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Rapid Opioid DetoxificationUsing Opioid Antagonists:History, Theory and the Stateof the ArtDavid L. Simon MD aa Nutmeg Intensive Rehabilitation Center , 359Merrow Road, Tolland, CT, 06084, USAPublished online: 17 Oct 2008.

To cite this article: David L. Simon MD (1997) Rapid Opioid Detoxification UsingOpioid Antagonists: History, Theory and the State of the Art, Journal of AddictiveDiseases, 16:1, 103-122, DOI: 10.1300/J069v16n01_07

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Rapid Opioid Detoxification Using Opioid Antagonists:

History, Theory and the State of the Art David L. Simon, MD

ABSTRACT. Rapid opioid detoxification is a technique for detoxi- Qing patients addicted to narcotics which is increasing in popularity. This technique is potentially useful in getting some patients through the withdrawal phase of substance abuse therapy so that they may engage in further treatment earlier in the course of their disease. However, this procedure, which can and should be done safely, has in the past been pushed to limits which approach boundaries outside of the provider’s area of expertise. This paper attempts to present a critical review of previous publications relating to rapid opioid detoxification to address these and other issues. There appears to be a pharmacologic basis for the efficacy of this treatment on a longer- term basis which centers around upregulation of opioid receptors induced by opioid antagonists. This paper also attempts to offer evidence in support of this theory. [Article copies available for afeefrom f i e Haworlh Document Delivety Service: 1-800-342-9678. E-mail address: [email protected]

INTRODUCTION

In the past several years a technique for detoxifying addicts from narcotic addiction has emerged which purportedly allows for acute withdrawal to be completed within several hours. The procedure is now performed under general anesthesia. Because the patient is anesthetized during the acute phase of withdrawal, it is purported that the patient does not con- sciously experience the unpleasant withdrawal experience.

David L. Simon is Medical Director at the Nutmeg Intensive Rehabilitation Center, 359 Merrow Road, Tolland, CT 06084.

Journal of Addictive Diseases, Vol. 16(1) 1997 0 1997 by The Haworth Press, Inc. All rights reserved. 103

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I04 JOURNAL OF ADDICTIVE DISEASES

The procedure is accomplished by administering a pure opioid antagonist, such as naloxone or naltrexone, to the addict while he is anesthetized. After the procedure, the patient is maintained on p.0. naltrexone for some time thereafter which has been alleged to decrease narcotic craving and remove the positive reinforcement of euphoria associated with adininistra- tion of exogenous opioids. Naltrexone maintenance with psychotherapy has yielded abstinence rates of approximately 80% at six months as evidenced by negative urine samp1es.l

This procedure has recently generated considerable controversy. Con- cerns have been raised regarding the safety of anesthesia as it relates to riskhenefit ratio; the elaborate nature of the procedure; the efficacy of the treatment as relating to alternative treatments; the possibility of death by narcotic overdose after cessation of naltrexone therapy; the paucity of prospective, randomized, double blinded, controlled studies relating to the procedure; the cost of the procedure relative to other methods of detoxification; and the elaborate claims made by some practitioners of the procedure.

This article attempts to address these and other issues relating to rapid opioid detoxification using opioid antagonists under general anesthesia. First, the history of the procedure will be discussed. A critique of past practices will be presented. Then, the rationale for the treatment will be explored using current pharmacologic theory. Finally, the present state of the procedure will be discussed along with a brief glimpse at future implications.

HISTORY

Resnick et aL2 reported that naloxone could be used to precipitate withdrawal as a method for induction onto naltrexone therapy in 1977. He suggested that the detoxification time period could be shortened in patients using low doses of opioids. In 1980, Riordan and Kleber reported successful detoxification in four patients by the concomitant use of naloxone and ~lonidine.~ Their goal was to shorten the detoxification period while ame- liorating symptoms of withdrawal.

In 1982, Charney et al? published the results of an investigation where- by naltrexone and clonidine were administered to patients on methadone maintenance therapy. They showed this to be a safe and effective treatment of withdrawal from methadone in which 91% of patients were able to withdraw completely in 6 days. Adjuvant medication included flurazepain which was required by 73% of the patients. During the 6 days, symptoms of craving, anxiety, restlessness, insomnia, muscular aching, anorexia and

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David L. Simon I05

hot and cold flashes increased over the symptoms experienced while maintained on methadone. Signs of piloerection, diarrhea and lacrimation increased as compared to methadone maintenance. One of the 1 1 patients dropped out of the study. All patients were conscious during treatment (when not sleeping). Of the 10 successhlly treated patients, 3 continued with naltrexone maintenance. On vague follow-up ranging from 4 months to a year after treatment, one of the 10 were found to have relapsed to habitual narcotic abuse."

Charney et al.5 in 1986 reported successful complete withdrawal from methadone within 5 days for 38 of 40 patients. They were converted to naltrexone maintenance using clonidine and flurazepain. Naltrexone was started at 6.7 mg on average for day one, and was gradually increased until 50 mg of naltrexone was administered on day 5. Patients experienced an increase in all symptoms except for nausea as compared to their baseline while on methad~ne.~

Kleber et a1.6 treated 14 heroin abusing patients with clonidine and naltrexone over a 5 day period. Twelve of the patients (86%) successfully withdrew from opioids. Two patients used intravenous heroin early in the protocol. The investigators titrated the doses of clonidine based on Wang scores after administration of a pure narcotic antagonist (naloxone or naltrexone). On day two 1 mg of naltrexone was given, on day three 4-7 mg, on day four 50 mg, on day five 150 mg. All patients experienced the usual symptoms of withdrawal to some extent. Signs and symptoms were monitored by observation and response to questions. The investigators compared signs and symptoms during the treatment phase to signs and symptoms of an initial naloxone challenge, and demonstrated that symptoms were ameliorated as compared to naloxone challenge. Chloral hydrate 1 g or flurazepam 30 mg were given as adjuvants. As in the previous study, all patients were conscious. One month after treatment, three of the 12 patients were using opioids regularly. Verification for abstinence in other patients was poor.6

In the Kleber study, published in 1987, patients were categorized during initial naloxone challenge; test as either having severe symptoms (Wang score greater than 20), or less severe symptoms (Wang score less than 20). The authors concluded that their treatment most effectively suppressed withdrawal symptoms when those symptoms are less severe.6

Vining et al.7 successfully withdrew 14 of 17 (82%) heroin users from opioids and attained maintenance levels of naltrexone in 3 to 5 days. Symptoms were monitored using a withdrawal line, craving line, opiate withdrawal scale and a visual analog scale. The three patients who dropped out had Wang scores ranging from 9 to 16 during initial naloxone

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106 JOURNAL OF ADDICTIVE DISEASES

challenge test. Ten of the 14 patients who successfully completed the program were maintained on naltrexone after treatment. One month later, 9 of the 10 were still taking naltrexone. Of the four patients not entered into naltrexone maintenance, two were using opioids 1 month after detoxification, and two were lost for follow-up. Chloral hydrate 1 g, flurazepam 30 mg and diazepam 10 mg were used as adjuvants. This study was published in 1988.7

Also published in 1988 was a paper by Brewer et a1.F in which 56 patients were withdrawn from heroin and other opioids over 48-72 hours. Here, clonidine was administered followed by naltrexone at 1-2 mg doses repeated every 4 hours. Clonidine 0.2 to 0.4 mg was administered every four hours as needed, Diazepam was used as an adjuvants. Successful detoxification was defined as being able to receive 50 mg of naltrexone in a 24 hour period and feeling well enough to return home. Using the criterion described, patients were able to be discharged home sooner than as previously cited. Diazepam dosages were typically about 70 mg per day. The authors state that patients were “always reusable." However, they also state that diazepam was chosen from available benzodiazepine because it is available in rectal and parenteral preparations, “which are useful if vomiting is a problem.”8 These statements of the authors give rise to serious concerns as to their appreciation for issues relating to proper management of sedated patients.

Definitions proposed by the American Dental Association Council on Dental Education for conscious sedation and deep sedation are as follows. Conscious sedation: Depressed level of consciousness which allows the patient the ability to independently and continuously maintain an airway and respond appropriately to physical stimulation and verbal command. Deep sedation (hypnosis): Controlled state of depressed consciousness accompanied by partial or complete loss of protective reflexes, including the ability to independently maintain an airway and respond purposefully to physical stimulation or verbal ~ o m m a n d . ~

From Brewer’s description, it appears his patients were in a state of deep sedation rather than conscious sedation8 The ability to be aroused is consistent with deep sedation. It is of great concern that a patient in deep sedation with a partial or complete loss of protective airway reflexes would be subjected to a situation in which vomiting is likely to occur. Administering a narcotic antagonist to an opioid addict certainly puts the patient at risk for vomiting. Loss of protective airway reflexes and a likeli- hood of vomiting constitutes an indication for endotracheal intubation.

Another publication by Brewer in 1988 describes detoxification using naltrexone, clonidine and lorazepam. l o In this study, total benzodiazepine

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David L. Simon 107

and clonidine doses were considerably less than in the aforementioned study. However, “additional sedatives, mainly phenothiazines” were required in 30 patients. Two patients were said to require parenteral fluids because of vomiting and diarrhea. One third of patients were said to develop a transient confusional state which the author concluded may have been due to “the rapidity of changes at the opiate receptor.” * O Other plausible explanations for this confusion are confusion due to excessive sedatives or carbon dioxide narcosis secondary to depressed ventilation. Patients were not intubated.

In 1989, Presslich and Loimer” published a study out of Vienna in which 6 opiate addicts underwent barbiturate anesthesia and detoxification using intravenous naloxone. After general anesthesia was induced, and the patient was intubated and stabilized on mechanical ventilation, the patient was given 10 mg of naloxone intravenously over one hour followed by a continuous i.v. infusion of naloxone at 0.4 mg/hr. After at least three hours post-induction of anesthesia, the patients were extubated. After extubation the infusion of naloxone was continued for a total of 24 hours. Under anesthesia, naloxone did not appear to provoke a withdrawal response as evidenced by cardiovascular parameters or other clinical signs. A naloxone challenge with the patients awakened from anesthesia did not indicate significant withdrawal on the Wang scale. However, 2 of the 6 patients suffered nausea, vomiting, and muscle pains which were described as mild for 4 to 6 hours after the procedure under anesthesia.

In another article published in 1989, Loimer et a1.I2 repeated a similar study except that there they carried out naloxone infusion for at least three days. They showed that neither continuous supply nor cessation of naloxone after 96 hours caused any severe withdrawal symptoms. A self-evalu- ation scale was given to patients the day before detoxification, 30 minutes before anesthesia, and every morning at 8 am thereafter during admission. Following naloxone administration only a limited susceptibility to opiate withdrawal symptoms could be observed on the self-rating scale after starting detoxification, indicating that the onset of withdrawal symptoms had been strongly attenuated. In their discussion, these authors explore a paradoxical effect of naloxone in suppressing withdrawal symptoms. l 2

In 1990, Loimer et al. published a report in which they concluded that a barbiturate such methohexitone blocked objective signs of naloxone induced opioid withdra~a1.I~ In 18 patients, they induced general anesthesia with methohexitone, intubated the patient, maintained anesthesia with a methohexitone infusion, and administered either naloxone 10 mg or a placebo. They correctly realized that the acute phase of withdrawal symptoms is blocked by administering methohexitone. They theorized that

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naloxone may have a paradoxical effect on withdrawal symptoms because the group which was detoxified with naloxone and continued on naloxone did not experience withdrawal symptoms after emergence from anesthesia, and because levels of withdrawal distress were as normally expected over the next six days in the placebo group which received methohexitone but no naloxone during anesthesia.I3

SenftI4 reported that 51 of 55 opioid addicts were successfully detoxified in 3 days using naltrexone, clonidine, dicyclomine, hydroxyzine, chlordiazepoxide, acetominophen and Kaopectate. Twelve and half milli- gram of naltrexone was administered on day one, 25 mg on day two, and 50 mg on day 3. Significant abstinence symptoms such as anxiety, restlessness, abdominal cramps, diarrhea, and transient vomiting were reported. Nausea or vomiting occurred in one third of the patients. Two patients developed delirium. Anesthesia and intubation were not used in this study. l4

Loitner et al. in 1991 published a work in which 7 methadone dependent patients were administered naloxone under what the authors term “sedation” with intravenous midazolam. After naloxone, opiate antago- nism was maintained with 50 mg of p.0. naltrexone every day. In this study the usual acute onset of withdrawal signs and symptoms were completely suppressed. They did not return when naloxone was discontinued, supporting the conclusion that the opioid receptors must remain blocked for some period of time in order to avert withdrawal symptoms (receptors were blocked with naltrexone after naloxone administration).

The techniques of patient management are very worrisome in this study. In fact, each patient was administered a single 30 mg intravenous bolus of midazolam prior to receiving 4 mg of naloxone by continuous intravenous infusion. “Sedation” was maintained “as necessary” with repeated injec- tions of midazolam, 50-75 mg. After the procedure, the patients required 2-6 mg of flumazenil, a benzodiazepine antagonist, to wake up. During the detoxification procedure, heart rate was recorded continuously by ECG and blood pressure was recorded with an automatic manometer. No men- tion was made of pulse oximetry, capnography or oxygen therapy. The care just described runs contrary to the principles of safe anesthetic management. A general anesthesia induction dose for midazolam is 0.2 to 0.3 mg per kilogram. Thus, a 70 kg person would be rendered unconscious with 2 1 mg of i.v. midazolam. The authors administered 30 mg as an initial dose. They also had a patient at great risk for vomiting and aspiration of vomitus into the lungs, and they did not take proper precautions to protect the airway and respiratory track of the patient. Minimal standards would at least require a pulse oximeter and oxygen administration to be utilized. It

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David L. Simon 109

would be strongly desirable to monitor respiration by measuring end-tidal carbon dioxide with a capnograph. None of these measures were imple- mented. Therefore, this article illustrates the very real danger that occurs when practitioners without the proper amount of skill, knowledge, and experience, embark on providing services which are best provided by competent anesthesia care providers.

Azatian et al. tried to replicate Kleber’s method.16 In a study published in 1994, they were unsuccessful in detoxifying addicts in a short time period using naltrexone and clonidine because of the severe withdrawal symptoms and side effects precipitated and intensified by naltrexone. The symptoms could not be effectively treated by clonidine and adjuvants medications. In fact, 91% of the subjects left treatment against medical advice. The authors conclude that an addict’s motivation to seek help can be seriously compromised after an episode of treatment that did not provide relief of troublesome symptoms. l 6

In 1994, Legarda and Gossop described a method where eleven poly- drug users addicted to opioids were detoxified in an intensive care unit using general anesthetic doses of intravenous midazolam and p.0. naltrexone.17 Twelve hours after the last dose of heroin, an addict was given 50 mg p.0. naltrexone and then a general anesthetic (0.5-0.7 mg/kg intravenous midazolam followed by continuous midazolam infusion) was administered. When the subject no longer showed signs of opiate withdrawal (primarily piloerection, sneezing, motor agitation), usually 4 hours after “sleep induction,” a naloxone challenge was performed. On emergence from anesthesia, guanfacine was given to control blood pressure. On dis- charge the following morning, patients were administered 50 mg p.0. naltrexone. In response to this dose of naltrexone, there were no physical signs or subjective responses to indicate the presence of opiate withdrawal symptoms. On follow-up 30 days later, all 11 patients were still taking naltrexone. All but two were known to have challenged naltrexone on one occasion.17 In this study, intubation was indicated under these circum- stances described, but was not employed. The authors are reported to be clinical psychologists.

In 1995, San et a1.I8 published a letter describing a life threatening complication which resulted in a patient cared for as described by Loimer in a previous publication. A patient was administered 60 mg p.0. midazolam, 0.3 mg p.0. clonidine, ondansetron 5 mg P.o., and 50 mg p.0. naltrexone. The patient was monitored with pulse oximetry, ECG, and BP ma- nometry. After 15 minutes the patient was given 4.0 mg naloxone inbavenously. Severe opioid withdrawal symptoms developed before “sedation” which included rhinorrhea, mydriasis, piloerection, perspiration, and

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restlessness. These symptoms lasted over 4 hours so the patient was given 30 mg of intravenous midazolam in incremental doses over an hour. Then, five hours after initiation of the procedure, the patient became bradycardic in association with impaired oxygen saturation. At this point, oxygen was administered by face mask. The patient then experienced diarrhea and vomited fecaloid material. The patient was then intubated and ventilated and transferred to an ICU. Serial chest X-rays never showed any evidence of pulmonary edema or aspiration pneumonitis. The authors admit that respiratory depression could have initially been attributed to the sedative effects of midazolam. They then go off on a tangent and seem to attribute the complication to naloxone-induced pulmonary edema. However, there was no evidence of pulmonary edema on x-rays. Furthermore, naloxone induced pulmonary edema is a controversial explanation for a very rare occurrence. Pulmonary edema in a setting like this is much more likely to have occurred secondary to rigorous inspiratory efforts against an obstructed airway. 19s20 But again, there were no findings consistent with pulmonary edema. 0 ther plausible explanations for the difficulties en- countered by San are hypercardia with resultant hypoxemia secondary to sedative induced hypoventilation, and laryngospasm from oral secretions in a setting of “light anesthesia.” This case illustrates unacceptable patient management by practitioners unskilled and inexperienced in managing a scenario which would be better managed by qualified anesthesia care providers.

In December of 1995, Legarda’s CITA Institute claimed to have treated 3,500 atients under anesthesia without any intra-procedure complica-

thesiologists and intensivists to supervise treatment.22 In April of 1996, Gooberman in the United States claimed to have treated 278 patients using general anesthesia with intubation without any significant complications.23

tions? P These figures are unsubstantiated. CITA claims to employ anes-

THEORY

There is evidence in the scientific literature to support claims that the opioid withdrawal process may be completed in as little as two hours. In addition, there are plausible explanations based on current knowledge of opioid receptor function which could explain many of the findings described above.

A study by Presslich and Loimer in 1989 showed that significant withdrawal symptoms last no more than several hours after blockade with a pure opioid antagonist.]] In a significant study on file with Ohmeda Phar-

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David L. Simon 111

maceutical Products Division, 52 opioid positive patients were given either i.v. nalmefen 1 mg, or i.v. nalonxone 2 mg for treatment of suspected opiod overdose. Nalmefene is thought to be twice as potent as naloxone, therefore equipotent doses of the two drugs were given. Both drugs caused an increase in withdrawal score. Siurprisingly, there were no statistical differences in peak effect or duration of treatment between the two drugs. Withdrawl scores declined to pretreatment levels for both durgs 150 minutes after admini~tration.~~ Some would expect the effects of naloxone to dissipate in about two hours because it is known that 0.5 mg naloxone administered subcutaneously causes a withdrawal reaction for about two hours duration in subjects dependent on morphine-like o p i o i d ~ . ~ ~ This is easily explained because naloxone has a serum half-life in the adult human of 30-81 minutes. However, nalmefene has a terminal half-life of 10.8 hours. That withdrawal symptoms last only two hours after nalmefene administration cannot be explained by the simple redistribution of nalmefene. Even though its redistribution half-life is approximately 4 1 minutes, data shows that it is only the effects of small doses of naimefene (1 microgram/kg) that have been shown to dissipate in 30-60 minutes as a result of redistribution. In fact, the effects of nalmefene seen when non-opioid dependent individuals are given nalmefene to reverse narcotic induced respiratory depression last longer than the effects of an equipotent dose of naloxone. “Fully reversing” doses of nalmefene at 1 mg/70 kg have been shown to last many hours in the presence of persistent opioid effects in non-addicts. Therefore it cannot be explained why naloxone and nalmefene both exert withdrawal effects for the same amount of time, 150 minutes, based on the pharmacokinetic properties of the two drugs. This time frame of acute withdrawal symptoms coincides with Presslich’s’ ’ findings and also LegardakZ2 Legarda states that his withdrawal process may be complete in 4 hours. However, included in those fours hours is the hour or two it takes to reach peak serum concentrations after p.0. administration of n a l t r e ~ o n e . ~ ~ ~ ~ ~ Thus, it appears that blockade of opioid receptors by naloxone, naltrexone and nalmefene, once adequate blood levels of drug are reached, causes a withdrawal syndrome in opioid dependent individuals which lasts approximately two to three hours.

It also appears that for symptoms to subside, all receptors must be blocked. Charney et al.,5 Kleber et a1.,6 Vining et al.,’ and others described techniques where less than a full 50 mg dose of naltrexone is given over days as withdrawal continues, though symptoms were ameliorated with clonidine and benzodiazepines. In all studies using naltrexone, the end point of detoxification coincides with the ability to withstand 50 mg of naltrexone without symptoms. This dose is believed to be associated with

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adequate blockade of receptors to typical doses of exogenous opioids. In fact, O’Connor et al. define successful completion of opioid detoxification as the ability to begin a patient on a blocking dose of naltrexone 50 mg qd without the development of acute opioid withdrawal symptoms.27 Higher p.0. doses of naltrexone are thought to be needed to block endogenous endorphins, enkephalins and the like.

Thus, what appears to be happening is as follows. There is an acute phase of withdrawal, of which the time course is inversely proportional to the rate at which opioid receptors become unoccupied with exogenous opioid agonists. When the receptors become unoccupied by mere cessation from ingestion of exogenous opioids, it may take days for enough receptors to become unoccupied such that withdrawal symptoms subside. This depends on not just the pharmacokinetics of the exogenous opioid, but also upon the pharmacodynamic relationship between receptor and exogenous opioid. Without a competing drug for the receptor, the exogenous opioid may be bound to narcotic receptors for days. When small doses of opioid antagonists are given the receptors become unoccupied faster from exogenous opioids and the acute withdrawal process is shorter in duration. When a full dose of antagonist is given, such as with 50 mg of p.0. naltrexone or 1 mg of i.v. nalmefene, all of the receptors become unoccupied at a very fast rate, and the acute withdrawal phase is very short, probably lasting little more than two hours.

When opioids are cleared rapidly from the mu receptors and functional- ly are unavailable, as occurs with the administration of opioid antagonists, neurons in the locus coeruleus (LC) are put into a state of hyperexcitabil- ity. The resultant noradrenergic hyperactivity plays an essential role in the development of withdrawal symptoms. Clonidine suppresses LC hyperactivity.28 Opioids calm the LC by activating its mu receptors.

The following speculative theory is offered. With chronic administration of exogenous opioids, there may be a down regulation of mu receptors in the LC. Therefore, in order to achieve the normal baseline “calming effect,” which is ordinarily provided by endogenous endorphins, enkephalins and the like, the addict must increase his dose of exogenous opioids to avert noradrenergic hyperactivity. The more he increases his dose, the more downregulation occurs. This explains the mechanism of tolerance seen with opioid addiction. When the LC is abruptly over- whelmed by complete blockade of mu receptors as happens with an intravenous bolus of 1-1.5 mg nalmefene, which is thought to fully block the receptors from exogenous opioids, perhaps the LC is fully excited, so much so that it depletes its capacity to generate norepinephrine. Perhaps it takes several hours for this depletion of norepinephrine to occur. An analo-

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David L. Simon 113

gous model for neurotransmitter depletion is suggested by the mechanism of action of re~erpine.2~ After this time, the symptoms associated with norepinephrine release, namely withdrawal symptoms, subside. Alterna- tively, there could be a decreased response from the neurons which receive norepinephrine due to unrecovered depolarization from an overwhelming amount of neurotransmitter. A mechanism similar to this is responsible for the depolarizing neuromuscular blockade seen with succinyl~holine.~~ These mechanisms could be consistent with an acute withdrawal response which lasts only several hours if an opioid antagonist is administered such that the receptors remain blocked. These theories, while highly speculative, could also explain why less than maximal blockade of opioid receptors results in a more prolonged withdrawal responss-the LC is not maximally hyperexcited and therefore does not deplete its capacity for release of norepinephrine or result in non-recovery of receiving neurons, over a short time period. That there may be patient variability in the amount of residual symptoins following a very rapid detoxification under anesthesia may be explained by individual variances of these mechanisms.

Thus, there may be a theoretical basis to explain observations that the withdrawal process can be greatly shortened by administration of opioid antagonists. Furthermore, it may be that clonidine aids in detoxification only in that it lessens the severity of symptoms due to sympathetic hyperactivity, and because it has sedating effects. Clonidine in and of itself probably plays little role in causing the acute phase of withdrawal to be shortened. This is supported by the data relating to nalmefene injection previously discussed, in which withdrawal symptoms lasted about 150 minutes in the absence of ~ l o n i d i n e . ~ ~ The major determinant of how long the acute phase of withdrawal lasts appears to be the dose of opioid antagonist administered.

Some mechanism of adaptation must ensue after the acute withdrawal reaction caused by the opioid antagonist. These mechanisms need to be worked out. In short-term adaptation, perhaps endogenous endorphins and enkephalins are released in response to the adrenergic stress which act to calm the nervous system several hours after the acute detoxification. It is known that endorphins are released in response to adrenergic stress and endorphins have been measured to objectively quantify the amount of pain perceived during labor.31 In addition, exogenous administration of opiates likely mimics endorphin action at receptors and as a result reduces endogenous opiate secretion through a negative feedback.32 Conversely then, if the effects of exogenous opioids were abruptly reversed, as with antagonist therapy, it would follow that the negative feedback is interrupted thus providing a stimulus for endogenous opioid release. In fact, naloxone has

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been shown to increase beta-endorphin levels.33 This theorized endogenous .release of endorphins in response to the stress of withdrawal could result in diminished withdrawal symptoms after the acute withdrawal phase is over (which presumably ends because of mechanisms previously described).

There is anecdotal evidence to support this theory. The blockade of opioid receptors by naltrexone is competitive and therefore dose dependent. Perhaps higher concentrations of opioid antagonist are needed to block endogenous opioids than are needed to block exogenous op io id~?~ though there is conflicting evidence of this. Intuitively, it makes sense that endogenous endorphins would have a higher affinity for naturally occur- ring opioid receptors than exogenous opioids because endorphins are produced to be “an exact fit” for the receptor, while exogenous opioids are less than perfect imitations. In fact, beta-endorphin is said to be 5 to 15 times more potent than morphine.34 Naltrexone 50 mg p.0. or nalmefene 1 mg i.v. may not block endogenous opioids, but these doses may block typical doses of exogenous opioids. Gooberman gives 0.4 mg i.v. naloxone, 2 mg i.v. nalmefene and 200 mg p.0. naltrexone under anesthesia. He reports that many of his patients have residual symptoms of withdrawal after emergence from anes the~ ia .~~ Perhaps he is giving doses of opioid antagonists that block endogenous endorphins in addition to blocking exogenous opioids. (Note: 200 mg is higher than the recommended p.0. dose for naltrexone.) This is in contrast to Loimer who reports that “After awaking from anesthesia, all (five) patients showed no or only mild withdrawal signs,” while receiving a naloxone infusion of 0.8 mg per hour.35 This dose of naloxone could theoretically block the effects of exogenous opioid while leaving intact the effects of endogenous opioids. It is unfortu- nate that Gooberman, and in some studies Loimer did not use an objective scale to measure withdrawal symptoms. One such scale is the Wang scale in which respondents numerically rate a list of withdrawal symptoms, yielding an additive score which can be compared vertically over time or horizontally to other studies.

Over the longer term, adaptation may involve upregulation of opioid receptors.

THE CURRENT STATE OF THE ART

The extreme distress produced by withdrawal sym toms encourages

and effective method for detoxification which addicts do not have to fear repeated administration of opiates to allay discomfort.2 P Providing a rapid

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David L. Simon 115

could be an important component in attaining abstinence from exogenous opioids.

Opoid antagonist administration appears to cause greatly hastened detoxification. The more rapid the acute phase of withdrawal, the more severe symptoms of withdrawal appear to be. When withdrawal is maximally hastened, it is necessary to mask the symptoms of withdrawal with general anesthesia in order to maintain a humane and compassionate treatment. All methods of rapid detoxification without anesthesia have caused increased withdrawal symptoms. In Azatian’s study, 9 1% of addicts dropped out of treatment against medical advice.16 Symptoms can be attenuated or eliminated by sedative doses approaching anesthetic levels. However, when these higher doses of medications are used, the patient is often not adequately cared for concomitant to the patient’s level of consciousness.

It is essential that this procedure evolves into one which is safe. Rapid opioid detoxification under general anesthesia can be safely performed by adhering to the current standards of practice of modern anesthesia care. This requires the participation of qualified anesthesia care providers. The minimal monitoring standards for a general anesthetic should be utilized: electrocardiography, continual blood pressure measurement, pulse oximetry, capnography and the ability to monitor t em~era tu re .~~ The practitioner of this technique must also be knowledgeable and experienced in proper airway management. In addition, potential complications should be planned for. This would include having resuscitative means available, such as a defibrillator, a transcutaneous pacemaker and the necessary medications. Ideally, the management of an anesthetic procedure should be under the supervision of an anesthesiologist. Prudent anesthetic management requires that these patients should be intubated to protect the airway and lungs whenever hypnotic doses of sedative medication is given.

Modern anesthesia in qualified hands is very safe. To put the riswbene- fit ratio of this procedure into perspective, consider the following. General anesthesia is routinely given for over four hours in surgeons’ offices and outpatient surgical facilities. In addition to anesthesia, patients also undergo the trauma of surgery which poses the greatest risk to the patients. Many of these patients are elderly and in poor health. Yet they undergo the aforementioned insults and are discharged home the same day. Many of the surgeries performed are purely elective surgery, such as cosmetic surgery. If a purely elective procedure under anesthesia presents an acceptable riskhenefit ratio, why would this ratio not be acceptable for detoxification under anesthesia? Heroin abuse, left untreated, itself carries a great risk for morbidity and mortality.

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Using general anesthesia for rapid opioid detoxification has been compared to administering epidural analgesia for childbirth. It represents the evolution of anesthetic techniques to alleviate suffering. Not all patients require epidural analgesia for labor. However, offering epidural services to laboring women has become the standard of care in obstetrics, and it would be considered unethical to withhold this treatment froin a woman desiring it. Given the risk of complications with epidural analgesia for labor, administering general anesthesia for rapid opioid detoxification can be thought to present no more risk to a patient than administering an epidural to a woman in labor. Complications associated with epidural analgesia for labor include hypotension, seizures, dural puncture with resultant post-procedure headache, high blockade which is potentially life- threatening, backache, and neurological sequelae. These complications may have detrimental effects on the fetus in addition to affecting the patient directly.37 One might assume that a patient would be better cared for if an anesthesiologist perfoiined the epidural procedure instead of another physician unskilled in the art. The same principle holds true for general anesthesia as applied to rapid opioid detoxification.

A procedure for which general anesthesia is routinely administered is electroconvulsive therapy. If the risk-benefit ratio is acceptable so that a patient should not have to experience an awake seizure, it would seein acceptable that a patient would not have to experience acute withdrawal. One could make a strong argument that there is higher risk with ECT under general anesthesia than there is with rapid detoxification under anesthesia because rapid opioid detoxification is not associated with the sinus arrest or asvstole coimnonly seen during ECT.38

One day opioid detoxification can be an economical and cost effective treatment. The detoxification procedure can be done at a comparable cost to detoxification with methadone replacement. For example, this author’s fee is $2,500 inclusive of all costs relating to detoxification under anesthesia. This compares favorably with $2,850 for a 10-day in-patient methadone deto~ification.~~ It is noteworthy that in Connecticut, where this author practices, it is legislatively mandated that insurance carriers inust provide for up to 45 days per year per patient of hospital-based care for chemical dependency. Some in-patient detoxification programs are signifi- cantly more expensive than, $2.850. Rapid detoxification under anesthesia is also cost-competitive to a 5-day awake outpatient detoxification using clonidine and naltrexone which costs about $ 1,500.38 The drop-out rate for detoxification using anesthesia is lower. and this should be taken into account when determining overall cost-effectiveness. In addition, maintenance with p.0. naltrexone as is instituted as part of the coiitinuuin of care

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David L. Simon I1 7

following rapid opioid detoxification, is much cheaper than methadone maintenance. Naltrexone is a “non-scheduled” drug with no potential for abuse. Therefore, it can be obtained with a prescription at any pharmacy. Methadone is a highly regulated scheduled narcotic which can only be administered in approved clinics. The costs of administering this drug on a daily basis is great compared to naltrexone therapy. To illustrate this point, consider the following. During 1995 in Connecticut, it cost $90 per week to administer each slot in a methadone program4O Based on a 30 day month, that is equivalent to $390 per month. The retail pharmacy price for naltrexone tablets is about $4.30 per tablet. That translates into $130 per month to be maintained on naltrexone. Thus, the cost savings of naltrexone maintenance over methadone maintenance in Connecticut would be $260 per month. This is a significant savings in today’s cost conscious environment of medical delivery.

The efficacy of rapid opioid detoxification under anesthesia followed by naltrexone maintenance and psychotherapy has the potential to be the most efficacious opioid abuse treatment. Firstly, the detoxification process is 100% effective in that every one who undergoes general anesthesia becomes detoxified. There are no reports of dropout from treatment during anesthesia. Therefore, resources are maximally utilized in this procedure. Secondly, there are unsubstantiated claims that 80% of those treated with rapid opioid detoxification using naltrexone and anesthesia are abstinent from opioid abuse six months after treatrner~t.~’ Furthermore, Gerra et al. reported in 1995 that about 80% of patients detoxified with naltrexone (without anesthesia) and followed up with psychosocial support and maintained on naltrexone, were abstinent from drug abuse six months after detoxification. Their findings have lead to an opinion by consultants for the National Institute on Drug Abuse that these unsubstantiated claims are “bel ie~able .”~~ If naltrexone and psychosocial support follow rapid detoxification under anesthesia, it is reasonable to believe similar abstinence rates can be attained. Gerra et al. also found a significant decrease in craving for narcotics with naltrexone maintenance.

There are several recent anecdotal reports describing patients who have overdosed from heroin after undergoing naltrexone therapy. These are as yet undocumented and unsubstantiated. One of these patients died after intravenous injection of a heroin-cocaine combination. It has been suggested that naltrexone may reduce tolerance to exogenous opioids!2 Thus, a long-time heroin addict who had built up his usual dose of heroin to substantial levels, could be more susceptible to overdose after naltrexone therapy if he took his “usual” dose after cessation of naltrexone.

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FUTURE IMPLICATIONS

If the anecdotal reports describing decreased tolerance to exogenous opioids with naltrexone therapy are true, this may represent the first clinical evidence of opioid receptor upregulation in response to an opioid antagonist. Such a finding would be very significant. One school of thought is that upon chronic administration of a receptor agonist, such as an exogenous opioid, the pharmacodynainic response is uncoupling of opioid receptors from second messenger systems. This leads to reduced sensitivity of the receiving neuron to opioid stimulation. Another theory links tolerance to a decrease in the number of opioid receptors through downregulation. Either explanation supports that more exogenous opioid is required to achieve an equivalent effect as time goes on in the addiction process. It is basic pharmacology in general, that the body responds to exogenous receptor agonist administration by downregulating receptors, and likewise responds to exogenous receptor antagonists by upregulation. These mechanisms have been clearly worked out for other medications, an example of which is beta-blockers and the “propranolol withdrawal syndrome.’, When a beta blocker such as propranolol is chronically administered, the amount of beta-1 receptors increases. This increases the sensitivity of the target cells to epinephrine and norepinephrine. If the beta blocker is abruptly discontinued, a rebound hypertension results from the increased effect of epinephrine and norepinephrine on those cells.43

The implication that an opioid antagonist such as naltrexone could reduce tolerance is that it may induce upregulation of opioid receptors. This may occur in the locus coeruleus or other central nervous system areas. This finding, if true, could represent a significant breakthrough in addiction treatment. There may exist the possibility that an opioid antagonist such as naltrexone can be administered over time to induce upregulation of mu receptors in the locus coeruleus (or other central nervous system locations) to bring the receptors back to a normal baseline level. The opioid antagonist can then gradually be weaned down in such a way as to leave a normal number of opioid receptors, and leave the patient independent of phannacologic therapy. The potential for reversal of pharmacodynamic changes induced by opioid abuse and restoration of normal microneuroanatomy is an exciting prospect.

If this is the case, then patients should be cautioned that they may have a reduced tolerance to exogenous opioids after treatment with naltrexone, and if they are to start using illicit drugs again they must start at a much lower dose than they took immediately prior to detoxification and treatment with naltrexone.

Since 1994, there have been at least a handful of published papers

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David L. Simon 119

lending evidence that the decrease response to abused opiates is due to downregulation, and that opioid antagonists such as naltrexone cause upregulation. Cvejic et al. implicate a COOH-terminal tail of the delta opioid receptor in d~wnregulation.~~ Baumhaker et al. showed that human neuroblastoma cells downregulate mu and delta receptors after exposure to opioid a g o n i ~ t s . ~ ~ Kim et al. found that down-regulation of opioid receptors in response to etorphine occurs at the level of both receptor protein modification and receptor gene expression, m-RNA decrease in response to etorphine was slow in onset, while loss of receptor number occurred more rapidly$6 It is almost stunning that Yoburn et al. in 1995 published an eloquent study which showed that “supersensitivity” to methadone, etorphine, fentanyl, meperidine and oxycodone could be induced in mice by chronic administration of naltre~one.4~ He showed that after naltrexone administration. the potency of these narcotics increased 1.9 to 3.2 times pre-naltrexone values. This supersensitivity was shown to be due to an increase in the number of mu, delta and kappa receptors, and was not due to changes in affinity of the receptors for the drugs. In another paper published in 1995, Marley et al$S correlated long-term sensitization to the behavioral effects of naltrexone with increases in the number of mu receptors in the hindbrain (and decreased binding in the midbrain). Again, the increased binding was a reflection on an increased number of receptors, and not a change in affinity of receptors.

Thus, we have claims that naltrexone therapy yields higher abstinence rates from abused narcotics, anecdotal reports to support a theory of upregulation due to naltrexone, and good basic research to support the theory that naltrexone induces upregulation of opioid receptors which may have been subject to downregulation by exogenous opioid administration. All this fits with current addiction theory.

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