FDA Meeting Package

Opiate dependence is a brain-related medical disorder. Despite the existence of treatment options, illicit opiate addiction remains a serious economic, health and social issue in the United States. An estimated 600,000 patients in the U.S. are dependent on opiates¹, with an increasing trend in new heroin users, especially among adolescents.² Opiate dependence has been linked to increased criminal activity,¹ increased prevalence of transmissible viral infections, and a greater number of emergency department visits.³

Methadone and LAAM, opiate agonists used for maintenance treatment of opiate addiction,⁴ are Class II scheduled drugs and have raised further social and political concerns. The use of naltrexone, a non-narcotic drug approved for the blockade of the pharmacological effects exogenously administered opioids, alleviates many of these issues. Naltrexone is a pure opioid antagonist that works by blocking opiate receptors,¹ and does not lead to either physical or psychological dependence. Oral doses are biologically available and can provide effective opiate blockade for up to three days. There is essentially no agonist activity,¹ and side-effects from the drug itself have been minimal.^5,6,7 Clinical trials with naltrexone tablets, marketed under the tradename Revia™ by Dupont Pharma, demonstrated "complete blockade of the euphoric effects-of opioids in both volunteer and addict populations.⁸ Naltrexone effectively blocks the cognitive and behavioral effects of opioids.¹

Naltrexone was discovered in the late 1960s and evaluated at some length in the 1970s.^9,10 It appeared to have great promise as an adjunctive therapy in the opiate detoxification process. Although some success with naltrexone has subsequently been reported with relatively "controlled" populations such as prisoners,^11,12 the drug has not lived up to its original promise. There appear to be two major reasons for this sub-optimal success. First, naltrexone cannot be given until a patient is fully detoxified from opiates, as naltrexone ingestion by an active user will precipitate sudden and violent withdrawal.¹³ Second, use of oral naltrexone as an adjunct in the post-withdrawal phase requires regular dosing; an addict who misses or avoids his/her oral dose for over three days will once again be susceptible to the effects of opioids.¹²

As with all orally administered products, Revia’s™ ability to bring about its indicated effects is dependent upon patient compliance. Unlike most other oral therapies though, Revia™ is indicated for use in patients whose lifes may make compliance extraordinarily difficult and rates of relapse are high.^11,14,15 Product information for Revia™ notes that: "there are no data that demonstrate an unequivocally beneficial effect of Revia™ on rates of recidivism among detoxified, formerly opioid-dependent individuals who self-administer the drug. The failure of the drug in this setting appears to be due to poor medication compliance."⁸

Early recognition of the compliance issue with oral naltrexone led to work in the development and evaluation of slow-release subcutaneous depo-naltrexone preparations,^1,17,18,19 but the surge of interest apparent in the 1980s has not yet led to a published study of an effective preparation being used clinically. Providing opiate addicted patients with effective doses of naltrexone in a long-acting subcutaneous (i.e., compliance-independent) dosage form would fill a demonstrated need in this population.

The medical literature contains reports of effective serum blood levels of naltrexone. Chiang et al have reported that patients attaining a serum plasma concentration of 1 ng/ml naltrexone are refractory to the effects of intravenous opiates.¹⁶

The early articles which described the manufacture of naltrexone-containing pellets and their biological release in both animals and human beings demonstrated 1) a promising release profile with reasonable drug levels, and 2) prolonged resistance to opiates in both human and non-human subjects after implantation was demonstrated.^17,18,19,20 Work with these preparations tapered off after the mid 1980s. Three reasons have been posited for this tapering: first, the system used for the preparation of pellets in those studies was protracted and extremely expensive; second, high doses of naltrexone apparently were not achieved by the methods described; and third, incomplete detoxification may have made it difficult to initiate naltrexone therapy.

Depo-naltrexone, subcutaneously implantable pellets which release naltrexone over a 30 or 60 day period, have been compounded by pharmacists to treat individual patients since 1996. To date, over 3,000 patients worldwide have received either the 30 or 60 day pellet of depo-naltrexone, which have been shown to provide a sustained release of greater than 1ng/ml naltrexone throughout the treatment period. This prolonged interval of compliance-independent exposure to effective drug levels provides an opportunity for the beneficial effects of social and psychological intervention to have a positive impact on the patient.

Pellets are implanted subcutaneously in the lower abdomen under general anesthesia during rapid opiate detoxification or under local anesthetic otherwise. An incision of approximately one centimeter is made through the dermis. A 3.5 cm tunnel is then created under the dermis such that the pellet does not lie directly below the incision line. The pellet is deposited at the distal end of the tunnel with a trochar. The incision is then closed with an absorbable suture material, Rapide (Ethicon, Somerville, NJ). After implantation , pellets can be viewed via echograph, noting longitudinal size, transverse size and echographic shadow. As the naltrexone is consumed, the pellet becomes small and loses its shadow. By the eighth week after implantation, the pellet is no longer present.

Long-acting depo-naltrexone pellets are not a solution to drug dependence. Detoxifications need to be accompanied by attempts at social support and social change such as a 12-step program. Naltrexone is not that therapeutic environment; naltrexone is an adjunctive therapy whose goal is to give patients capable of change the opportunity to change over an extended interval during which relapse into drug-taking behavior will not renew chemical dependence.

Depo-naltrexone (60 day) is a white cylindrical pellet approximately 12.5 mm in diameter and 9.5 mm in height containing 1000 mg. In addition to naltrexone base, the final dosage form contains magnesium stereate and trimacinalone. The compounding procedure currently employed to make the pellets is described in the attachment. The pellet is irradiated for sterilization prior to implantation.

As an opiate antagonist, naltrexone binds to opioid receptors in the brain and competitively inhibits the actions of opioid drugs. This inhibition markedly attenuates or completely blocks opioid-induced euphoria and physical dependence. ^8,21 The major metabolite of naltrexone, 6-beta-naltrexol, is also thought to have opiate antagonist activity. The USP provides the following pharmacokinetic data for naltrexone (and 6-beta-naltrexol):²¹

Plasma serum concentrations of naltrexone and 6-beta-naltrexol have been obtained from 139 samples of patients receiving naltrexone pellets. The figures below demonstrate the serum concentrations of both naltrexone and 6-beta-naltrexol from six to 100 days post-implantation.

Naltrexone levels are initially in the range of 20 ng/ml, and level off to approximately 10 ng/ml for the remainder of the 60 day period. The metabolite, 6-beta-naltrexone remains at relatively constant concentrations between 5-10 ng/ml for the majority of the 60-day period, peaking at less than 15 ng/ml. As can be seen from this data, mean plasma naltrexone concentrations exceeded 1 ng/ml, the effective dose level for opioid antagonism¹⁰, for the entire 60-day period.

Several potential problems with depo-naltrexone need to be acknowledged. First, a patient with active naltrexone blockade will not be susceptible to routine narcotic analgesia for emergent situations. Second, the effects of naltrexone on pregnancy have not been established. While one could argue that it may be safer to administer tiny doses of naltrexone via a slow-release system than to allow intermittent opiate usage during pregnancy, there is no available clinical information which one can use to evaluate risk. This clinical issue needs to be addressed. Third, the use of subcutaneous deposition does require an invasive technique, albeit minor.

While naltrexone is not associated with the development of opiate tolerance or dependence, it is important to note that detoxified patients, whether detoxification occurs through opiate blockade or some other method, must be cautioned against a return to their pre-detox opiate doses immediately after their blood levels of naltrexone return to baseline (0.0 ng/ml). Previously tolerated opiate doses could be life-threatening in patients who have lost their tolerance due to long-term blockade.

1. Oral Naltrexone

Naltrexone has been shown to be of significant benefit post-detoxification in "controlled" populations such as prisoners. Brahen et al. used the blocking effect of naltrexone to allow previously opiate-addicted prisoners, who were willing to take naltrexone, access back to the community in a work-release program.¹¹ 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 naltrexone in a work-release program and noted a 1-year success rate of 76.3% after initiating a naltrexone program versus a 24% 1-year success before naltrexone.¹² 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 naltrexone.²² Unfortunately, the clinical efficacy of naltrexone in these controlled populations has not held true for patients outside of such environments, likely due to compliance issues.

The concept of sustained-release naltrexone is not new. A sustained-release naltrexone preparation that blocks the effects of narcotics for about a month was a goal of NIDA in the 1980s and is the subject of several publications.^16,23

No adjunct in 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 depo-naltrexone is narrow; to allow more time after detoxification during which other interventions might be instituted without being detailed by recurrent intoxication.

2. Direct Opiate Challenge

A pilot study was conducted on the use of a subcutaneous depot naltrexone pellet. Fifteen patients who had received depo-naltrexone were tested with direct opiate challenge at intervals ranging from 21 to 70 (mean 41.7) days post implant. None had a response consistent with opiate effect. Depo-naltrexone may effect an extended intoxication-free interval during which efforts at lasting social and behavioral modification can be made.

The purpose of this study was to confirm that anecdotal resistance with controlled observed opiate challenge in patients with a depo-naltrexone pellet in place and to evaluate the duration of efficacy of the pellets.

1. Methods

All patients initially underwent rapid opiate detoxification, as previously described.²⁴ Initial pellet insertion occurred before the patient awoke from anesthesia. Some patients received subsequent pellets; in these cases, the insertion was performed under local anesthesia using 2% lidocaine with epinephrine.

All pellets used in this study contained 1000 mg of naltrexone compressed into a cylindrical form 12.5 mm in diameter and 9.5 mm high. Pellets were placed subcutaneously in the lower abdomen. An incision of approximately one centimeter was made through the dermis. A 3.5 cm tunnel was then created under the dermis such that the pellet did not lie directly below the incision line. The pellet was deposited at the distal end of the tunnel with a trochar. The incision was then closed with an absorbable suture material, Rapide (Ethicon, Somerville, NJ).

Intravenous fentanyl was used as the challenge agent. Fentanyl is a synthetic opioid with approximately 80 times the potency of morphine.²⁵ It has the shortest duration of action of the available opioid analgesics,²⁶ making it a good candidate for opiate challenge. Five cc (250 μ g) of fentanyl were given intravenously for each challenge procedure. This dose is the pharmacologic equivalent of a 20 to 25 mg bolus of morphine. At this dosing, even active opiate users would be expected to have definitive physiologic responses. Patients were observed pre-challenge and post-challenge for forty-five minutes in a stable environment with no changes in lighting or any other factor which might have exogenously altered monitored parameters.

Written consent was obtained from all subjects. Separate consents were obtained for precipitated withdrawal with initial pellet insertion and for later pellet insertion in post-withdrawal patients. All participants also gave permission for the therapeutic challenges with fentanyl.

2. Results

Nine of the fifteen challenge subjects were men and 6 were women. The mean age of the challenge subjects was 34.5 with a range of 19 to 39. Challenges were performed as early as 21 and as late as 70 days after depo-naltrexone implantation; the mean time after implantation was 41.7 days. Fifteen challenges were performed. The results are presented in the following table.

Click to see Responses to Fentanyl Challenge

As can be seen, there were no significant changes in pupillary size or respiratory rate as measured by direct observation at 30 minutes post infusion. In patient nine, there was a subjective impression of slight pupillary change which, if present, was too slight to be reflected in a change in measured pupillary size. The most significant adverse event after fentanyl administration was what appeared to be a vasovagal response in patient five. This was short-lived and not accompanied by objective evidence of opiate intoxication.

3. Discussion

This pilot study suggests that depo-naltrexone effects prolonged opiate blockade, many times that achieved by oral naltrexone dosing. There was no opiate effect in 15 challenges performed a mean of 41.7 days after depo-naltrexone insertion (and as long as 70 days after insertion in one individual). This lack of response to exogenous opiate was consistent with the anecdotal reports of lack of response to street opiate usage by patients with depo-naltrexone pellets in place.

The blockade against opiate effect exhibited by the depo-naltrexone preparation is potentially crucial. Even though it cannot prevent experimentation with street drugs post-detoxification (which patients reported but which was not documented with urine testing), our evidence suggests that the depo-naltrexone did prevent those drugs from having a significant physiologic effect. Prolonged opiate blockade could prevent early re-addiction and allow a longer period for rehabilitation.

4. Conclusion

In summary, a challenge study of patients given a depo-naltrexone preparation has been described. The results suggest that depo-naltrexone is capable of effecting prolonged opiate blockade. The use of this pellet may be a valuable adjunct to the process of helping addicts to break the vicious cycle of opiate dependence.

C.Literature Report of Fentanyl Challenge

Brewer and Gastfriend²⁷ who have subcutaneously implanted 100 ng depo-naltrexone pellets into selected patients since March 1997, recently reported the results of a fentanyl challenge test performed on one patient, two weeks after receiving a second implant, to determine whether the depo-naltrexone would block opioid doses roughly equivalent to a dose of intravenous street heroin (0.25 – 0.5g).

The 30-year-old male subject underwent a 20-minute, 1000 μ g intravenous fentanyl challenge while being monitored for vital signs, pupil size and oxygen saturation. The investigators reported that "No opiate effects were noted either subjectively or objectively." The subject was then given 0.4 mg intravenous naloxone and 50 mg oral naltrexone and remained asymptomatic.

D.Comparative Study of Abstinence Rates

A retrospective study of 655 detoxified patients was conducted to evaluate the impact of oral naltrexone versus depo-naltrexone, inserted at the time of detoxification, on self-reported 30-day abstinence rates.

1. Methods

Between March, 1995 and October, 1997, 959 patients underwent rapid opiate detoxification at a private clinic in New Jersey.²⁴ 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.²⁴

The treating physician, in the presence of a caretaker selected by the patient, explained the procedure to the patient. A detailed informed consent form was signed prior to detoxification. Oral or subcutaneous naltrexone maintenance therapy was initiated before the patient awoke from anesthesia. 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 655 patients for whom sustained follow-up was attempted from the subjects of this report.

Starting in November of 1996, consent for detoxification included consent for the subcutaneous implantation of depo-naltrexone; the pellet was inserted prior to termination of anesthesia. The initial pellets totaled 600 mg with the dose later increased to 1000 mg/pellet. These two subsets are joined in the analyses described below. This change to the routine use of depo-naltrexone allows division of the population into two groups, those maintained on oral naltrexone post detoxification, the oral naltrexone group, and those receiving depo-naltrexone, the depo-naltrexone group. The two groups were compared with respect to self-reported opiate relapse. The baseline data were obtained at the time of detoxification. The follow-up data were obtained via sequential telephone contact by office staff. T-testing was used for between-group comparisons, with a p <0.05 considered significant. Each group was considered in toto and then broken down in gender and by prior drug utilization pattern to determine if any subset behaved differently from the groups as a whole.

It is important to note that patients who claimed not to be using opiates regularly 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 and 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 naltrexone upon craving or initial behavior, but rather at the most crucial outcome, presence of absence of relapse.

2. Results

   Sustained follow-up was not possible in all cases. Office staff achieved some prolonged follow-up (defined as more than 72 hours) for 655 out of the 959 detoxifications performed during the study period. There were 487 men and 168 women, with a mean age of 36 (range, 19-62). Of the 655 patients, 432 were treated with oral naltrexone and 223 were treated with depo-naltrexone. Similar percentages of each group were followed for at least 30 days after detoxification; 304 (70.4%) of the oral naltrexone subjects had 30-day follow-up data, and 162 (72.6%) of the depo-naltrexone patients had 30-day follow-up data. The breakdown is represented in the following figure.

    

   Study Population
   

   The demographics of the oral naltrexone and depo-naltrexone groups are presented in the table below. There were two statistically significant differences between the two groups. First, the mean age of the oral naltrexone group was 37.1, slightly older than 34.9, the mean age of the depo-naltrexone group. Second, total duration of follow-up was longer for the oral naltrexone group. Average follow-up for oral naltrexone group was 97.4 days, with a range of 1 to 780 days. Average follow-up for the depo-naltrexone group 74.3 days, with a range of 1 to 412 days. Opiate or combination of opiates used prior to detoxification and the amount of opiate used were not found to be different for the oral naltrexone and depo-naltrexone groups. Breaking each group down by gender failed to reveal any difference between groups not evident in the whole-group comparisons.

   Patient Demographics

   

   

    

   The 30-day reported relapse results for the two populations were significantly different. Of the 304 patients in the oral naltrexone 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 depo-naltrexone group for whom 30-day follow-up was available, 99.4% (161) stated that they were not using opiates, while one patient (0.6%) admitted to relapse. The difference is highly significant (p <0.0001).

   

   Since a significant number of patients in both populations was not successfully followed for 30 days (128, or 29%, of oral naltrexone population and 61, or 27% of the depo-naltrexone population), one could argue that they could not be contacted because they had relapsed. Although this assumption is biased against the efficacy of depo-naltrexone, the numbers given the assumption that every patient not contacted had relapsed to regular opiate usage would be as follows: a relapse rate of 53% in the oral naltrexone group versus 18% in the depo-naltrexone group. This difference would still be significant, with a p <0.001.

   There were no significant differences in reported non-usage and relapse rates within populations for men versus women. For men in the oral naltrexone group, the relapse rate was 33.8% versus 0.8% for men in the depo-naltrexone group. For women in the oral naltrexone group, the relapse rate was 31.8% versus 0% for women in the depo-naltrexone group. Thus same-gender results within groups were not statistically different, while same-gender results between groups remained significant (p <0.00.1) Likewise, 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 population is broken down by choice of opiates, relapse rates remained significantly greater for all oral naltrexone groups for which numbers were large enough to allow valid statistical analysis. For those using exclusively heroin, the relapse rate was 31.8% for the oral naltrexone population versus 1.0% for the depo-naltrexone population (p <0.0001). For the combination of heroin plus methadone, the relapse rate was 39.3% for the oral naltrexone population and 0.0% for the depo-naltrexone 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 26.4% (n=19) for oral naltrexone, and 0.0% (n=18) for the depo-naltrexone populations. The exclusive "other opiates" results were 22.3% (n=9) for the oral naltrexone, and 0.0% (n=7) for the depo-naltrexone population.)

3. Discussion

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

   The weaknesses of the study are obvious; 1) the study was retrospective, 2) only 68% of the patients detoxified over the study interval were included in the study, and 3) the results were obtained by telephone follow-up. Yet the groups in the oral naltrexone and depo-naltrexone groups were remarkably similar, both groups were approached similarly with no evident reason why one population would lie more than the other about active opiate usage, and the statistical significance. This is evidenced by the results given the assumption that all patients not followed for 30 days had resumed opiate usage. In reality, one major reason for loss of follow-up was limitations in office staff, not a documented inability to reach patients.

   The only statistical difference between the oral naltrexone and depo-naltrexone groups was a decreased mean age for the depo-naltrexone group, 34.9% versus 37.1 for the oral naltrexone group. Because early patients received oral naltrexone and later patients received depo-naltrexone, the implication is that the mean age of opiate users is decreasing. There is no obvious way in which this age difference could have biased the results.

   One patient, the single patient in the depo-naltrexone group who reported resumption of opiate usage, was studied further, as he reported getting high on opiates whereas prior work with depo-naltrexone had suggested that this should not be possible. (Bartter and Gooberman, submitted for publication.) He asked for repeat detoxification and agreed to come to the office for testing. After giving consent, 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 depo-naltrexone pellet and that his reported highs from heroin did not represent a physiologic response.

Current experience with depo-naltrexone provides preliminary evidence that the pellets are easy to administer, provide a relatively consistent release of drug for 60 days, biodegrade as drug is released and have demonstrated an absence of adverse tissue reactions – all criteria which have been listed by the National Institute for Drug abuse as ideal for a naltrexone sustained release system.²⁸

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