Addiction Medicine Practice

From U. S. Detox, Inc., Merchantville NJ (Drs. Gooberman and Bradway), and from the Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Medicine and Dentistry of New Jersey at Camden (Dr. Bartter)

Corresponding author: Thaddeus Bartter MD

 

Abstract

Objective. To evaluate the impact of a depo-naltrexone pellet inserted at time of heroin detoxification upon a 30-day addiction relapse rates

Design. A study looking at outcomes for two cohorts of detoxified opiate addicts.

Setting. A privately-owned outpatient detoxification center.

Patients. 959 patients were detoxified over the study interval. The 665 for whom prolonged follow-up was attempted form the study patients.

Interventions. Two post-detoxification opiate blockade methods were used in historical sequence. Initially, oral naltrexone was initiated during detoxification. All patients so treated form cohort 1. This was changed in later cases to the subcutaneous insertion of a depo-naltrexone pellet during detoxification; patients so treated formed the second cohort. Telephone follow-up was performed by a staff member.

Main outcome measures. Reported relapse rates for the two cohorts.

Main results. For those who responded, the rate of relapse to regular drug use at 30 days was 33.2% for patients treated with oral naltrexone versus only 0.6% for the depo-naltrexone group (p<0.0001). If all patients for whom follow-up was attempted but not sustained for 30 days were assumed to have relapsed to opiate usage, a method which would bias the results against efficacy, the rate of relapse would have been 53%for the oral naltrexone group versus 28% for the depo-naltrexone group, still significant at a p<0.001 despite the bias.

Conclusions. Depo-naltrexone is effective in preventing early relapse and can allow more time after detoxification during which interventions can be instituted to help an addict to sustain abstinence.

 

 

In 1897, MaCleod reported that withdrawal from opiates could be attained "…within three days without suffering."¹ This was accomplished by the accidental administration of heavy sedation with bromide. Two years later, MaCleod reported the intentional use of sedation with bromide to facilitate withdrawal.²The procedure was not without its risks,² and the idea disappeared from the literature for almost 100 years. Around 1977, opiate antagonists, initially used as antidotes for heroin overdoses, began to be used to accelerate opiate detoxification.³ This led to efforts to decrease the intensity of this compacted withdrawal; several refinements in the management of precipitated withdrawal evolved over the next 12 years, including the use of sedatives.^4-8 Management of withdrawal culminated in rapid opiate detoxification under general anesthesia.⁹ This process, too, has been refined over the past several years. It is now possible to effect opiate detoxification and blockade over a period of several hours with minimal patient discomfort.^10,11 This is a highly effective technique with a short-term success rate of 100%; patients who ask for the procedure are sedated and awake hours later completely detoxified.

Although rapid opiate detoxification represents an exciting advance in the treatment of opiate dependence, it is obvious that the goal of treatment is not only detoxification but sustained maintenance of abstinence. Naltrexone (NTX) is an orally available opiate antagonist which effectively ablates opiate effect when taken regularly. This need for regular dosing has, however, limited its clinical utility for patients post-detoxification. We report a series of 655 patients, contrasting 30-day abstinence rates for those treated with oral naltrexone (O-NTX) with abstinence rates for those treated with a long-acting subcutaneous depo-naltrexone (D-NTX) preparation. This preparation appears to have promise for the prevention of relapse after detoxification.

Methods

Between March, 1995 and October, 1997, 959 patients underwent opiate detoxification under general anesthesia. All subjects had requested rapid opiate detoxification.¹² The inclusion criterion was active opiate dependence. Exclusion criteria were (1) history of cardiac arrhythmia, myocardial infarction or decreased left ventricular function (2) pregnancy, and (3) age greater than 65 years. All procedures were performed in a private outpatient setting.¹²

The treating physician, in the presence of a caretaker selected by the patient, explained the procedure to the patient. After explanation, a detailed written consent form was signed prior to detoxification.

History and physical examination was followed by the initiation of continuous monitoring of temperature, electrocardiogram, blood pressure, and pulse oximetry (with exhaled carbon dioxide levels monitored after intubation). If all parameters fell within normal limits, anesthesia was induced. The patients were intubated and placed on a ventilator. When the airway was secure, neuromuscular blocking agents were administered to maintain paralysis. Withdrawal was then precipitated with a narcotic antagonist. The patients were maintained under general anesthesia for 3-6 hrs, during which time naltrexone maintenance therapy was initiated. Patients were then brought out of anesthesia and extubated. An observation period followed extubation, during which time patients were assisted to the bathroom and in dressing. Patients were required to ambulate a distance of at least 300 ft. prior to discharge. Two short-term post-detoxification procedures were utilized. First, the caretaker who accompanied the patient to the detoxification had agreed a priori to stay with the patient for 48 hours after detoxification. Second, physician follow-up was attempted for all patients in the 72 hours following detoxification. In many cases, there was an attempt at sustained follow-up by an office staff member. The patients for whom sustained follow-up was attempted form the subjects of this report.

Starting in November of 1996, the detoxification included the subcutaneous implantation of D-NTX; the pellet was inserted prior to termination of anesthesia. The initial pellets totaled 600 mg with the dose later increased to 1000 mg/pellet.(Bartter & Gooberman, submitted for publication) These two subsets are joined in the analyses described below. This change to the routine use of D-NTX allows division of the population into two groups, those maintained on oral naltrexone post detoxification, the O-NTX group, and the D-NTX group. This study focuses upon the comparison of these groups with respect to opiate relapse. T-testing was used for between-group comparisons, with a p < .05 considered significant.

Results

Of the 959 total detoxifications, office staff made at least one contact with 655 in an effort to continue with sustained follow-up. (Sustained follow-up was not possible in all cases.) Those 655 patients were divided into O-NTX and D-NTX groups. There were 487 men and 168 women, with a mean age of 36 (range, 19-62). Out of the 665 patients, 432 were treated with O-NTX and 223 were treated with D-NTX. Three hundred and four (70.4%) of the O-NTX subjects had follow-up for at least 30 days, and 162 (72.6%) of the D-NTX patients had follow-up for at least 30 days. The breakdown is represented in Figure 1.

Exhaustive review of the demographics of the O-NTX and D-NTX subjects is presented in Table 1. There were only two significant differences between the two groups. First, the mean age of the O-NTX group, 37.1, was slightly greater than 34.9, that of the D-NTX group. Second, the duration of follow-up was longer for the O-NTX group. Average follow-up for the O-NTX group was 97.4 days, with a range of 1 to 780 days. Average follow-up for the D-NTX group was 74.3 days, with a range of 1 to 412 days. The following were compared and shown not to be significantly different between groups: opiate or combination of opiates used prior to detoxification, and amount of opiate used. These were looked at for the total O-NTX and D-NTX groups and then broken down by gender within each group, with no differences between groups for any breakdown (see Table 1).

The 30-day reported relapse results for the two populations were significantly different. Of the 304 patients in the O-NTX group for whom 30-day follow-up was available, 66.8% (203) stated that they were not using opiates, while 33.2% (101) admitted relapse to regular opiate usage. For 162 patients in the D-NTX group for whom 30-day follow-up was available, 99.4% (161) stated that they were not using opiates, while one patient admitted to relapse. The difference is highly significant (p < 0.0001). It is important to note that patients who were not using at day 30 may have tried opiates sporadically and abandoned them due to lack of efficacy. The distinction here is between those who had relapsed to regular usage versus those who had not reverted to addictive drug-taking; patients who tried opiates but did not relapse to regular use are in the "non-user" category in this study. The study is thus designed as an outcome study looking not at the effect of NTX upon craving or initial behavior, but rather at the most crucial outcome, presence or absence of relapse.

Since a significant number of patients in both populations were not successfully followed for 30 days (128 for the O-NTX and 61 for the D-NTX population), the argument could be made that the reason that they could not be contacted was that they had relapsed. Although this assumption is biased against the efficacy of D-NTX, the numbers would be as follows given the assumption: a non-relapse rate of 47% in the O-NTX group versus 72% in the D-NTX group (p < 0.001).

There were no significant differences in non-usage and relapse rates within populations for men versus women. For the O-NTX population, there was a 30-day abstinence rate of 66.2% (n=147) for men versus 68.2% (n = 56) for women; and for the D-NTX population, men had a abstinence rate of 99.2% (n=124) versus 100% (n=38) for women. The same-gender results between O-NTX and D-NTX groups were highly significant for both men (p < 0.001) and women (p = 0.0003). Similarly, gender-based statistics given the assumption that all patients not followed for at least 30 days had gone back to regular opiate usage remained significant for between-group comparisons.

When the populations were broken down by choice of opiates, non-relapse rates remained significantly greater for all D-NTX groups for which numbers were large enough to allow valid statistical analysis. For those using exclusively heroin, the non-relapse rates were 68.2% (n=192) for the O-NTX population versus 99.0% (n=103) for the D-NTX population (p < 0.0001). For the combination of heroin plus methadone, the non-relapse rates were 60.7% (n=84) for the O-NTX population and 100.0% (n=33) for the D-NTX population (p < 0.0001). There were not enough patients to demonstrate a significant difference using the same tests of statistical significance in the exclusive methadone users or the users of "other opiate combinations." (The exclusive methadone results are 73.6% (n=19) for O-NTX, and 100% (n=18) for the D-NTX populations. The exclusive "other opiates" results were 77.7% (n=9) for the O-NTX, and 100% (n=7) for the D-NTX population.)

Discussion

This study documented reported 30-day relapse rates after detoxification for patients receiving oral naltrexone maintenance (the O-NTX group) and patients receiving subcutaneous depo-naltrexone (D-NTX). The results were statistically very significant in favor of D-NTX. They stayed significant even when all patients lost to sustained follow-up were assumed to have resumed active opiate usage, an assumption which would bias results against any such significance.

The weaknesses of the study are obvious; the study was retrospective, only 68% of the patients detoxified over the study interval were included in the study, and the results were obtained by telephone follow-up. Yet the groups in the O-NTX and D-NTX groups were remarkably similar, both groups were approached similarly with no evident reason why one population would lie about active opiate usage and the other group not lie, and the statistical significance of the findings was large enough to tolerate considerable error without losing significance. This is evidenced by the results given the assumption that all patients not followed for 30 days had resumed opiate usage. (In fact, one reason for loss of follow-up was limitations in office staff, not a documented inability to reach patients.)

There were two differences between the O-NTX and D-NTX groups. One was a decreased mean age for the D-NTX group, 34.9 versus 37.1 for the O-NTX group. The implication is that the mean age of opiate users is decreasing, a distressing implication. There is no obvious way in which this age difference could have biased the results. The second difference was the mean follow-up, which is greater for the O-NTX group since the two groups were studied in sequence and not simultaneously; there was a longer available time for the O-NTX patients to have been followed. The 30-day point used in this report ablates the meaning of that difference for this study.

One patient, the single patient in the D-NTX group who reported resumption of opiate usage, was studied further, as he reported getting high on opiates whereas prior work with D-NTX had suggested that this should not be possible.(Bartter and Gooberman, submitted for publication.) He asked for repeat detoxification and agreed to come into the office for testing. He was challenged twice. First, he was given a challenge of 250 mcg of intravenous Fentanyl (morphine equivalent, approximately 20 mg).¹³ There were no pupillary changes, respiratory changes, or mental status changes. He was then given an intravenous challenge of 4 mg of naloxone. There were no signs of withdrawal. The interesting implication is that the patient had remained fully blocked by his D-NTX pellet and that his reported highs from heroin did not represent a physiologic response.

NTX has been shown to be of significant benefit post-detoxification in "controlled" populations such as prisoners. Brahen et al. used the certain blocking effect of NTX to allow previously opiate-addicted prisoners willing to take NTX access back to the community in a work-release program.¹⁴ They documented the efficacy of this program over a 10-year period. Chan, working in Singapore where all known addicts are detained by executive order, also used NTX in a work-release program and noted a 1-year sobriety rate of 76.3% after initiating a NTX program versus a 24% 1-year sobriety before NTX.¹⁵ Cornish, in a study of parolees with a history of opiate abuse demonstrated 46% fewer re-incarcerations in a subset of parolees who agreed to take oral NTX.¹⁶ The majority of the drop-outs in this study occurred during the first month, a time during which D-NTX would have rendered opiates ineffective. Unfortunately, the clinical efficacy of NTX in more controlled populations has not held true for patients outside of such environments.

The concept of sustained-release NTX is not new. A sustained-release naltrexone preparation that blocks the effects of narcotics for about a month has been a goal of NIDA since the 1980s and is the subject of several publications.^17-19 These early efforts did not come to fruition in the form of a readily available preparation. We have now had extensive experience with our preparation.(Gooberman and Bartter, submitted for publication) To our knowledge, this is the first report looking at the effect of such a preparation upon sustained abstinence rates.

No adjunct to the process of treating a chronic relapsing problem should be considered a "cure." Abstinence is not an event; it is a sustained process which includes motivation, detoxification, and social/emotional interventions perhaps best achieved with a 12-step program. The goal of D-NTX is narrow; its goal is to allow more time after detoxification during which other interventions might be instituted without being derailed by recurrent intoxication.

In conclusion, D-NTX has been shown to demonstrate success in helping addicts avoid relapse for at least 30 days after a rapid opiate detoxification. The data support the insertion of D-NTX as a standard part of the detoxification procedure. The battle against opiate dependence has been too arduous and disappointing for us to make dramatic claims about the use of D-NTX. It does, nonetheless, appear to be yet another step which may help an addict towards sobriety.

return to top

 

References

1. Macleod N. Morphine habit of long standing cured by bromide poisoning. Br Med J 1897;i:76-77

2. Macleod N. Cure of morphine, chloral hydrate, and cocaine habits by sodium bromide. Br Med J 1899;i:896-898

3. Resnick R, Kestenbaum R, Washton A, Poole D. Naloxone-precipitated withdrawal: a method for rapid induction onto naltrexone. Clin Pharmacol Therap 1977;21:409-413

4. Gold MS, Pottash AC, Sweeney DR, Kleber HD. Opiate withdrawal using clonidine. JAMA 1980;243:343-346

5. Gold MS, Pottash ALC, Sweeney DR, Kleber HD. Effect of methadone dosage on clonidine detoxification efficacy. Am J Psych 1980;137:375-376

6. Gold MS, Pottash AC, Sweeney DR, Extein I, Annittto WJ. Opiate detoxification with lofexidine. Drug Alc Dependence 1981;8:307-315

7. Kleber HD, Topazian M, Gaspari J, Riordan CE, Kosten T. Clonidine and naltrexone in the outpatient treatment of heroin withdrawal. Am J Drug Alcohol Abuse 1987;13:1-17

8. Vining E, Kosten TR, Kleber HD. Clinical utility of rapid clonidine-naltrexone detoxification for opioid abusers. Br J Addiction 1988;83:567-575

9. Presslich O, Loimer N. Opiate detoxification under general anesthesia by large doses of naloxone. Clin Toxicol 1989;27:263-270

10. Brewer C. Ultra-rapid, antagonist-precipitated opiate detoxification under general anesthesia or sedation. Addiction Biology 1997;2:291-302

11. Simon DL. Rapid opioid detoxification using opioid antagonists: history, theory and state of the art. J Addictive Dis 1997;16:103-122

12. Bartter T, Gooberman LG. Rapid Opiate Detoxification. Am J Drug Alcohol Abuse 1996;22:489-495

13. Hardman JG, Goodman AG, Limbird LE. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw Hill:543

14. Brahen LS, Brewer C. Naltrexone in the Criminal Justice System. In Brewer C, Ed. Treatment Options in Addiction; Medical Management of Alcohol and Opiate Abuse London:Gaskell, 1993; 46-53

15. Chan KY. The Singapore naltrexone community-based project for heroin addicts compared with drugfree community-based program: the first cohort. J Clin Forensic Med 1996;3:87-92

16. Cornish JW, Metzger D, Woody GE, Wilson D, McLellan AT, Vandergrigft B, and O’Brien CP. Naltrexone pharmacotherapy for opioid dependent federal probationers. J Substance Abuse Treatment 1997;14:529-534

17. Chiang CN, Hollister LE, Kishimoto A, Barnett G. Kinetics of a naltrexone sustained-release preparation. Clin Pharmacol Ther 1984;36:704-708

18. Chiang CN, Hollister LE, Gillespie HK, Foltz RL. Clinical evaluation of a naltrexone sustained-release preparation. Drug Alcohol Dependence 1985;16:1-8

19. Sharon AC, Wise DL. Development of drug delivery systems for use in treatment of narcotic addiction. In Wilette RE and Barnett G, eds. Naltrexone: Monograph 28, National Institute on Drug Abuse, 1980. pp. 194-213

return to top

---

 

return to top

---

Figure 1. Breakdown of study population.

---

 

Figure 2. Opiate use at 30 days.

---