PATIENTS with opioid addiction often struggle

ACADEMIC EMERGENCY MEDICINE January 2002, Volume 9, Number 1 www.aemj.org 63 Complications of Ultrarapid Opioid Detoxification with Subcutaneous Naltrexone Pellets RICHARD J. HAMILTON, MD, RUBEN E. OLMEDO, MD, SACHIN SHAH, MD, OLIVER L. HUNG, MD, MARY ANN HOWLAND, PHARMD, JEANMARIE PERRONE, MD, LEWIS S. NELSON, MD, NEAL L. LEWIN, MD, ROBERT S. HOFFMAN, MD Abstract. Rapid and ultrarapid opioid detoxification (ROD and UROD) centers promise quick, painless, same-day detoxification treatment for patients with opioid addiction. The goal of ROD and UROD is to provide a rapid transition from opioid dependency to oral naltrexone therapy. The patient is given general anesthesia and high-dose opioid antagonists. This induces a severe withdrawal but spares the patient the experience. In theory, the process is complete within four to five hours. The patient awakens without opioid dependency and is started on oral naltrexone. Any subsequent, persistent withdrawal symptoms are treated symptomatically. A novel, unapproved approach is to compound a pellet of naltrexone and implant it in the subcutaneous tissue. In theory, this should result in continuous therapeutic levels for this drug, and avoid issues with noncompliance. Case series: This article reports six cases of complications from the same detoxification center that performed UROD with naltrexone pellet implantation, including pulmonary edema, prolonged withdrawal, drug toxicity, withdrawal from cross-addiction to alcohol and benzodiazepines, variceal rupture, aspiration pneumonia, and death. Conclusions: The risks of this procedure are great and further studies should assess its safety and the novel use of naltrexone. Key words: opioids; heroin; addiction; detoxification; rapid detoxification; ultrarapid detoxification; naltrexone. ACADEMIC EMERGENCY MEDICINE 2002; 9:63 68 PATIENTS with opioid addiction often struggle to achieve detoxification. Discontinuation of opioid use results in the severe discomfort of withdrawal. Many find methadone maintenance undesirable. For these patients, rapid and ultrarapid opioid detoxification (ROD and UROD) centers promise quick, painless, same-day detoxification treatment for patients with opioid addiction. This allows rapid transition from opioid dependency to oral naltrexone therapy. General anesthesia is given via endotracheal tube as well as highdose opioid antagonists. The induced withdrawal is complete within four to five hours and the patient awakens without opioid dependency. The patient is then started on oral naltrexone and any subsequent, persistent withdrawal symptoms are treated symptomatically. A novel, unapproved approach is to compound a pellet of naltrexone and From MCP Hahnemann University (RJH), Philadelphia, PA; New York University (REO, OLH, MAH, LSN, NLL, RSH), New York, NY; Albert Einstein College of Medicine (SS), Bronx, NY; St. John s University College of Pharmacy (MAH), Jamaica, NY; and University of Pennsylvania (JP), Philadelphia, PA. Received May 23, 2001; revision received August 13, 2001; accepted August 14, 2001. Address for correspondence and reprints: Richard J. Hamilton MD, MCP Hahnemann University, Department of Emergency Medicine, 3300 Henry Avenue, Philadelphia, PA 19129. Fax: 215-843-5121; e-mail: richard.hamilton@drexel.edu implant it in the subcutaneous tissue. In theory, this results in continuous therapeutic levels for this drug, and avoids issues with noncompliance. Patients who do not successfully transition to oral naltrexone therapy may present to emergency departments (EDs) for treatment of complications, and emergency physicians need to be aware of the complications that can occur with this therapy. We report six patients treated with a UROD procedure at a single facility with the implantation of a subcutaneous pellet of naltrexone who experienced major side effects and complications following the procedure. The patients were seen in the EDs of five different hospitals in New York and Pennsylvania during the years 1997 to 1999. The authors became aware of each other s cases through local and national toxicology meetings and conferences. Three of these cases were reported in abstract form to the North American Congress of Clinical Toxicology: cases 1, 2, and 6. 1,2 CASE REPORTS Case 1. A 38-year-old man presented to the ED with acute dyspnea. The patient was agitated, was yawning, and had diarrhea. Auscultation of the lungs revealed diffuse rales. A chest radiograph confirmed the diagnosis of acute pulmonary edema

64 OPIOID DETOX Hamilton et al. ULTRARAPID OPIOID DETOXIFICATION with normal cardiac silhouette. The previous day he had been treated with UROD. A pellet reported to be naltrexone in a sustained-release delivery vehicle had been implanted in his subcutaneous tissues. He had been given octreotide-preloaded syringes for self-injection of octreotide to control diarrhea. In the ED, the patient was treated for pulmonary edema and given nitroglycerin by intravenous (IV) drip and furosemide, 80 mg IV push. His persistent withdrawal symptoms were treated with clonidine 0.1 mg by mouth and 2 mg of IV lorazepam. The naltrexone pellet was removed and the patient requested discharge after 12 hours when his withdrawal symptoms resolved. He was lost to follow-up. Case 2. A 27-year-old woman presented to the ED complaining of five days of vomiting, diarrhea, dry mouth, weakness, fatigue, poor urine output, and hyperalgesia, which started immediately after her UROD procedure. None of these symptoms responded to her self-administered octreotide. In the ED, the patient s urine output improved and the remainder of her symptoms lessoned after the administration of 3.0 L of IV normal saline. At the patient s request, the pellet was removed and confirmed to contain naltrexone by gas chromatography/mass spectrometry analysis. She was discharged from the ED and referred to a methadone maintenance clinic and entered into a drug addiction program. Case 3. A 31-year-old woman underwent UROD and was discharged under the care of a private nurse in a local hotel room. She was advised to take baclofen suppositories for myoclonic jerks, parenteral octreotide for nausea and vomiting, and fluoxetine and alprazolam for anxiety. The evening after her discharge she received a baclofen suppository, and subsequently experienced a generalized tonic clonic seizure. She had no prior history of seizure disorder. She was taken to a local hospital by fire rescue and she was admitted to intensive care for overnight observation. A computed tomography (CT) of the brain was reported to be normal. She was later transferred to the psychiatric ward and signed out against medical advice one week later. During her entire post-detoxification treatment period, she complained of intractable nausea and vomiting, which did not respond to antiemetics. She presented to the ED two weeks after rapid detoxification still complaining of persistent nausea, vomiting, weakness, dry mouth, and poor urine output. Her medications on admission to the ED included ondansetron as needed for nausea, alprazolam 2 mg three times a day, fluoxetine 20 mg every day, and zolpidem at bedtime. Her social history included a 15-pack-year cigarette smoking habit as well as daily ethanol use. She used cocaine recreationally in addition to her IV heroin and oral opioid addiction. She denied any opioid use since the detoxification. The patient reported a 15 to 20- pound weight loss, chills, sneezing and coughing, anorexia, abdominal pain, and vomiting over the two weeks after her UROD procedure. On physical examination she was found to be afebrile with stable vital signs. Pertinent findings on physical examination included dry mucous membranes, dry skin, multiple scars on the upper extremities from her heroin injections, and abdominal tenderness to deep palpation. Her affect was found to be depressed. Complete blood count and serum chemistries were unremarkable. She was started on IV fluids. After consent of the patient and family, the pellet was removed intact and confirmed to be naltrexone. The patient was admitted for rehydration and treatment of withdrawal symptoms with phenergan and clonidine. She was treated for nicotine withdrawal with a nicotine patch. A urine drug screen was negative for opioids. Serum naltrexone and 6 beta-naltrexal (an active metabolite) levels drawn at the time of pellet removal were 0.0 and 6.5 ng/ml, respectively (see Discussion below for therapeutic values). Fourteen hours later they were both nondetectable. Within 24 hours the patient was tolerating an oral diet and was discharged to home. Her discharge medications included alprazolam, fluoxetine, zolpidem, clonidine, ondansetron, and oral naltrexone. The patient had requested to restart the opioid antagonist therapy, with the option of discontinuing the drug if adverse sequelae developed. Two weeks after discharge, the patient was noncompliant with oral naltrexone therapy, and she injected heroin. She experienced respiratory arrest at home and was pronounced dead on the scene by paramedics. Case 4. A 24-year-old woman underwent UROD and naltrexone pellet implantation. She was discharged from the center with baclofen, trazodone, prochlorperazine, octreotide, and a transdermal fentanyl patch under the care of her parents. Six hours after the procedure, the family found the patient unresponsive in bed with vomitus around her mouth. Emergency medical services transported the patient to an ED where the following vital signs were noted: pulse 48 beats/min, blood pressure 144/67 mm Hg, oral temperature 99 F, respiratory rate 20 breaths/min, fingerstick glucose 130 mg/dl, and pulse oximetry 100% on room air. There was no response to incremental doses of naloxone up to a total of 10 mg IV. Neurologic examination was significant for 3 4 mm pupils that sluggishly reacted to light. Noxious stimuli elicited

ACADEMIC EMERGENCY MEDICINE January 2002, Volume 9, Number 1 www.aemj.org 65 moaning and symmetrical extremity movement. The reflexes were normal. Three sutures were noted in the right lower quadrant of the abdominal wall with a palpable subcutaneous object. The remainder of the physical examination was normal. A CT of the head and a lumbar puncture were negative. The patient s mental status improved over 12 16 hours. Following a complete neurologic recovery, she denied any supplemental ingestion. Serum naltrexone levels were 11 ng/ml and 6-betanaltrexol levels were 20 ng/ml. A serum baclofen level was noted to be 1.0 g/ml (therapeutic 0.08 0.4 g/ml). This level, coupled with the clinical characteristics of bradycardia, hypertension, and deep sedation, supports the final diagnosis of baclofen toxicity. Case 5. A 30-year-old man was admitted to the ED of an outlying hospital after being found at home unresponsive, twitching, with frothy salivation at the lips. His heart rate was 140 beats/min; his blood pressure was 138/93 mm Hg. The respiratory rate was 40 breaths/min. He became more agitated and began to show extensor posturing. He was given diazepam 5 mg IV, and the twitching and agitation briefly resolved. His medical history was significant for heroin, benzodiazepine, and alcohol addiction. The day prior to admission he had undergone UROD with implantation of subcutaneous naltrexone pellet in his anterior abdominal wall. Serial CT scans of the brain were normal, and the patient was treated for combined alcohol and benzodiazepine withdrawal with 120 mg of diazepam over six hours. Symptoms of withdrawal persisted and the patient was loaded with phenobarbital (10 mg/kg) IV, which resulted in sedation without respiratory depression. Lorazepam was administered periodically over the next 72 hours for minor agitation symptoms. The patient continued to improve over the next five days and was transferred to an unmonitored bed for continued treatment of his withdrawal symptoms. He was discharged without sequelae to an inpatient drug addiction service. Case 6. A 30-year-old man with a history of heroin use was in a methadone maintenance program. To end his methadone maintenance therapy, he underwent UROD with propofol, midazolam, ketamine, and parenteral naloxone. Naltrexone pellets were implanted in the subcutaneous tissues of his abdomen wall. The patient was then discharged to a hotel room where a nurse visited him the next day. In the hotel room he was given octreotide (for nausea and vomiting), acetaminophen, diphenhydramine, and trazodone. On the third day the patient s family found him unresponsive. He was taken to the ED, where he was in respiratory distress, with a blood pressure of 170/100 mm Hg, a pulse of 140 beats/min, and a temperature of 104 F. He was intubated and diagnosed as having bleeding esophageal varices by endoscopy and probable aspiration pneumonia by chest radiography. The naltrexone tablets were removed. Laboratory studies showed prerenal azotemia (blood urea nitrogen 72 mmol/l; creatinine 2.6 mg/dl) and leukocytosis (23,000 cells/mm 3 ). Multiple seizures complicated his subsequent course and he died of a cardiac arrest 18 hours after hospitalization. Autopsy revealed mediastinitis and an esophageal tear. Premortem blood analysis revealed a naltrexone level of 39 ng/ml. After the collection of these cases, the Food and Drug Administration (FDA) was contacted for information about naltrexone complications that may have been reported by other entities. This information was made available via the Freedom of Information Office from the FDA s Center for Drug Evaluation and Research. The FDA reported ten deaths between April 1998 and July 2001 in patients who had recently had a naltrexone pellet implanted for detoxification one for maintenance of detoxification one month after a UROD and nine in concert with a UROD procedure. These cases were provided to us stripped of identifying information such as name or state. To the extent that can be determined, we believe the two fatal cases in our series are not represented in the FDA s ten fatal cases (Table 1). DISCUSSION Withdrawal from opioids, although usually not lifethreatening, can last for several days and is intensely uncomfortable and distressing to patients. Two common treatments of opioid dependence are 1) cessation of opioid use and methadone, levomethadyl acetate (LAAM), or buprenorphine maintenance, and 2) cessation of opioid use and supportive therapy (both medical and psychiatric) during withdrawal. Methadone maintenance continues the physiologic opioid addiction, but the harmful medical and behavioral consequences are minimized. A less common approach is to institute naltrexone therapy after cessation of opioid use and resolution of withdrawal. Naltrexone blocks the euphoric effects of opioid use and discourages recidivism. 3,4 In addition, evidence exists to support a role for naltrexone and other opioid antagonists in blunting drug craving. 5,6 Although the mechanism is not entirely clear, the speculation is that receptor occupancy by an antagonist is sufficient to blunt cravings. The transition from drug withdrawal or abstinence to naltrexone maintenance must be made as

66 OPIOID DETOX Hamilton et al. ULTRARAPID OPIOID DETOXIFICATION TABLE 1. Deaths Recorded by the Food and Drug Administration Center for Drug Evaluation and Research during the Period April 1998 to July 2001 Related to the Use of Naltrexone Implant* Patient Age/Sex Adjunct Medications Narrative 44 years, male None specified Patient underwent UROD with naltrexone implant and within 12 hours developed dyspnea and tachypnea and subsequently died. 33 years, male None specified and was released to the care of his parents and died in a local motel room within 12 hours of the procedure. Unknown age, male None specified and died within 12 hours of the procedure. 44 years, male Cefadroxil, cefazolin, clonidine, baclofen, citric acid/ sodium citrate, dexamethasone, fentanyl, glycopyrrolate, ketamine, midazolam, nalmefene, octreotide, propofol, trazodone, vecuronium 33 years, male Clonidine, baclofen, citric acid/sodium citrate, dexamethasone, fentanyl, glycopyrrolate, ketamine, midazolam, nalmefene, octreotide, propofol, trazodone, vecuronium, ondansetron, metoclopramide, droperidol 20 years, female Albuterol, aminophylline, baclofen, citric acid/sodium citrate, dexamethasone, fentanyl, glycopyrrolate, ketamine, midazolam, nalmefene, octreotide, propofol, trazodone, vecuronium 30 years, male Clonidine, baclofen, citric acid/sodium citrate, dexamethasone, fentanyl, glycopyrrolate, ketamine, midazolam, nalmefene, octreotide, propofol, trazodone, vecuronium 43 years, male Baclofen, cefazolin, citric acid/sodium citrate, dexamethasone, fentanyl, glycopyrrolate, ketamine, midazolam, nalmefene, naloxone, octreotide, propofol, trazodone, vecuronium 50 years, male Clonidine, baclofen, citric acid/sodium citrate, dexamethasone, diazepam, enalapril, fentanyl, glycopyrrolate, ketamine, midazolam, nalmefene, octreotide, propofol, trazodone, vecuronium for heroin addiction (12 20 bags per day). Patient was discharged to the care of his parents and died the next day. (1,000 mg) for heroin (2 5 bags per day) and methadone addiction. Patient was discharged to the care of his parents and died later that night. (1,500 mg) for heroin addiction (10 15 bags per day). Patient was discharged to the care of her parents and died the next day. (1,500 mg) for methadone addiction (300 mg per day). Patient was discharged to care of his caretaker and died 3 days later. (1,500 mg) for heroin addiction (10 15 bags per day). Patient was discharged to the care of his parents and died at home that evening. for heroin addiction (2 3 grams per day) and methadone. Patient was discharged to the care of a caretaker and was found dead the next morning. 22 years, male No adjunct medicines Patient did not undergo UROD; he had only implant of naltrexone. The patient had his second implant (to be replaced every 30 days). The patient developed abdominal pain, diarrhea, and vomiting and died an unspecified time later. *Records were stripped of state and other personal identifiers prior to release to authors and obtained via the FDA s Freedom of Information Office. UROD = ultrarapid opioid detoxification. rapidly as possible, as patients frequently relapse during this phase. Early studies demonstrated that this transition could be made rapidly by inducing the withdrawal under general anesthesia with high-dose antagonists. 7,8 Furthermore, data from early studies suggested that when high-dose opioid antagonists induced withdrawal, symptoms were greatest within the first few hours of treatment and declined to tolerable levels rapidly. 9,10 This assertion is not without controversy, however, as some studies demonstrate that withdrawal symptoms persist for up to one week after rapid detoxification. 11 In fact, one rat model demonstrated that withdrawal symptoms were more intense and prolonged after rapid detoxification. 12 Nonetheless, the rapid transition to naltrexone maintenance from opioid dependence (rapid opioid detoxification ROD or rapid opioid detoxification under anesthesia RODA) seemed to be a promising method of treatment.

ACADEMIC EMERGENCY MEDICINE January 2002, Volume 9, Number 1 www.aemj.org 67 While most of the early investigations focused on rapid withdrawal and transition to naltrexone treatment within 24 to 48 hours, the desire for same-day detoxification led practitioners to accelerate this procedure to ultrarapid opioid detoxification (UROD). In this variation of the technique, the transition to naltrexone therapy is made on an outpatient (same-day) service. Many centers report success with this process and tout it as a safe, comfortable, same-day, outpatient treatment for heroin addiction. 13,14 This has led to a proliferation of UROD drug treatment centers that are widely advertised on television, in newspapers, in magazines, on billboards and on the Internet. This marketing frequently appeals to the desire for rapid, successful treatment in patients who have otherwise been unable to abstain. 15 The success of ROD and UROD therapy is debatable. While all studies suggest that the detoxification procedure is physiologically successful as measured by the response to antagonist challenge, recidivism ranges from 10% to 50%. 10,16 In addition, the outpatient nature of UROD may lead to diminishment of the importance of continued medical and psychosocial support to ensure success. 17 These patients are sent home with a large number and variety of potent medications to counter the continued withdrawal symptoms, including clonidine, baclofen, octreotide, ondansetron, benzodiazepines, and trazodone with little ongoing therapy provided by the center. One UROD facility, instead of transitioning to oral naltrexone, compounds the naltrexone into a pellet and implants it into the subcutaneous tissues. 14 This is not an FDA-approved route for the oral drug and there is no parenteral form available. While UROD and ROD flourishes as an alternative means of treating opioid dependency, evidence that the procedure may not be completely safe is beginning to accumulate. A number of reports of ROD and UROD complications have been published. These include reports of death, prolonged respiratory depression, and an abstract of a case series of patients who experienced persistent withdrawal symptoms. 17 20 A limited number of reports also suggest that the use of naloxone may be associated with pulmonary edema, perhaps due to the excessive release of catecholamines during unrecognized hypercarbia from hypoventilation. 21,22 Of note, these two reports of pulmonary edema were associated with the use of general anesthesia a scenario similar to UROD in that the patient is mechanically ventilated and given general anesthetics in both situations. This is in contradistinction to the typical use of naloxone by clinicians attempting to reverse the opioid toxidrome. There is only one additional case report of complication of UROD with naltrexone pellet implant, and in that case the patient developed severe rhabdomyolysis. 23 To the best of our knowledge, no comprehensive studies have investigated the safety of ROD, RODA, or UROD with naltrexone pellet detoxification programs. Complications of detoxification that we report here can be classified as 1) consequences of UROD therapies (cases 1 to 4) and, 2) effects of UROD on preexisting medical conditions (cases 5 and 6). Consequences of UROD therapies include persistent withdrawal symptoms, dehydration, pulmonary edema, and toxicity of supportive drug therapy (baclofen). Effects of UROD on preexisting medical conditions include bleeding esophageal varices (perhaps induced by recurrent vomiting) and withdrawal from cross-addictions not treated by UROD therapy. The limited data from this case series suggest that the naltrexone pellet delivery system may not be effective in delivering therapeutic levels of naltrexone. Following a single oral dose of 100 mg, the mean peak plasma level of naltrexone is 20 ng/ml and the mean peak plasma level of the active metabolite 6 beta-naltrexal is 206 ng/ml. Serum levels of 10 to 30 ng/ml of naltrexone are effective at antagonizing the euphoric effects of 25 mg of intravenous heroin. Naltrexone levels as low as 2 ng/ml are 87% effective. The naltrexone metabolite 6 beta-naltrexol is also effective at antagonizing opioid effects, but at serum levels of 80 to 130 ng/ml. 2 Sufficient 6 beta-naltrexol was present in case 6 (six hours after implantation) to achieve opioid antagonistic effects, but not in case 4 (14 days after implantation). In the latter case, the presence of the pellet may falsely reassure patients that further opioid use is safe because naltrexone will prevent opioid toxicity. In addition, patients may titrate opioid use to higher doses to overcome the naltrexone effect. The role of the pellet itself in these complications is unclear. Some of the patients improved after pellet removal, but this may correspond with other therapeutic interventions such as correction of volume depletion. Particular concern is warranted for the cocktail of withdrawal suppression medications prescribed for these patients. Baclofen toxicity was suspected in two cases and supported in one by an elevated drug level. Self-administration of octreotide may lead to adverse effects and/or toxicity from dosing errors. Of particular concern is the use of a fentanyl patch after detoxification. Why this drug might be prescribed after a UROD with naltrexone pellet implantation is confusing. CONCLUSIONS Our study suggests that the numbers of UROD are substantial. However, a recent analysis of the ex-

68 OPIOID DETOX Hamilton et al. ULTRARAPID OPIOID DETOXIFICATION isting literature on rapid detoxification concluded that studies to date are limited and that more research on clinical effectiveness, safety, and cost is necessary. Future studies should include a larger number of subjects, use a unified protocol, randomize entry, compare results with those of control groups, and include analysis of long-term outcomes. 24,25 These studies are paramount for developing conclusive evidence regarding this technique. References 1. Hamilton R, Hung O, Gold J, Lewin N, Nelson L, Hoffman R. Prolonged withdrawal and pulmonary edema associated with rapid heroin detoxification: two case reports. J Toxicol Clin Toxicol. 1997; 35:553. 2. Olmedo RE, Hoffman RS, Howland M, Nelson L. Death as a complication of ultrarapid opioid detoxification (UROD). J Toxicol Clin Toxicol. 2000; 38:536 7. 3. Kirchmayer U, Davoli M, Verster A. Naltrexone maintenance treatment for opioid dependence. Cochrane Database Syst Rev. 2000; (2):CD001333. 4. Gonzalez JP, Brogden RN. Naltrexone: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence. Drugs. 1988; 35:192 213. 5. Loimer N, Schmid RW, Presslich O, Lenz K. Continuous naloxone administration suppresses opiate withdrawal symptoms in human opiate addicts during detoxification treatment. J Psychiatr Res. 1989; 23:81 6. 6. Loimer N, Schmid R, Presslich O, Lenz K. Naloxone treatment for opiate withdrawal syndrome. Br J Psychiatry. 1988; 153:851 2. 7. Resnick RB, Kestenbaum RS, Washton A, Poole D. Naloxone-precipitated withdrawal: a method for rapid induction onto naltrexone. Clin Pharmacol Ther. 1977; 21:409 13. 8. Loimer N, Schmid R, Lenz K, Presslich O, Grunberger J. Acute blocking of naloxone-precipitated opiate withdrawal symptoms by methohexitone. Br J Psychiatry. 1990; 157:748 52. 9. Loimer N, Lenz K, Schmid R, Presslich O. Technique for greatly shortening the transition from methadone to naltrexone maintenance of patients addicted to opiates. Am J Psychiatry. 1991; 148:933 5. 10. Loimer N, Linzmayer L, Schmid R, Grunberger J. Similar efficacy of abrupt and gradual opiate detoxification. Am J Drug Alcohol Abuse. 1991; 17:307 12. 11. Scherbaum N, Klein S, Kaube H, Kienbaum P, Peters J, Gastpar M. Alternative strategies of opiate detoxification: evaluation of the so called ultra rapid detoxification. Pharmacopsychiatry. 1998; 31:205 9. 12. Spangel R, Kirschke C, Tretter F, Holsboer F. Forced opiate withdrawal under anesthesia augments and prolongs the occurrence of withdrawal signs in rats. Drug Alcohol Depend. 1998; 52:251 6. 13. Albanes AP, Gevirtz C, Oppenheim B, Field JM, Abels I, Eustace JC. Outcome and six month follow up of patients after ultra rapid opiate detoxification (UROD). J Addict Dis. 2000; 19:11 28. 14. Gooberman L. L: Rapid opioid detoxification [letter]. JAMA. 1998; 279:1871. 15. Brewer C, Williams J, Carreno Redndueles E, Barcia JB. Unethical promotion of rapid opiate detoxification under anaesthesia (RODA) [letter]. Lancet. 1998; 351:218. 16. Seoane A, Carrasco G, Cabre L, et al. Efficacy and safety of two new methods of rapid intravenous detoxification in heroin addicts previously treated without success. Br J Psychiatry. 1997; 171:340 5. 17. San L, Puig M, Bulbena A, Farre M. High risk of ultrashort noninvasive opiate detoxification [letter]. Am J Psychiatry. 1995; 152:956. 18. Fuasen GW, Nathan MS, Duyon S. Acute complications following ultra rapid opiate detoxification [abstract]. J Toxicol Clin Toxicol. 1997; 35:538. 19. Dyer C. Addict died after rapid opiate detoxification [abstract]. BMJ. 1998; 316:170. 20. Pfab R, Hirtl C, Zilken T. Opiate detoxification under anesthesia: no apparent benefit but suppression of thyroid hormones and risk of pulmonary and renal failure. J Toxicol Clin Toxicol. 1999; 37:43 50. 21. Taft RH. Pulmonary edema following naloxone administration in a patient without heart disease. Anesthesiology. 1983; 59:576 7. 22. Andree MA. Sudden death following naloxone administration. Anesth Analg. 1980; 59:782 4. 23. Chanmugam AS, Hengeller M, Ezenkwele U. Development of rhabdomyolysis after rapid opiate detoxification with subcutaneous naltrexone maintenance therapy. Acad Emerg Med. 2000; 7:303 5. 24. Stephenson J. Experts debate merits of 1-day opiate detoxification under anesthesia. JAMA. 1997; 277:363 4. 25. O Connor PG, Kosten TR. Rapid and ultrarapid opioid detoxification techniques. JAMA. 1998; 279:229 34.