Usefulness of Propoxyphene Napsylate for Maintenance Treatment of Narcotic Addiction

2015

Recently several studies have examined the use of propoxyphene napsylate (Darvon-N) in the detoxification and maintenance of narcotic addicts. Tennant () reported that three programs in Los Angeles had succeeded in detoxifying 280 heroin addicts with propoxyphene napsylate, while maintaining 92 others on an outpatient basis for periods up to 240 days. In a doubleblind detoxification study comparing propoxyphene napsylate and methadone, he found that propoxyphene patients were more likely than methadone patients to be opiate abstinent at one month followup ().

However, in this doubleblind study, Tennant found propoxyphene to be less effective than methadone in suppressing withdrawal complaints. He also noted side effects from propoxyphene, such as mild visual hallucinations, slurring of speech and seizurelike symptoms (). Jasinski () reported that propoxyphene napsylate used in maximum non toxic doses (about 1200 mg per day) produced narcotic-like activity equal to that of only 20 to 25 mg of subcutaneously administered morphine, or 10 mg of orally administered methadone. Again, he found that propoxyphene napsylate doses greater than 700 mg produced disturbing side effects in many subjects.

This paper will report the results from two studies, one carried out in Los Angeles and one in Philadelphia. Both were designed to evaluate the usefulness of propoxyphene napsylate in the maintenance treatment of opiate addiction. In both studies, propoxyphene was prescribed in divided doses. This allowed patients to receive the higher amounts required for maintenance that would have been toxic in a single dose. The protocols followed by the two clinics were similar, thus allowing data to be pooled.

Methods

At each location, addicts applying for methadone maintenance treatment between the ages of 19 and 55 with “mild to moderate” opiate habits were selected. Those with larger habits, who were expected to require more than 30 mg methadone, were excluded. An ample number of patients was available, because the average daily methadone dose was 35 mg in each clinic. Current physical dependence was verified by signs of abstinence and use. Patients with psychoses, seizure disorders, hepatitis, severe liver disease, or any other serious illness were excluded. Approval from the Food and Drug Administration (FDA) was obtained for a waiver of the two year minimum addiction requirement for methadone maintenance, so that patients who had been addicted for six months or more were eligible for treatment in the experimental programs. Individuals were allowed to remain in the study for a maximum of six months. A double blind format insured that neither patients nor therapists were informed about the individual’s experimental group.

Both medications were prepared in capsules that were identical in taste and appearance. Medicines were prescribed in divided doses, to be taken in the clinic, and at home approximately 12 hours later. The maximum dose of methadone was 36 mg per day, all of which was ingested at the clinic (takehome doses for the methadone group were placebo). This design was arranged by consultation with the FDA, the Drug Enforcement Administration (DEA), the National Institute on Drug Abuse (NIDA), and both research groups. It was a compromise intended to prevent methadone diversion while allowing propoxyphene to be prescribed in divided doses, in order to minimize its side effects and maximize its therapeutic effectiveness.

The protocol was explained to all prospective candidates and informed consent was obtained. All had the option of choosing any other form of treatment offered at the clinic. In Philadelphia, before signatures were accepted a short quiz was given to assure full understanding of all items included in the consent form.

Patients in each study were given a complete physical examination, including chest x-ray, CBC, urinalysis, SMA-6/12, EEG and EKG. A Beck Depression Inventory, a symptom check list, and a narcotic withdrawal scale were also done. The physical examinations, including laboratory tests, were repeated at two weeks, and monthly, until termination. The EKG was administered at three months and six months. The chest x-ray and EEG were repeated at termination. Vital signs and urinalyses for drug screening were collected weekly. Patient and counselor reports of employment, personal adjustment, and criminal activity were given weekly. The Philadelphia group also gave a Brief Psychiatric Rating Scale, Hamilton Anxiety and Depression ratings. Gordon Personality Profile, Wonderlic I.Q. test, anxiety checklist, and a sentence completion test at intake, one month, three months, and six months (or termination). All physical and psychological measures taken during the study were done 24 hours after the patient received his last medication.

One hundred and twenty-seven patients received propoxyphene (79 in Philadelphia, 48 in L.A.) and 103 patients were treated with methadone (68 in Philadelphia, 35 in L.A.). Methadone patients who reached the maintenance state of treatment were stabilized on an average of 32 mg per day, while propoxyphene patients stabilized on 1000 mg per day.

Results

The characteristics of the Los Angeles and Philadelphia samples at intake are summarized in Table I. As can be seen, the samples differ significantly with regard to racial and sexual composition and in terms of educational and legal status at intake. Differences in background and drug history were also compared between medication groups for each of these samples, and no statistically significant differences were found.

Physical examinations were completed on all patients at the start of treatment. Results indicated no significant differences between the two medication groups. Serial EEGs and laboratory analyses were performed during the study. EEG results for both groups showed the increases in high frequency, lower voltage activity typically found in people taking psychotropic drugs, and no patient had an epileptic seizure during treatment. Laboratory test results indicated that SGOT levels in the methadone clients were elevated at intake and decreased to normal levels during the study. In the propoxyphene group bilirubin values decreased from high normal to mid normal levels during treatment. Serious toxi-city was absent in both groups despite relatively long treatment duration (average six weeks) and is discussed in more detail elsewhere ().

Duration of treatment is summarized in Table II. Patients were divided into short term (less than one month) and long term (more than one month). In both studies, methadone patients tended to stay in treatment longer than propoxyphene patients. In Philadelphia this finding was significant at the .01 level. In Los Angeles, although results were not significant, they were in the same direction.

Treatment was divided into three periods: Induction (first four weeks), Maintenance (from week five until detoxification or termination), and Detoxification (until detoxification was complete or allotted treatment time ran out). A wide variety of physical symptoms and drug side effect data were examined and analyzed for each patient. Propoxyphene patients reported more symptoms, and greater symptom severity, than methadone patients during the Induction period, but these results were only significant for the Induction period in the Philadelphia study, although the Los Angeles results were in the same direction. These physical symptoms were usually related to withdrawal rather than side effects of propoxyphene itself. For example, in the Philadelphia study propoxyphene patients reported more difficulty sleeping, greater anxiety or nervousness, and heightened irritability.

During the Maintenance period, overall indices of symptoms and their weighted severity scores did not distinguish between medication groups in either study. So few patients reached Detoxification stage (4 propoxyphene and 8 methadone patients in Los Angeles; 2 propoxyphene and 11 methadone patients in Philadelphia) that statistical tests were not meaningful.

One of the most important measures taken from each patient was the weekly urinalysis. Urine was tested for the presence of various illicit street drugs, and especially for evidence of morphine. Among short term patients in both studies, propoxyphene and methadone groups did not differ in frequencies of positive urines. Among long term patients, however, an examination of the pooled data shows that 64% of the propoxyphene patients had positive urines for at least half of the weeks tested, while among methadone patients, the comparable proportion was 41%. These results are significant at the p < .05 level (X2 = 4.0, df = 1). Use of amphetamines and barbiturates was infrequent and did not differ between medication groups.

Counselor reports of social adjustment were also analyzed and no differences were found between medication groups in either study. The most important factor in predicting vocational adjustment was pretreatment employment status; those employed before treatment tended to remain employed. Ratings of psychological adjustment were obtained for long term patients in both studies. Medication groups differed only on ratings of apathy (propoxyphene patients showed more apathy).

Reasons for termination were coded into categories based upon their positive (completion of treatment, detoxification), negative (medications not working, extended absence), or neutral (jail, scheduling problems) implications for effectiveness of the treatment medication. The distribution of patients’ reasons for termination are presented by these codes for both the propoxyphene and methadone patients in Table III. The data for both the Philadelphia and Los Angeles samples are combined in the table as there were no statistically significant differences between them. Thirty percent of the methadone patients terminated for positive reasons, 57% for negative reasons, while 13% terminated for reasons unrelated to the medications. The comparable figures for the propoxyphene groups were 13%, 75%, and 12%. These distributions of answers differ significantly (p< .01) between the two groups.

Followup interviews were scheduled for both samples at one month following treatment and additionally at six months in the Philadelphia sample only. Patients were interviewed extensively concerning drug use, living arrangements, physical and psychological well being, vocational and crime data, and benefits from treatment. Patients’ urine samples were also collected.

An average of 85% of the eligible patients were contacted in both clinics at the one month interval and results were examined separately for the two samples. No significant differences between methadone and propoxyphene patients were found in either sample, although patients in both treatment groups reported less drug use than at intake. Results of the six month followup at Philadelphia produced similar findings, showing no significant differences in posttreatment adjustment between the two groups. Approximately 22% of the patients in each treatment group were drug free (by urine and interview) at that time.

Comments

Our findings indicate that propoxyphene is a less satisfactory medication than methadone for maintenance treatment of narcotic addiction. Propoxyphene patients tended to drop out of treatment earlier, and those who did remain in treatment one month or longer were more likely to terminate for a reason which indicated poor progress. Propoxyphene patients tended to drop out early. Those who stayed in treatment longer than one month were more likely to abuse heroin. The early dropout rate of propoxyphene patients usually was related to higher withdrawal symptom complaints during the first four weeks of treatment. A small number of propoxyphene patients dropped out due to signs and symptoms of CNS irritability. This finding is consistent with the reported side effects of high dose propoxyphene (). However, side effects were relatively minor due to the divided dose schedule for propoxyphene used in both studies.

We note that to some degree the validity of these conclusions may be a function of local conditions, such as the availability of methadone treatment. In the Philadelphia study, patients had immediate access to methadone treatment after termination from the study. In that setting, about three-fourths of the patients treated with propoxyphene dropped out within one month. Some patients left the clinic, while others switched to methadone maintenance. However, despite these short term differences, follow-up data indicated that posttreatment adjustment between treatment groups did not differ.