Opioid Antagonists Under Heavy Sedation or General Anesthesia as a Technique of Opioid Detoxification
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The use of relatively high doses of opioid antagonists under deep sedation or general anesthesia is a technique for opioid detoxification and is known as ultrarapid detoxification. It is a potential alternative to standard detoxification that allows patients to avoid the acute symptoms associated with initial detoxification. Ultrarapid detoxification is used in conjunction with maintenance treatments (eg, oral opioid antagonists, psychosocial support).
· With opioid addiction
|Interventions of interest are:|
· Ultrarapid detoxification under general anesthesia
|Comparators of interest are:|
· Traditional detoxification programs or approaches
|Relevant outcomes include:|
· Medication use
· Treatment-related mortality
· Treatment-related morbidity
The traditional treatment of opioid addiction involves substituting the opiate (ie, heroin) with an equivalent dose of a longer acting opioid antagonist (ie, methadone), followed by tapering to a maintenance dose. Methadone maintenance therapy does not resolve opioid addiction but has been shown to result in improved general health, retention of patients in treatment, and a decrease in the risk of transmitting HIV or hepatitis. However, critics of methadone maintenance point out that this strategy substitutes 1 drug of dependence for the indefinite use of another. Detoxification followed by abstinence is another treatment option, which can be used as the initial treatment of opioid addiction or offered as a final treatment strategy for patients on methadone maintenance. Detoxification is associated with acute symptoms followed by a longer period of protracted symptoms (ie, 6 months) of withdrawal. Although typically not life-threatening, acute detoxification symptoms include irritability, anxiety, apprehension, muscular and abdominal pains, chills, nausea, diarrhea, yawning, lacrimation, sweating, sneezing, rhinorrhea, general weakness, and insomnia. Protracted withdrawal symptoms include a general feeling of reduced well-being and drug craving. Relapse is common during this period.
Detoxification may be initiated with tapering doses of methadone or buprenorphine (an opioid agonist-antagonist), treatment with a combination of buprenorphine and naloxone (an opioid antagonist), or discontinuation of opioids and administration of oral clonidine and other medications to relieve acute symptoms. However, no matter what type of patient support and oral medications are offered, detoxification is associated with patient discomfort, and many patients may be unwilling to attempt detoxification. In addition, detoxification is only the first stage of treatment. Without ongoing medication and psychosocial support after detoxification, the probability is low that any detoxification procedure alone will result in lasting abstinence. Opioid antagonists (eg, naltrexone) may also be used as maintenance therapy to reduce drug craving and thus reduce the risk of relapse.
Dissatisfaction with current approaches to detoxification has led to interest in using relatively high doses of opioid antagonists, such as naltrexone, naloxone, or nalmefene under deep sedation with benzodiazepine or general anesthesia. This strategy has been referred to as "ultrarapid," "anesthesia-assisted," or "one-day" detoxification. The use of opioid antagonists accelerates the acute phase of detoxification, which can be completed within 24 to 48 hours. Because the patient is under anesthesia, he or she has no discomfort or memory of the symptoms of acute withdrawal. Various other drugs are also administered to control acute withdrawal symptoms, such as clonidine (to attenuate sympathetic and hemodynamic effects of withdrawal), ondansetron (to control nausea and vomiting), and somatostatin (to control diarrhea). Hospital admission is required if general anesthesia is used. If heavy sedation is used, the program can potentially be offered on an outpatient basis. Initial detoxification is then followed by ongoing support for the protracted symptoms of withdrawal. In addition, naltrexone may be continued to discourage relapse.
Ultrarapid detoxification may be offered by specialized facilities. Neuraad™ Treatment Centers, Nutmeg Intensive Rehabilitation, and Center for Research and Treatment of Addiction are examples. These programs typically consist of 3 phases: a comprehensive evaluation, inpatient detoxification under anesthesia, and, mandatory postdetoxification care and follow-up. The program may be offered to patients addicted to opioid or narcotic drugs such as opium, heroin, methadone, morphine, meperidine, hydromorphone, fentanyl, oxycodone, hydrocodone, or butorphanol. Once acute detoxification is complete, the opioid antagonist naltrexone is often continued to decrease drug craving, with the hope of reducing the incidence of relapse.
In October 2002, a buprenorphine monotherapy product, Subutex®, and a buprenorphine/naloxone combination product, Suboxone® (both Reckitt Benckiser) were approved by the U.S. Food and Drug Administration through a new drug application for use in opioid addiction treatment.
[INFORMATIONAL NOTE: Pursuant to the New Jersey State Mandate on substance use disorder (P.L.2017, c.28, effective May 16, 2017), health benefit plans are required to provide unlimited benefits for medically necessary inpatient (IP) and outpatient (OP) treatment of substance use disorder at in-network facilities. It also prohibits any prior authorization or prospective utilization management for the first 180 days per plan year of medically necessary IP and OP treatment of substance use disorder, including outpatient prescription drugs. In addition, it places restrictions on prescription of opioids, such as a 5-day supply limit on initial prescriptions for treatment of acute pain.
For additional information and specific provisions, please refer to the mandate.
For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.]
Opioid antagonists under heavy sedation or anesthesia are considered investigational as a technique for opioid detoxification (ie, ultrarapid detoxification).
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for Rapid Opiate Detoxification. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.
[RATIONALE: This policy was originally created in 1997 and has been updated regularly with searches of the MEDLINE database. The most recent literature review was performed through January 29, 2019. Following is a summary of the key literature to date.
This assessment of ultrarapid opioid detoxification focuses on data reporting the severity and duration of withdrawal symptoms and the short- and long-term outcomes of maintenance of abstinence in distinct populations of patients, based on type and duration of addiction. Efficacy outcomes will be balanced against the safety considerations of deep sedation or general anesthesia in conjunction with naloxone.
In 2010, Gowing et al published a Cochrane review on opioid antagonists under heavy sedation or anesthesia for opioid withdrawal.1 Nine studies (total N=1109 participants) were eligible for inclusion, of which8 were randomized controlled trials (RCTs) and 1 was a non-RCT. Four studies compared the intervention to conventional approaches of withdrawal, and 5 compared different regimens of antagonist-induced withdrawal. In 5 studies, all participants were withdrawing from heroin or other short-acting opioids; in 3 studies, they were using heroin and/or methadone; and in 1 study, all participants were withdrawing from methadone.
Due to differences in study designs (eg, antagonist and anesthesia or sedation regimens, comparison interventions, outcome variables), few pooled analyses could be conducted. Findings from 3 trials (total N=240 patients) comparing antagonist-induced and conventional withdrawal were pooled for several outcome variables. The number of participants completing maintenance treatment was significantly higher in the antagonist-induced group than in the conventional treatment group (relative risk [RR], 4.28; 95% confidence interval [CI], 2.91 to 6.30). The number of participants who continued maintenance treatment or were abstinent at 12 months also favored the antagonist-induced group (RR=2.77; 95% CI, 1.37 to 5.61). Safety data from these 3 studies were not pooled. One of the studies reported no adverse events (AEs), and 1 only reported AEs in patients who received octreotide (a somatostatin analog) during the anesthetic procedure; 7 (64%) of these 11 patients experienced vomiting and/or diarrhea. The third study reported 3 serious AEs, all of which occurred in the anesthesia group. There were no pooled analyses of the results of studies that evaluated the efficacy of differing opioid antagonist withdrawal regimens. One meta-analysis of safety data from 2 studies (total N=572 patients) found a statistically significantly higher rate of AEs with heavy sedation compared with light sedation (RR=3.21; 95% CI, 1.13 to 9.12). Other AEs included high rates of vomiting in several studies and, in 1 study, episodes of irregularities in respiratory patterns during withdrawal.
The Cochrane reviewers commented that, due to variability among the trials, “it is not possible to identify ’standard’ treatment regimens for antagonist-induced withdrawal in conjunction with heavy sedation or anesthesia.” They concluded that “the increased risk of clinically significant adverse events associated with withdrawal under heavy sedation or anesthesia make the value of anesthesia-assisted antagonist-induced withdrawal questionable.”
A representative RCT included in the Cochrane review is a 2005 trial by Collins et al.2 In this study, 106 persons addicted to heroin were randomly assigned to undergo detoxification with an anesthesia-assisted rapid opioid detoxification, buprenorphine-assisted rapid opioid detoxification, or clonidine-assisted opioid detoxification. All study participants received an additional 12 weeks of outpatient naltrexone maintenance. Mean withdrawal severities were similar among the 3 groups, and treatment retention in the 12-week follow-up period was also similar. However, the anesthesia procedure was associated with 3 potentially significant life-threatening AEs. The authors concluded that the data did not support the use of general anesthesia for heroin detoxification.
Among the AEs reported in the Cochrane review, vomiting under sedation is particularly worrisome due to the threat of aspiration. Techniques reported to minimize this risk include intubation, use of prophylactic antibiotics, and use of medication to diminish the volume of gastric secretions. Several deaths occurring either during anesthesia or immediately thereafter have been reported.3-6 Also, deaths subsequent to ultrarapid detoxification have been reported.7 Of particular concern is the fact that the use of opioid antagonists results in loss of tolerance to opioids, rendering patients susceptible to overdose if they return to predetoxification dosage of illicit drugs.8
Relapse after ultrarapid detoxification was examined in a 2014 study by Salimi et al.9 A total of 424 patients with self-reported opioid use entered a treatment program at a single institution in Iran. Treatment consisted of rapid detoxification under general anesthesia and naltrexone maintenance therapy. Four hundred (94%) of the 424 patients completed 2 years of follow-up. Among completers, 97 (24%) patients experienced at least 1 incident of relapse. Patients who relapsed had significantly lower rates of long-term compliance with naltrexone therapy, and all patients who relapsed had discontinued naltrexone use prior to relapse. Mild AEs were common and did not differentiate between patients with successful abstinence and relapse. For example, 52% of those with treatment success and 56% who relapsed (p>0.05) experienced mild muscle pain in the first 3 months after withdrawal. This study was uncontrolled and does not provide data on the relative efficacy of detoxification methods.
A follow-up study was done by Forozeshfard et al to evaluate relapse after ultrarapid detoxification.10 This prospective study, done in Iran, included 64 patients undergoing the procedure with general anesthesia, followed by outpatient treatment using naltrexone oral therapy, and free-of-charge monthly psychiatric visits. Of the 64 patients undergoing treatment, 48 (75%) patients suffered relapse within the first month, with 12 patients returning to opioid abuse at 3 months, and the remaining 4 patients by 6 months. Four (6%) patients had life-threatening complications during the procedure, including pulmonary edema, pneumothorax, bradycardia, and refractory delirium with hypertension and cardiac arrhythmia. None of these patients had a fatal event.
Up to Date has noted: "We recommend that this approach not be used, consistent with recommendations of the American Society of Addiction Medicine and the National Institute for Health and Care Excellence consortium in England. A meta-analysis of multiple clinical trials of antagonist-induced withdrawal with heavy sedation/anesthesia did not influence the intensity or duration of the withdrawal but had a greater risk of adverse events compared with light sedation (risk ratio 3.21, 95% CI 1.13-9.12). Serious complications including death have been reported."15
A search of ClinicalTrials.gov in February 2019 did not identify any ongoing or unpublished trials that would likely influence this review.
Ongoing and Unpublished Clinical Trials
The evidence for ultrarapid detoxification under general anesthesia in individuals who have opioid addiction includes both randomized and nonrandomized clinical trials as well as prospective follow-up studies, which compare other approaches not involving deep or general anesthesia. Relevant outcomes are hospitalizations, medication use and treatment-related morbidity and mortality. There is a paucity of data in the controlled trials and a lack of standardized approaches to ultrarapid detoxification. Additionally, significant adverse effects, including life-threatening complications, are a concern using this treatment. Most patients subsequently return to daily use shortly after this technique. The evidence is insufficient to determine the effects of the technology on health outcomes.
Summary of Evidence
Practice Guidelines and Position Statements
National Institute for Health and Clinical Excellence
In 2007, the National Institute for Health and Clinical Excellence issued clinical practice guidelines on “drug misuse, opioid detoxification.”11 The guidelines include the following statement on ultrarapid detoxification: “Ultra-rapid detoxification under general anesthesia or heavy sedation (where the airway needs to be supported) must not be offered. This is because of the risk of serious adverse events, including death.” This guidance was reviewed in February 2014.
American Psychiatric Association
In 2006, the American Psychiatric Association Work Group on Substance Use Disorders released a practice guideline for the treatment of patients with substance use disorders.12 The practice guideline included the following recommendation: “Anesthesia-assisted rapid opioid detoxification is not recommended because of lack of proven efficacy and adverse risk-benefit ratios.”
American Society of Addiction Medicine
In 2005, the American Society of Addiction Medicine (ASAM) published a public policy statement on opiate detoxification under sedation or anesthesia.13 It included the following recommendations:
1. Opioid detoxification alone is not a treatment of opioid addiction. ASAM does not support the initiation of acute opioid detoxification interventions unless they are part of an integrated continuum of services that promote ongoing recovery from addiction.
2. Ultra-Rapid Opioid Detoxification (UROD) is a procedure with uncertain risks and benefits, and its use in clinical settings is not supportable until a clearly positive risk-benefit relationship can be demonstrated. Further research on UROD should be conducted.
3. Although there is medical literature describing various techniques of Rapid Opioid Detoxification (ROD), further research into the physiology and consequences of ROD should be supported so that patients may be directed to the most effective treatment methods and practices.”
U.S. Preventive Services Task Force RecommendationsNo U.S. Preventive Services Task Force recommendations for opioid detoxification under heavy sedation or general anesthesia have been identified.]
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Opioid Antagonists Under Heavy Sedation or General Anesthesia as a Technique of Opioid Detoxification
Rapid Opiate Detoxification (ROD)
Detoxification, Rapid or Ultrashort
Opiate Detoxification, Rapid or Ultrashort
ROD (Rapid Opiate Detoxification)
Ultra Rapid Detoxification
Ultrashort Opiate Detoxification
1. Gowing L, Ali R, White J. Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal. Cochrane Database Syst Rev. 2010(1):CD002022. PMID 20091529
2. Collins ED, Kleber HD, Whittington RA, et al. Anesthesia-assisted vs buprenorphine- or clonidine-assisted heroin detoxification and naltrexone induction: a randomized trial. Jama. Aug 24 2005;294(8):903-913. PMID 16118380
3. Bearn J, Gossop M, Strang J. Rapid opiate detoxification treatments. Drug Alcohol Rev. 1999;18(1):75-81. PMID
4. Dyer C. Addict died after rapid opiate detoxification. Bmj. 1998;316(7126):170.
5. Gold CG, Cullen DJ, Gonzales S, et al. Rapid opioid detoxification during general anesthesia: a review of 20 patients. Anesthesiology. Dec 1999;91(6):1639-1647. PMID 10598605
6. Solomont JH. Opiate detoxification under anesthesia. Jama. Oct 22-29 1997;278(16):1318; author reply 1319. PMID 9343458
7. Brewer C, Laban M, Schmulian C, et al. Rapid opiate detoxification and naltrexone induction under general anaesthesia and assisted ventilation: experience with 510 patients in four different centres Acta Psychiatr Belg 1998;98:181-189.
8. Public policy statement on opioid antagonist agent detoxification under sedation or anesthesia (OADUSA). American Society of Addiction Medicine (ASAM). J Addict Dis. 2000;19(4):109-112. PMID 11110069
9. Salimi A, Safari F, Mohajerani SA, et al. Long-term relapse of ultra-rapid opioid detoxification. J Addict Dis. 2014;33(1):33-40. PMID 24471478
10. Forozeshfard M, Hosseinzadeh Zoroufchi B, Saberi Zafarghandi MB, et al. Six-month follow-up study of ultrarapid opiate detoxification with naltrexone. Int J High Risk Behav Addict. Dec 2014;3(4):e20944. PMID 25741479
11. National Institute for Health and Clinical Evidence. Drug misuse in over 16s, opioid detoxification. NICE Clinical Guideline 52. 2007; http://www.nice.org.uk/Guidance/CG52. Accessed January, 2016.
12. Kleber HD, Weiss RD, Anton RF, et al. Work Group on Substance Use Disorders. Treatment of patients with substance use disorders. American Psychiatric Association. Am J Psychiatry. 2006;163(8 suppl):5-82.
13. American Society of Addiction Medicine. Public Policy Statement on Rapid and Ultra Rapid Opioid Detoxification. 2005; http://www.asam.org/advocacy/find-a-policy-statement/view-policy-statement/public-policy-statements/2011/12/15/rapid-and-ultra-rapid-opioid-detoxification. Accessed January, 2016.
14. Center for Medicaid and Medicare Services. Medicare Policy 35-22.2. http://www.cms.gov/manuals/downloads/Pub06_PART_35.pdf Accessed October, 2014.
15. Sevarino K. Medically supervised opioid withdrawal during treatment for addiction. Hermann R, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on January 25, 2018.)
16. Sevarino K. Medically supervised opioid withdrawal during treatment for addiction. Saxon AJ, Hermann R. (eds.) In UpToDate. Waltham, MA: UpToDate Inc. (Accessed on February 6, 2019.)
17. Rapid and Ultra-Rapid Detoxification in Adults with Opioid Addiction: A Review of Clinical and Cost-Effectiveness, Safety, and Guidelines [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016 Jan 15.
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