Richard B. Resnick

Naltrexone: Disposition, metabolism, and effects after acute and chronic dosing

The disposition of naltrexone during acute and chronic administration of 100‐mg oral dose was studied in 4 subjects. Following an acute dose the mean (X) peak naltrexone plasma level was 43.6 ± 29.9 ng/ml at 1 hr and for the major biotransformation product, β‐naltrexol, was 87.2 ± 25.0 ng/ml at 2 hr. Twenty‐four hours after the dose the X levels of naltrexone and f3‐naltrexol declined to 2.1 ± 0.47 and 17.6 ± 5.0 ng/ml, respectively. Following chronic administration the X peak plasma levels of naltrexone and β‐naltrexol rose to 46.4 ± 18.5 and 158.4 ± 89.9 ng /ml at 1 hr, but by 24 hr both compounds declined to levels of the same order as in the acute state at 24 hr. Plasma levels of naltrexone and f3‐naltrexol measured 24 hr after the daily doses of naltrexone throughout the study indicated that steady‐state equilibrium was rapidly attained and that there was no accumulation of naltrexone and beta naltrexol in the plasma after chronic treatment on 100 mg oral doses. Biexponential kinetics were observed for naltrexone and β‐naltrexol in the first 24 hr. The half‐life of naltrexone and β‐naltrexol decreased slightly from the acute to the chronic study from 10.3 ± 3.3 to 9.7 ± 1.1 hr and from 12.7 ± 2.6 to 11.4 ± 2.0 hr. The plasma levels of naltrexone declined slowly from 24 through 72 hr from 2.4 to 1.7 ng/ml, with an apparent half‐life of 96 hr. The renal clearance data indicate that naltrexone is partially reabsorbed while beta naltrexol is actively secreted by the kidney. During acute and chronic naltrexone administration the mean fecal excretion was 2.1% and 3.6%, while urinary excretion was 38% and 70% of the dose in a 24‐hr period. Opiate antagonism to 25 mg heroin challenges was nearly complete through 48 hr after naltrexone. At 72 hr the objective responses reappeared to a greater extent than the subjective ones. Correlation coefficient (r) between naltrexone plasma levels and opiate antagonism was 0.91 and between individual half‐life of naltrexone and opiate antagonism it was 0.99.

Methadone in man: pharmacokinetic and excretion studies in acute and chronic treatment.

The biologic disposition of methadone in acute and during chronic administration was studied in 12 human volunteers. In the acute study a biexponential methadone plasma level deeay was observed. The acute primary half‐life (t½) of 14.3 hr in combination witn the acute seeondary t½ of 54.8 hr were longer than the single exponential chronic t½ of 22.2 hr determined in the same subjeets. The urinary and feeal excretion of methadone and its mono‐Nvdemethylated metabolite increased from 22.2% in the acute to 62.0% in the ehronic phase of the study. The urinary metabolite 1 to methadone ratio tripled from the acute to the ehronie phase. The pupillary effeets of methadone monitored throughout 24 hr were nearly the same in magnitude in the acute and the chronic studies, whereas the plasma levels increased 3‐ to 8‐fold following chronic methadone administration, These findings suggest that both dispositional and pharmacologic toleranee are involved in the development of toleranee following chronic administration of methadone.

Cocaine pharmacokinetics in humans.

Cocaine was given by intravenous administration to human subjects and the concentrations in plasma were measured by gas chromatography--mass spectrometry. Many pharmacokinetic parameters were found to have a strong dose dependence over the range 1 - 3 mg/kg. The terminal plasma half-life in minutes is given by the equation t1/2(beta) = 13.5 + 24.5 dose (r = 0.946). The total plasma clearance in liters/kg per h is 2.51--0.67 dose (r = -0.973). From analysis of previously published data the absorption half-life t1/2(ab) is approximately 8 min for gastrointestinal and for nasal inhalation absorption. The bioavailability for nasal inhalation is approximately 60%. While routes of administration for modern recreational use could lead to unexpected drug accumulation in the blood it is not likely to occur from chewing coca leaves.

Naloxone‐precipitated withdrawal: A method for rapid induction onto naltrexone

We examined naloxone‐precipitated withdrawal as a meansfor rapid opiate detoxification and induction onto naltrexone, In 29 patients dependent on methadone (5 to 20 mg/day), abstinence was precipitated by an injection qf naloxone. Repeated injections of naloxone were given subsequently until symptoms of abstinence were no longer induced. Successive injections induced less intense withdrawal assessed by vital signs and ratings on abstinence scales. The most rapid procedure consisted of 1.2 mg naloxone every 30 min for 3 to 6 hr, followed by hourly increasing doses of naltrexone. This procedure allowed transition from opiate dependence to naltrexone maintenance (50 to 100 mg/day) within 48 hr. The results are consistent with assumptions that antagonists actively displace opiates from receptor sites.

Cyclazocine treatment of opiate dependence: A progress report

Abstract A rapid method of induction to maintenance levels of cyclazocine is described. Fifty per cent of patients selecting cyclazocine treatment sustain treatment for 6 mo or longer. The typological characteristics of treatment successes and failures are discussed.

Methadone dose, plasma level, and cross-tolerance to heroin in man.

The development of cross-tolerance between methadone and heroin was studied in postaddict volunteers who had been drug-free for at least 6 weeks. Two methadone dose schedules were used; each was employed in six subjects. One schedule brought the subjects to a dose of 40 mg, while the other brought them to 80 mg of methadone a day. Subjects received injections of heroin (0.214 mg/kg) and placebo at various times before and during methadone treatment. Pupillary and subjective effects of injections were measured. Plasma levels of methadone were determined concurrently. Subjects on both treatment schedules developed an incomplete cross-tolerance to this dose of heroin. As the dose and plasma level of methadone increased with time, the cross-tolerance to all heroin effects increased. Plasma levels did not affect the development of cross-tolerance independently of methadone dose. The most important contribution to the cross-tolerance to pupillary effects was made by the duration of methadone treatment. Furthermore, the cross-tolerance to the subjective effects of heroin developed earlier than that to the pupil effect.

CLINICAL OUTCOME WITH NALTREXONE

Much work on clinical applicability of narcotic antagonists in treatment of opiate abuse has focused on two interrelated questions: Which patients are more likely to benefit from antagonist treatment, and How effective is this modality of treatment in combating opiate abuse? When cyclazocine was first introduced as a treatment for detoxified opiate addicts, patients were accepted for treatment after meeting minimum psychiatric and medical eligibility criteria. Cyclazocine was the only treatment offered in our clinic at that time and no attempt was made to select the most appropriate treatment modality for each individual. It soon became evident cyclazocine was helpful for only a small proportion of patients; many patients discontinued it and became readdicted to opiates almost immediately. Clinical impressions suggested cyclazocine was not an appropriate form of treatment for certain “types” of opiate addicts. This impression was explored by Resnick et al.’ who presented a typological classification of opiate addicts, based on patients’ self-ratings of the role opiates played in their daily lives. The self-rating scale consisted of eleven statements, such as: On heroin the patient felt closer to others, better about himself, more ambitious, and generally more capable of functioning “normally,” as compared with periods when he was “clean” (i.e., opiate free). Each statement was rated by the patient on a scale from 1 (always true) to 5 (always false) and a total score was obtained. After administering this scale to 31 patients on cyclazocine for varying periods of time, investigators found patients who remained in treatment for as long as two and one-half years had significantly higher scores, reflecting less dependence on opiates for normal functioning than those who discontinued treatment within the first six months. It was also found that patients involved in a stable “marital” relationship with a nonaddict mate were more likely to sustain cyclazocine and remain abstinent than patients who lacked such a relationship. It was suggested that, in general, patients with low scores are better suited for methadone maintenance treatment because they perceive themselves as needing opiates in order to feel and function “normally.” Patients with a high score, on the other hand, do not use opiates to relieve chronic difficulties in feeling or functioning; these patients often do well in antagonist treatment. In a subsequent study, Resnick et ai.’ assessed the power of these self-rating scores and demographic variables to predict treatment outcome with cyclazocine. “Success” in treatment was defined as sustained use of cyclazocine for at least six months, without use of opiates or “excessive” use of non-narcotic substances. Unlike the earlier findings, there was no difference in mean scores between success and failure groups. As for demographic variables, marital and employment

Acute Systemic Effects of Cocaine in Man: A Controlled Study of Intranasal and Intravenous Routes of Administration

An upsurge in cocaine use has been anticipated by workers in the drug abuse field for some time (Ellinwood, 1973), and the popular press recently has been reporting major nationwide increases in the non-medical use of the drug. The increase is apparently occurring both in opiate users and the general population. For example, out of 55,745 students in the seventh through twelfth grades in Dallas, Texas, 2,108, or 4%, reported using cocaine; and 1,250 of them reported they had used it at least one time during the week the questionnaire was answered (Gossett, Lewis, and Phillips, 1971). A series of surveys have indicated that up to 84% of regular heroin users also use cocaine (Chambers, Taylor, and Moffet, 1972; Edmundson, Davies, Acker, and Myer, 1972). The New York State Narcotic Addiction Control Commission reported 81.7% of 180 randomly selected, certified narcotic addicts during 1969–1970 abused cocaine. The Clinical Research Center at Lexington found that, of 1,096 opiate addicts, 72.9% reported cocaine abuse during 1968–1969; and a 10% increase in cocaine use among heroin addicts in San Francisco between 1971 and 1972 has been reported (Gay, Sheppard, Inaba, and Newmeyer, 1973).

Problems of methadone diversion and implications for control.

With the expansion of methadone maintenance there has been an increase in accidental ingestion and related deaths. This is at least partially due to programs involving take-home methadone. The use of 1-alpha-acetylmethadol (LAAM), a congener of methadone that suppresses withdrawal for up to 72 hours, may reduce diversion and accidental overdose.

Opiate Antagonists in the Treatment of Heroin Dependence

Opiate addiction is a complex social and psychological disorder of diverse origins that defies conventional therapeutic efforts, both social and medical. Treatment is discouraged by the high rate of recidivism. Rehabilitation programs frequently reduce recidivism either by the careful selection of suitable patients (accepting only those with the best motivation for recovery) or by imprisonment and primitive systems of parole or by methadone substitution, which satisfies opiate craving by cross tolerance. Each treatment program for opiate dependence—whether forced imprisonment, group therapy, reeducation, psychotherapy, or social rehabilitation— requires an adjuvant to “engage” the subject in the treatment schedule. Methadone substitution fulfills such a role, although the addicting properties of methadone is a continuing hazard.