Dextropropoxyphene

INTRODUCTION

The addiction to opiates has been known for centuries. Their capacity to induce tolerance and dependence is widely established. In modern times, multiple derivatives have been synthesized in an attempt to keep the pharmacological effects and eliminate the addictive ones.

Dextropropoxyphene (DPX), an opiate derivative, described as an abused drug since the early 1970s, was introduced to the United States market in 1957. It was described as a highly effective analgesic, synthetic opiate derivative, mildly sedative, and without abusing and dependence potential (1).

Miller et al. in 1970 (1) published an extensive review of the DPX literature in an attempt to determine whether its extended use and popularity were justified. They found 243 articles, and by studing only those that were controlled and double blind, reduced the number to 20. Their conclusions were: "propoxyphene had no superior analgesic effect than aspirin or codeine; no definite statement as to relative incidence of side effects could be made; it appeared that factors other than intrinsic therapeutic value were responsible for its commercial success and finally the addiction liability was low but several reports had demonstrated its abuse potential" (1).

In 1973, Tennant (2) published a report of DPX abuse by soldiers stationed in a U.S. military base in West Germany from 1969 to 1971. A random questionnaire survey revealed that 5,300 out of 180,000 soldiers had used DPX once or more for nonmedical reasons. The administration routes were oral, subcutaneous, and intravenous. Multiple medical and psychiatric complications were reported to include 13 deaths.

The most important medical complications were respiratory arrest, phlebitis, and withdrawal symptoms. The psychiatric complications, disorientation, delusions, hallucinations, and extreme confusion were successfully treated with chlorpromazine.

In 1974 the U.S. Drug Awareness Network (DAWN) found DPX to be eighth among the most abused drugs. It had a wide street distribution and a high dependence potential (3). During this decade, publications in favor and against the use of DPX appeared in the literature (4, 5).

The recommendations included its use as part of the detoxification maintenance treatment of heroin addicts, with doses equivalent to 650 mg/day of DPX (10 Darvon caps) (6). As an analgesic, it was supposed to be safe if well indicated and supervised (7).

Collins and Kiefer (8) reported a case of dependence secondary to prescribed use of DPX. They also proposed that the most common way to acquire the drug was through doctor's prescription. It was established that the oral route is addictive, causes tolerance, and its interruption is followed by specific symptomatology. The biochemical similarity between DPX and methadone was outlined, and a crossed tolerance with other opiates was proposed because of the intoxication symptomatology and its reversibility with naloxone.

In 1983, Young described the intoxication and overdose with DPX as an endemic phenomenon in developed countries (9). The clinical picture includes nausea, vomiting, miosis, seizures, tachycardia, hypo- or hypertension, CVA, and cardiorespiratory arrest. Young estimated that 30% of abusers would develop some kind of complication, and because of its rapid deterioration, he considered its recognition and treatment very important.

Besides the conventional treatment of cardiorespiratory arrest and seizures, Young recommended management with naloxone IV. Dopamine has been proposed by others (10). Young found that at least 33% of DPX abusers were polydrug users, and most deaths included concurrent use of alcohol and/or benzodiazepines. He concluded, "DPX is a drug of paradoxes. It is of scientifically uncertain effectiveness, yet its popularity is immense and although unique among the common causes of self-poisoning in having a totally effective antidote, acute DPX overdosage is ... frequently fatal at present."

DPX is readily absorbed orally, reaches peak levels in less than an hour, is highly demethylated into norpropoxyphene (active metabolite), and is then slowly eliminated. The half life is 12 hours for propoxyphene and 36 hours for norpropoxyphene. Prolonged use diminishes its metabolism and elimination, reaching higher levels and longer half lives. It crosses placenta and is highly deposited in fat tissue, liver, and lung (9). Alcohol diminishes its hepatic biotransformation (11).

The need for an effective treatment for the DPX withdrawal syndrome was described by Strode (12). Most of the cases in his report were patients with chronic pain (arthrosis or headaches) of difficult management who became dependent on prescribed DPX. Following the detoxification treatment, which consisted of a slow dose tapering, they could demonstrate that the pain was controllable with other analgesics combined or not with anti-inflammatory drugs. Clonidine was proposed as only part of the detoxification because of its involvement in the withdrawal syndromes of other opiates.

In Mexicali, DPX seems to be a "preferred" street drug. It is a noncontrolled substance in Mexico, but its availability has been restricted because of the social phenomenon around it. This, in turn, has led to its illegal distribution. The current administration route seems to be exclusively oral, frequently in combination with other psychoactive drugs.

As described by the abusers, a "bunch" of pills at one time (5-15 caps) is necessary to feel the toxic "hit," followed by relaxation and diminished anxiety, or by disinhibition and overconfidence. The DPX withdrawal syndrome starts 8 to 12 hours after the last dose, and closely resembles the heroin withdrawal syndrome.

In our institution, patients frequently come requesting detoxification and rehabilitation services for DPX dependence. Therefore, we decided to review our records in an attempt to define a profile of the sociodemographic characteristics of the DPX abuser.

METHODS

This was a retrospective, noncontrolled study of the records of patients admitted to the Detoxification Unit in the Mental Health Institute in Mexicali, Mexico from March to December 1988.

The inclusion criteria were:

(a) Diagnosis of DPX dependence based on DSM-III-R criteria for psychoactive substance dependence.

(b) Chief complaint of withdrawal symptomatology or inability to quit using DPX.

The exclusion criteria were:

(a) Associated psychiatric pathology (e.g., drug-induced thought or mood disorder) according to the progress notes and discharge diagnoses of the attending physician based on DSM-III-R criteria.

(b) Incomplete records or cases with not enough features to meet the DSM-III-R criteria for psychoactive substance dependence were excluded.

A structured questionnaire designed specifically for this study was applied to the selected files. It included demographic data and the history of substance abuse (13). The results were studied by chi square.

RESULTS

Two hundred and nine files were reviewed. Seventy had a diagnosis of alcohol dependence, 35 had a diagnosis of heroin dependence, 23 had concomitant psychiatric diagnosis, and 8 were incomplete. Eventually, 73 files were included in this study.

Seventy-one subjects were males (97%), 31 were single (42%), and 38 had no dependents (52%). The average number of school years was 8.5, and one-third of the sample was unemployed. More than half lived in their parents household (66%), and only a third (34%) had lived in the United States for more than 1 month.

The median age of admission was 26 years. The median age of first use of DPX was 21 years. Most of the subjects had abused DPX for at least 4 continuous years.

The number of DPX capsules ingested ranged from 3 to 55 per day (195-3,575 mg), with an average of 21/day. This amounts to 3.5 times the maximum therapeutic dose recommended.

Generalized seizures were confirmed in 53% of the patients. In all cases except one there was no history of seizures prior to the abuse of DPX. Seizures appeared during the state of intoxication in all cases.

The most frequently used drug along with DPX was a benzodiazepine (38%) (p<.01), followed by marijuana (15%), heroin (14%), alcohol (8%), cocaine and amphetamines (5%), and inhalants (1%). Fourteen subjects (19%) were pure DPX abusers.

DPX was the first opiate ever abused by 67% (p<.01) of the subjects (N = 49); a third of them used heroin later in their lives (N= 16). Fourteen subjects (19%) abused heroin before using DPX. Ten subjects (14%) started using DPX and heroin at the same time.

The subjects whose first abused opiate was DPX and who eventually abused heroin, used an average of three drugs besides DPX. Those who abused heroin before DPX or started using both at the same age used 2.2 drugs besides DPX. Those subjects who did not use heroin abused only 1.3 drugs besides DPX.

DISCUSSION

DPX, an analgesic of uncertain effectiveness, is widely abused in our community. Its abuse carries serious complications, including a new onset of generalized seizures as the most prevalent (9).

Physicians in emergency departments should keep DPX in mind whenever an individual without IV track marks presents unconscious and with symptomatology of opiate intoxication or with new onset generalized seizures.

The withdrawal symptomatology is identical to any other opiate withdrawal syndrome in that it readily responds to clonidine. In our center we have successfully treated DPX patients by following guidelines established by Gold and others (14-16).

Our analysis shows that for most of our subjects, DPX was the first opiate ever abused, supporting the hypothesis that DPX is a drug of primary abuse, more commonly abused than heroin. This is unlike the abuse reported by DAWN in the midseventies, when its popularity was still behind that of heroin (3), and different than that described in the mideighties when its dependence was secondary to prescribed DPX (12).

Our analysis also conveys the belief that the greater accessibility, the lower cost, and the less complicated stigmata surrounding "being on pills" instead of "taking shots" lead the abuser through a false door into becoming dependent on a drug with properties extremely similar to "heavy drugs" (e.g., heroin).

DPX abuse is a public health problem in our community, affecting our younger population and offering social features common to any other street drug.

REFERENCES

1. Miller, R., Feignold, A., and Paxinos, J., Propoxyphene hydrochloride. A critical review, JAMA 213:996-1006 (1970).

2. Tennant, F., Complications of propoxyphene abuse, Arch. Intern. Med. 132:191-194 (1973).

3. Cushman, P., Propoxyphene revisited, Am. J. Drug Alcohol Abuse 6:245-249 (1979).

4. Glatt, M., A note in the misuse of pentazocine and dextropropoxyphene, Br. J. Addict. 52:253-254 (1977).

5. Whittington, R., Dextropropoxyphene addiction, Lancet 6:743-744 (1979).

6. Woddy, G., McLellan, A., and O'Brien, C., Lack of toxicity of high dose propoxyphene napsylate when used for maintenance treatement of addiction, Clin. Toxicol. 16:473-478 (1980).

7. Owen, M., How safe is dextropropoxyphene?, Med. J. Aust. 1:617-618 (1980).

8. Collins, G., and Kiefer, K., Propoxyphene dependence. An update, Postgrad. Med. 70:57-61 (1981).

9. Young, R., Dextropropoxyphene overdosage. Pharmacological considerations and clinical management, Drugs 26:70-79 (1983).

10. Krantz, T., and Thisted, B., Severe acute propoxyphene overdose treated with dopamine, Clin. Toxical. 23:347-352 (1985).

11. Sellers, E., and Hamilton, C., Pharmacokinetie interaction of propoxyphene with ethanol, Br. J. Clin. Pharmacol. 19:398-401 (1985).

12. Strode, S., Propoxyphene dependence and withdrawal, American Family Physician 32:105-108 (1985).

13. Greene, B., Concurrent and sequential use of drugs and alcohol: Patterns, characteristics of users, and implications for treatment and prevention, Am. J. Drug. Alcohol Abuse 6:447-462 (1979).

14. Gold, M., Redmond, D., and Kleber, H., Clonidine blocks acute opiate-withdrawal symptoms, Lancet 9:599-602 (1978).

15. Johnson, D., and Boham, M., Propoxyphene withdrawal with clonidine, Am. J. Psychiatry 140:1217-1218 (1983).

16. Baleris, G., Cross, P., and Hammarsten, J., The use of clonidine for management in a chronic pain patient, Mayo Clin, Proc. 57:657-660 (1982).

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