs are most commonly used by intravenous administration, but they may also be snorted in both liquid and solid form, swallowed, or smoked. The fentanyl-containing gel used in the transdermal preparation is commonly extracted, dissolved, and injected. Pentazocine was synthesized in 1967 and marketed as an analgesic. On account of its significant abuse liability, a more recent formulation was manufactured which contains the antagonist naloxone in quantities sufficient to counteract the morphine-like effects of pentazocine if the tablets are dissolved and injected. If taken orally, the naloxone is eliminated through first pass metabolism by the liver and does not reduce analgesic efficacy. Butorphanol was first synthesized as an analgesic available in injectable formulations for human and veterinary use. Although it clearly has abuse potential, significant diversion and abuse was not common until the nasal spray formulation became available in 1992. www.anesthesiaclinics.com 72 ’ ’ Bryson Opioids Used as Addiction Treatment Agents In some cases, addiction treatment includes maintenance with opioid medications such as methadone (Dolophine), levo alphacetylmethadol (LAAM; ORLMM), or buprenorphine (Buprenex, Suboxone, and Subutex). Methadone was first synthesized during World War II because of a shortage of morphine and introduced in 1947 as an analgesic. It is available in oral solutions, tablets, and injectable formulations. Although methadone is primarily used for the treatment of narcotic addiction, it is increasingly used for chronic pain management. Its effects typically last up to 24 hours and high-dose methadone can block the effects of heroin, making it ideal for administration in heroin detoxification and maintenance programs. Even though methadone administration discourages the use of heroin by addicts in treatment, tolerance and dependence does result and cessation of methadone maintenance is associated with a withdrawal syndrome. Methadone is encountered on the illicit market and recent increases in the use of methadone for pain management have been associated with increasing numbers of overdose deaths.13 The current increase in methadone-related deaths is thought to involve illicitly obtained methadone used in excessive or repetitive doses in an attempt to achieve euphoric effects, resulting in the accumulation of methadone to harmful serum levels, or methadone used in combination with other prescription medications, especially benzodiazepines, alcohol, or other opioids. LAAM is a synthetic compound that is structurally similar to methadone but with an even longer half-life that allows for less frequent administration. It was introduced in 1994 as a treatment drug for opioid addiction but a high-abuse liability and potential for cardiovascular toxicity have limited the use of this drug as a first-line therapy for addiction treatment. Buprenorphine is a semisynthetic opioid derived from thebaine that was initially marketed in the United States as an analgesic, but approved for the treatment of narcotic addiction in 2002. Like methadone and LAAM, buprenorphine has a long duration of action and can be administered orally, but is associated with less respiratory depression and is considered to have an improved safety profile with less risk of fatal overdose. ’ Anesthetic Implications for the Opioid-abusing Patient Tolerance is a common phenomenon associated with all chronic opioid use, and the opioid-abusing patient who presents for a procedure or surgery that requires sedation or anesthesia will require a greater amount of opioid anesthetics per weight than the opioid-naive patient. The diagnostic and statistical manual IV defines tolerance as it relates to the addict as the ‘‘need for markedly increased amounts of substance to www.anesthesiaclinics.com Anesthetic Implications of Illicit Opioid Abuse ’ 73 achieve intoxication or desired effect, and markedly diminished effect with continued use of the same amount of substance.’’ Proposed mechanisms to explain the development of tolerance include desensitization, in which uncoupling of G-proteins results in receptors that are still expressed on the surface of cells but are less responsive to opiates and down-regulation, in which the internalization of activated opioid receptors through endocytosis actually reduces the number of receptors expressed on the cell surface.14 Opiate hyperalgesia or hyperesthesia is characterized by dramatically increased sensitivity to painful stimuli in the chronic opioid-abusing patient, thought to develop through spinal sensitization to glutamate and substance P.15 The chronic opioid abuser may have become hypersensitive to surgical and other stimuli in addition to developing tolerance and often will require even higher doses of anesthetic agents than would be expected from tolerance alone. Occasionally, allodynia, in which pain is elicited by a normally nonpainful stimulus, may occur. It has been postulated that these reactions may result from N-methyl D-aspartate (NMDA) receptor agonist action as NMDA antagonists have been shown to be effective in the reduction of opioid hyperalgesia.16 Agents such as ketamine should be considered in refractory cases. ’ Clinical Presentation A detailed history and physical examination is essential. Most opioidabusing patients have experienced withdrawal, some even in the hospital setting, and are often honest regarding their drug use to avoid experiencing withdrawal again. Many will actually exaggerate their daily dose requirements in an attempt to receive increased medication doses. Specific questions should be posed such as: 1. What drug(s) the patient has been taking? 2. How much of the drug has the patient been taking? 3. What was the time of last use? Information regarding use or abuse of other drugs or alcohol as polysubstance abuse should be obtained. The presence of physical signs such as needle tracks, soft-tissue infection, myosis, altered mental status, or respiratory depression are suggestive of prior opioid abuse but may not be present. In the case of the obtunded patient who can not give a history, it is appropriate to inquire about drug use from friends or family. ’ Opioid Overdose Opioid overdose is an acute life-threatening emergency and should be addressed immediately. The initial approach should be to assess the adequacy of ventilation and provide assistance with 100% oxygen if www.anesthesiaclinics.com 74 ’ Bryson indicated through positive pressure device. Endotracheal intubation and mechanical ventilation should be considered if administration of 0.4 to 0.8 mg of naloxone hydrochloride does not reverse respiratory depression. For patients who do not respond to initial naloxone administration, an increased dose of up to 2 mg may be administered while other causes for central nervous system depression are considered. Even if drug use is suspected or confirmed, the clinician should remember that acute mental status changes can result from many causes other than intoxication and the opioid addict is at higher risk for developing these complications. Opportunistic infections related to HIV, liver disease related to hepatitis B or C infection, hypoglycemia, or other fluid and electrolyte imbalances may also be present and should be investigated concurrently. The patient who responds to naloxone completely should be observed for 2 to 3 hours to ensure that ingestion of sustained release agents which would remain active after regression of clinically relevant naloxone levels does not result in delayed respiratory depression. Should respiratory depression occur, naloxone may be repeated or an infusion begun. ’ Clinical Management The chronic opioid-abusing patient should be treated in much the same way a chronic pain patient who has become tolerant to opioids. An attempt to calculate the 24-hour dose and convert to an oral or intravenous equivalent dose for maintenance (Table 1) should be made. Division by 24 estimates the patients’ hourly requirement. The practitioner may assume a 20% to 30% increase in acute opiate requirements consistent with that required for opiate-naive patients. An opioid rotation strategy takes advantage of the incomplete crosstolerance of m receptors across different opioid agents. Resumption of the opiates postoperatively is indicated. An intravenous patient-controlled anesthesia device with the following dosing guidelines should be considered: Morphine 2 to 5 mg (bolus) 5 to 15 minutes interval or Hydromorphone 0.1 to 0.5 mg (bolus) 5 to 15 minutes interval or Fentanyl 10 to 20 mg 5 to 10 minutes interval (Iontophoretic 10 mg 10 min interval). Nonopioid agents such as intravenous or oral nonsteroidal antiinflammatory drugs, the centrally acting m agonist tramadol, the a-2 agonist clonidine, or other adjuvant medications such as gabapentin and pregabalin may be useful. (Table 2) Muscle relaxants such as cyclobenzaprine (Flexeril), metaxalone (Skelaxin), or baclofen may be used to treat postoperative splinting or spasm. The NMDA antagonist ketamine www.anesthesiaclinics.com Anesthetic Implications of Illicit Opioid Abuse ’ 75 Table 1. Conversion Table for Opioid Medications Using 10 mg Intravenous Morphine as the Standard for Comparison Original Drug Morphine Morphine CR Morphine SR Oxycodone Oxycodone CR Hydromorphone Meperidine Methadone Codeine Hydrocodone Oxymorphone Levorphanol Fentanyl Fentanyl patch Orally (mg) 30 30 30 20 20 7.5 300 20 200 30 10 4 Intravenously (mg) 10 Half-life (h) 2-3 8-12 8-12 2-3 2-3 2-3 2-3 36-120 2-3 2-3 2-3 12-15 7-12 16-24 Duration (h) 2-4 8-12 8-12 3-4 8-12 2-4 2-4 4-12 2-4 3-4 2-4 4-6 1 48-72 1.5 100 10 100 1 2 100 mg/h 100 mg/h Fentanyl patch doses are only standardized when used as directed by the manufacturer. When dissolved and injected, the total dose of fentanyl is administered all at once and can be as much as 7200 mg depending on the product used. Calculate the 24-hour dose of current drug and divide to obtain appropriate dosing interval or total dose for patients who will receive continuous infusions. has been shown to decrease chronic neuropathic pain and is useful in opiatetolerant patients.17 In refractory cases, decreasing the dose of opioid or administering a bolus or infusion of magnesium, or using transcutaneous electrical nerve stimulation therapy may be helpful. Regional anesthesia targets the site of surgery and allows for the administration of lower doses of opioids. Peripheral nerve blocks and central (neuraxial) techniques using local anesthetics with or without Table 2. Suggested Doses for Adjuvant Therapy Ketamine—0.1-0.5 mg/kg IV bolus preincision followed by 0.1-0.5 mg/kg/h infusion Clonidine—0.3 m/kg IV bolus preincision followed by 0.3 m/kg/h infusion Clonidine—1 mg/mL added to local anesthesia for epidural or peripheral nerve block Celecoxib (Celebrex)—400 mg initially, followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily as needed Ketorolac (Toradol)—30 mg IV every 6 h as needed Acetaminophen (Tylenol)—650 mg PO every 4 to 6 h as needed. Reduce dose if acetaminophen-containing opioid analgesics are also administered Pregabalin (Lyrica)—75-150 mg PO twice daily or 50-100 mg PO 3 times daily The use of nonsteroidal anti-inflammatory drugs perioperatively may increase risk for bleeding and the decision to use should be made after discussion with the surgical team. IV indicates intravenously; PO, orally. www.anesthesiaclinics.com 76 ’ Bryson opiates inhibits the conduction of pain and avoids central sensitization and remodeling (neuroplastic changes) in the dorsal horn of the spinal cord. These techniques have immediate effect as they result in less perioperative pain, and long-term analgesia as the risk that a chronic pain state will develop is decreased. Side-effects such as nausea and vomiting can be treated with antiemetics. Constipation may be reduced by a peripherally acting m-receptor antagonist such as methylnaltrexone which does not cross the blood-brain barrier and will not reduce the central analgesic effects; however, all patients receiving opioids should be given a stool softener. Postoperative ileus may respond to another peripherally acting m-opioid receptor antagonist, alvimopam, 12 mg given preoperatively and continued for up to 7 days postoperatively. Pruritis is common and can be effectively treated with antihistamines such as diphenhydramine. Sedation is common and ventilation status (respiratory rate and oxygen saturation) should be closely monitored. A significant decrease in either signals the presence of effective levels of opioid in the patient and the clinician should decreasing the opioid dose, stopping or changing the opiate altogether. If the decision is made to administer a central-acting m-receptor antagonist, the patient should be monitored for signs of opioid withdrawal (Table 3). In the case of urinary retention, the bladder may need to be catheterized and an antagonist administered. ’ Informed Consent The problem of obtaining informed consent for a procedure or surgery in the patient who is opioid addicted can be complicated. Patients who are acutely intoxicated and require life-saving procedures should receive such treatment under the rubric of implied consent. Elective procedures should be postponed until the patients clouded sensorium has Table 3. Signs of Opioid Withdrawal Elevated resting heart rate Diaphoresis not accounted for by ambient temperature or activity Restlessness, frequent shifting, or extraneous movements Mydriasis greater than expected given ambient light Bone or joint aches unrelated to injury or surgery Rhinorrhea or lacrimation not accounted for by cold symptoms or allergies Nausea, vomiting, or diarrhea Tremor of outstretched hands Yawning Anxiety or irritability Piloerection www.anesthesiaclinics.com Anesthetic Implications of Illicit Opioid Abuse ’ 77 resolved to the point where they are able to make an informed decision. Patients maintained on methadone for prior opioid abuse or patients on chronic opioids for pain management may have some difficulty with cognition and each case should be evaluated on its own merits. In the case of the chronic heroin user who arrives for surgery having just dosed himself, the concern should be less about his ability to provide informed consent but rather concern regarding the substances which he may have unknowingly ingested along with the heroin. ’ Conclusions The management of the opioid-abusing patient can present a significant challenge during the perioperative period. The anesthesiologist needs to be aware of the basic pharmacologic properties of the opioids of abuse and maintain a high index of suspicion regarding illicit use. The acutely intoxicated patient and the chronic opioid abuser in withdrawal can present in ways that can mimic other organic processes and may, in fact, obscure the presentation of concurrent medical issues. Careful evaluation and supportive management as outlined above are essential. The anesthesiologist can and should play an important role in the identification of opioid misuse and encourage subsequent referral for detoxification and treatment. ’ References 1. Joranson DE, Ryan KM, Gilson AM, et al. Trends in medical use and abuse of opioid analgesics. JAMA. 2000;283:1710–1714. 2. Substance Abuse and Mental Health Services Administration. Results From the 2005 National Survey of Drug Use and Health. Rockville, MD: National Finding; 2006. (http:// www.oas.samhsa.gov/nsduh/2k5nsduh/2k5results.htm) 3. Carise D, Dugosh KL, McLellan AT, et al. Prescription OxyContin abuse among patients entering addiction treatment. Am J Psychiatry. 2007;164:1750–1756. 4. Nedeljkovic SS, Wasan AD, Jamison RN. Assessment of efficacy of long-term opioid therapy in pain patients with substance abuse potential. Clin J Pain. 2002;18:S39–S51. 5. Gilson AM, Ryan KM, Joranson DE, et al. 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Prevalence and correlates of former injection drug use among young noninjecting heroin users in Chicago. Subst Use Misuse. 2010;45:2000–2025. 11. Bryson EO, Silverstein JH. Addiction and substance abuse in anesthesiology. Anesthesiology. 2008;109:905–917. 12. Cicero TJ, Ellis MS, Paradis A, et al. Determinants of fentanyl and other potent micro opioid agonist misuse in opioid-dependent individuals. Pharmacoepidemiol Drug Saf. 2010;19:1057–1063. 13. Centers for Disease Control and Prevention (CDC). Emergency department visits involving nonmedical use of selected prescription drugs-United States, 2004-2008. MMWR Morb Mortal Wkly Rep. 2010;59:705–709. 14. Joseph EK, Reichling DB, Levine JD. Shared mechanisms for opioid tolerance and a transition to chronic pain. J Neurosci. 2010;30:4660–4666. 15. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006;104:570–587. 16. Mizoguchi H, Watanabe C, Yonezawa A, et al. New therapy for neuropathic pain. Int Rev Neurobiol. 2009;85:249–260. 17. Berti M, Baciarello M, Troglio R, et al. Clinical uses of low dose ketamine in patients undergoing surgery. Curr Drug Targets. 2009;10:707–715. www.anesthesiaclinics.com