INTRODUCTION

 

Detoxification from opiates has created difficulties for as long as these drugs have been available for the relief of pain or the production of euphoria. Although the withdrawal syndrome is rarely life threatening, its symptoms are distressing enough in the acute phase to make it difficult for many addicted individuals to cease use of drugs, and the chronic persistence of low-level symptoms has no doubt been a contributing factor to early relapse. The withdrawal "cures" proposed over the last 100 years have at times been worse than the disease, introducing drugs which are even more addicting or using other methods that either cause more distress or even at times a significant mortality rate. Examples of the former include the use of injectable morphine to cure opium eating (Allbutt, 1870) and the use of heroin to treat morphine addiction (Kramer, 1977); while examples of the latter include the Towns-Lambert belladonna mixture, Narcosan, sodium thiocyanate (Kolb and Himmelsbach, 1938), and electroconvulsive therapy (Thigpen et al, 1953). Because of this distressing history, one must be especially careful in proposing new techniques that they meet the twin demands of safety and efficacy. Any claims for a new method should be put forward with modesty and viewed with skepticism until amply documented by careful experimental procedures.

 

Approximately 30 years ago, methadone was used in this country to treat the heroin withdrawal syndrome (Isbell and Vogel, 1948) and, approximately 15 years ago, its use was extended to serve as a maintenance agent in treating the narcotic addict (Dole and Nyswander, 1965). In the United States alone there are currently about 80,000 individuals on methadone maintenance programs, and over 10,000 of these are in the process of withdrawing from methadone at any one time (Senay et al, 1977). While the use of methadone as a withdrawal agent alleviated many of the problems associated with earlier methods of withdrawal, its use as a maintenance agent has created a new set of withdrawal difficulties. The outlook for these 10,000 individuals in the process of withdrawing, and the others to follow, is cloudy. Although figures vary widely from study to study, it can be said as a general rule that no more than 50 percent of the patients attempting detoxification are able to achieve zero dosage at any one time and of those that do, only about 50 percent are able to maintain it (Kleber, 1977). In the classic withdrawal study done by Senay et al (1977), it was found that a slow gradual withdrawal technique over 30 weeks significantly improved the rate obtained compared with detoxification carried out over 10 weeks. Even so, only 53 percent of the patients in the slow withdrawal group were able to achieve zero dosage. Factors such as psychological readiness for withdrawal, age, length of addiction, anxiety, expectation and rate of withdrawal appear to have an important bearing on the outcome (Kissin et al, 1978; Lowinson et al, 1976). Physiological dependence upon methadone may be at least partially responsible for the low rates, but the extent of its role is unclear (Martin et al, 1973). Detoxification becomes more difficult when the dose gets below 20 mg per day (Martin et al, 1977).

 

Thus, while methadone maintenance, when given in the overall context of a treatment program, has often proven to be a useful tool in aiding the overall rehabilitation of the narcotic addict and his ability to avoid using illicit drugs, patients continue to have a difficult time withdrawing from it even when their social/vocational and psychological situation has changed. Improved detoxification methods would be useful, therefore, in the overall treatment strategy for narcotic addicts. The techniques described below have been tried either for detoxification from heroin, detoxification from methadone, or in both situations.

 

One important need for improved withdrawal procedures stems from the possibility of switching opiate addicts to the narcotic antagonist, Naltrexone (Martin et al, 1977; Report, 1978). This agent, which blocks the euphoria and addicting potential of narcotics (in appropriate dosages) without being addicting itself can only be used when the individual is off narcotics at least 5-10 days. If taken before this, unpleasant withdrawal symptoms may be precipitated and the patient will drop out of treatment. Using current withdrawal methods which substitute declining doses of methadone for heroin or gradual decrements of the maintained methadone dose, many patients are unable to wait the requisite period drug free and relapse back to opiates (Resnick et al, 1974). A method which could avoid this drug free wait would increase the usefulness of naltrexone and move treatment closer to the sequence envisioned by Goldstein in his STEPS proposal (Goldstein, 1976).

 

One must also keep in mind that chronic methadone maintenance might be having untoward effects on endorphin levels and a withdrawal method which enhances the patients' chances for abstinence could decrease the time spent on methadone. Unlike the typical heroin addict on the street whose intake is usually quite variable—high on Monday, sick on Tuesday, less high on Wednesday, etc—the methadone-maintained client is getting a steady dose of a pharmacologically pure and potent medication. This regular intake could lead to suppression of endorphine levels and in some patients the levels might not bounce back even after gradual withdrawal. This should not be taken to mean we should not use methadone. Currently it is the most widely accepted and useful technique for treatment of opiate addicts we have (as long as we remember it is a drug, not a treatment, and must be given in a context of psychosocial supports and therapy) (Kieber, 1980). As clinicians, therefore, we need it for our patients. As scientists, however, we must continue to point out potential flaws, risks, etc, in any method we use and continue to strive for better ones. Finally, in this context, one must add that the long-term effect of naltrexone on possible endorphin suppression is also not known.

 

PROPANOLOL

 

Propanolol, a beta-adrenergic blocking agent, has been tried in the treatment of narcotic withdrawal. It was found that patients treated with the drug required a somewhat smaller methadone dose for detoxification and that the patients who responded favorably had milder withdrawal symptoms. The overall conclusion, however, was the "the small benefit from the drug hardly merits its consideration as an adjunct to the treatment of withdrawal from opiates" (Hollister and Prusmack, 1974).

The attempt to use propanolol in narcotic withdrawal was suggested by the work of Grosz (1972) who noted that propanolol given to heroin addicts abolished the euphoric effect of the narcotic as well as the compulsive craving for the opiate which followed heroin withdrawal. Although he did not feel that the drug helped in the management of the acute physical withdrawal syndrome, Hollister et al (Hollister and Prusmack, 1974), decided to try it anyway because Grosz had noted that it possessed narcotic antagonist potential.

 

PROPDXYPHENE

 

Propoxyphene, a mild analgesic derived from methadone but having less addictive and analgesic potential, has been tried to relieve the symptoms of narcotic withdrawal, and particularly its napsylate form has received a good deal of attention in this regard. The napsylate form is only slightly soluble in water, whereas propoxyphene hydrochloride is very water soluble. This lowered water solubility leads to slower absorption in the g.i. tract, lower peak plasma levels, and, therefore, it is believed to have a much lower overdose potential. Because of the similarities to methadone and because, at times, it has been difficult to use methadone in many places on an outpatient basis for withdrawal, programs have tried the propoxyphene napsylate for withdrawal. The results to date suggest that while this drug is not as good an agent as methadone in suppressing the full spectrum of narcotic withdrawal, it can partially block the development of withdrawal symptoms with the notable exception of insomnia (Tennant, 1974; Inaba et al, 1974). Because it is addicting itself and because, especially mixed with alcohol, the additive effects on respiratory depression can be fatal, it is important that, if the drug be used, the amounts given the patient to take by prescription be not excessive. The studies seemed to indicate that 800-1,000 mg a day given in two or three divided doses is sufficient. It should also be pointed out that this use of propoxyphene in either the hydrochloride or napsylate form is not an approved indication for the drugs and that, if research is to be done, an IND would be required from the Food and Drug Administration. Since October 1980 it has been illegal to use it for withdrawal without an IND from the FDA.

 

ACUPUNCTURE

 

The use of acupuncture to manage pain goes back thousands of years in Chinese medicine. Its use to treat narcotic withdrawal is a relatively recent phenomena, however, with the first paper reporting results in 1973 by Wen and Cheung (1973). They report on 40 patients using acupuncture with electrical stimulation. This paper as well as others, were critically reviewed by Whitehead (1978), who concluded that, "the use of acupuncture in the management of withdrawal symptoms is insufficiently reported as to constitute an adequate clinical trial. No control subjects and no control conditions have been employed. Those results that have been reported are incomplete and inadequate and these same results have been misinterpreted by others in the direction of 'gilding the lily' . . . " In later papers, Chen (1977) suggested that acupuncture may work by stimulating enkephalin in release, and Wen (1977) reported that if patients were treated with naloxone at the same time as receiving acupuncture, the whole procedure was markedly shortened.

Although a controlled trial would add considerably to evaluation of the technique, there is debate over the possibility of a double-blind trial. Even without this, it appears that acupuncture with electrical stimulation (AES) has some effect on withdrawal symptoms but is cumbersome, has to be given frequently, and takes seven to eight days to detoxify patients. The new procedure using naloxone may improve the usefulness of the technique but better designed studies need to be done to prove this.

 

VITAMIN C

 

Since high doses of ascorbic acid (vitamin C) have been used to treat or prevent a number of conditions as varied as the common cold, heart disease, leprosy, and viral hepatitis, it is not surprising that it would be tried with narcotic withdrawal. Libby and Stone (1977) reported 100 cases of heroin addicts they had detoxified using doses of ascorbic acid in the 25-85 mg/day range. The patients were treated for one to two weeks in a residential setting and then discharged on holding doses of 10 gram/day. The patients reported a loss of craving for narcotics while taking the mega-doses of vitamin C. Free and Sanders (1978) reported an outpatient trial of the ascorbic acid regime, Patients volunteered for one of three groups—ascorbic acid only, symptomatic medications (eg, propoxyphene, librium, chlorahydrate), and symptomatic medications for three days followed by mega-dose ascorbic acid. Group 1 had 30 clients, Group 2 had 186 clients and Group 3 had 11 clients. The combined group reported fewer withdrawal symptoms and a shorter withdrawal period. In addition, many subjects in either Group 1 or 3 using ascorbic acid reported increased energy, loss of drug craving and some block of narcotic effect if they used narcotics while they were taking the vitamin C. Doses of vitamin C in Group 1 were 24-48 g/day for five to seven days, tapering to 8-12 g/day for 14 days. In addition to the vitamin C, patients were given multivitamin amd mineral preparations, calcium and magnesium tablets, and liquid protein.

 

Although no side effects other than nausea in one subject and a rash in a second one were reported, mega-doses of vitamin C have been suggested to cause kidney stones, destruction of vitamin B12, pentosuria, and possible increased chance of infertility and abortion. Given these possible complications, the fact that the two trials to date were uncontrolled studies, and that the improvement noted was not very large, mega-dose ascorbic acid treatment should be considered experimental and risky.

 

NALOXONE PRECIPITATED WITHDRAWAL

 

Although the usual methods of withdrawal tend toward the slow gradual approach, some authors have tried to markedly compress the abstinence syndrome on the theory that total discomfort may be less in such an approach even though the peak may be higher. Both Blatchly et al (1975) and Resnick et al (1975) have used naloxone-precipitated withdrawal to bring about this shortened detoxification syndrome. The technique consists primarily of giving i.m., or i.v. naloxone repeatedly at frequent intervals for one or two days until further injections produce no withdrawal symptoms. Blatchly used dioperidol, propanolol, and Ketamine to handle the symptoms produced but these agents had minimal ameliorating effect. Resnick initially used amobarbital, atropine and chlorpromazine but later gave nothing except nighttime sedation and found the acute symptoms subsided about an hour after each dose. More recently he has premedicated with diazepam and atropine (Resnick et al, 1977). Probably because of the persistence of unpleasant symptoms, the technique has not caught on and is rarely used.

 

CLONIDINE

 

Gold, Redmond, and Kleber first reported in 1978 (Gold et al, 1978) that clonidine, an alpha adrenergic agonist used to treat hypertension, could suppress or reverse the symptoms of opiate withdrawal. They have since published a number of papers on this (Gold et al, 1978; 1979a; 1979b; 1980), extending the original findings and their results have been confirmed by Washton and Resnick (1979). The major withdrawal symptoms not totally blocked are insomnia and irritability. Clonidine has been used to treat both heroin and methadone withdrawal. The usual regime for methadone withdrawal from doses of up to 25 mg methadone/day (in an individual of average weight—approximately 70-75 Kg) is as follows:

 

Day 1 —0.1 mg clonidine test dose in a.m.

0.2 mg at 5 p.m. 0.2 mg at 10 p.m.

Day 2 —0.2 mg three times a day

Day 3-10 —0.3 mg three times a day (may vary between total dose of 0.8-1.5)

Day 11 —half of dose of Day 10

Day 12 —half of dose of Day 11

Day 13 —half of dose of Day 12

 

For heroin withdrawal, the length of the clonidine treatment can usually be reduced to four days and lower doses can be used. To check for completeness of detoxification, a naloxone test dose (0.8 mgm) can be given the next day to see if any symptoms are precipitated.

 

The major side-effects of clonidine are sedation and lowered blood pressure so patients should be checked for this up to two hours after each dose. If blood pressure is less than 85/60 at the time to receive the next clonidine dose, it should be postponed until the pressure has risen. There have also been instances of acute psychiatric problems after clonidine detoxification is over so patients with a prior history of schizophrenia or major affective disorder should probably be excluded from this technique. It is important to keep in mind that although clonidine increases the chance of an individual completing detoxification, it does nothing to keep addict off and the relapse rate remains at 50 percent or higher.

 

The total daily dose of clonidine may need to be less on an outpatient than inpatient regime because of the problems of sedation and hypotension. On an outpatient basis, patients should be warned about the sedative effects of clonidine especially in relation to driving and operating machinery. Patients probably should not drive at least the first five days of being on the drug and longer if sedation or hypotension is a problem. To deal with persistent insomnia, one should use sedatives such as chloral hydrate. Patients should be warned that mixing alcohol with the clonidine can be especially dangerous because of alcohol's hypotensive effect. Amitriptyline if started after clonidine, may also increase the hypotensive effect.

 

The discovery of clonidine's acting on opiate withdrawal has suggested the following model of how withdrawal takes place in the brain.

 

" . . . opiate withdrawal may be due, in part, to increased noradrenergic neural activity in areas such as the locus coeruleus which are regulated by both opiates through opiate receptors and clonidine through alpha-2 adrenergic receptors. . . . Opiates administered systemically turn off the locus coeruleus by stimulation of inhibitory opiate receptor sites with reversal of this effect by the opiate antagonist, naloxone. Clonidine also inhibits the locus coeruleus but by stimulation of a different receptor, this effect being reversed by specific alpha-2 adrenergic antagonists . . . " (Gold et al, 1980).

 

CLONIDINE-NALOXONE

 

Building on the naloxone flush technique of Resnick et al (1975) and Blachly et al (1975) and the clonidine work of Gold, Redmond and Kleber (1978), Riordan and Kleber (1980a; 1980b) combined the two techniques to produce an ultra short and yet comfortable method of withdrawal. Patients on doses up to 30 mg/day of methadone have their dose abruptly halted and are given clonidine 0.7 mg in divided doses on day 1. On day 2 this is increased to 1.2 mg in divided doses and Naloxone i.v. or i.m. is given hourly in increasing doses.

 

Typically: 8:00 a.m.-clonidine 0.4 mg and at 2 + hours

9:30 a.m.-Naloxone 0.1 10:30 a.m.-Naloxone 0.1 11:30 a.m.-Naloxone 0.2

Day 2: 12:30 p.m.-Naloxone 0.2

1:30 p.m.-Naloxone 0.3

2:30 p.m.-Naloxone 0.3

3:30 p.m.-Naloxone 0.4 X 4 doses

on

8:00 a.m.-Clonidine 0.4 and at 2 p.m.

9:30 a.m.-Naloxone 0.4

10:30 a.m.-Naloxone 0.4

Day 3: 11:30 a.m.-Naloxone 0.4

12:30 p.m.-Naloxone 0.4

1:30 p.m.-Naloxone 0.8 X 6 doses

 

Chloral hydrate 1 Gm is given as needed for sleep. On day 4 1.2 mg Naloxone is given as test dose. We have also noted that on day 6 some discomfort occurs and is relieved by low doses clonidine 0.1 b.i.d. for a few days. We hypothesize that using naltrexone from day 4 on may prevent these mild withdrawal symptoms. We are currently trying to modify the technique so it can be done all orally using naltrexone instead of naloxohe with an eye to possible outpatient use.

 

ISBELL/WIKLER 1948 STUDIES

 

Before closing it may be useful to be reminded of what it is we are trying to treat. Current studies indicate it is especially hard to get from 25-30 mg/day of methadone to zero whereas going from the higher doses to 25 mg is not that difficult. Most attrition occurs at the lower dosage and may relate to methadone at those doses not lasting a full 24 hours so patients have daily withdrawal symptoms. When Isbell and Vogell studied methadone in 1948, they addicted individuals to doses as high as 200-400 mg/day and then abruptly stopped all medication. Their results were as follows:

 

Changes Following Withdrawal of Methadone

 

Withdrawal of methadone was abrupt and complete in all cases. Observations were carried out for only six days on the ten men who received the drug for twenty-eight to fifty-six days. The six-day period of observation was based on experience with the morphine abstinence syndrome and is sufficiently long for evaluating the withdrawal sickness after discontinuance of the use of morphine. However, because of the continuation of complaints by these 10 subjects, who were the first from whom methadone was withheld, after discharge from the research ward, the observation period was extended to fourteen days for the five men who were given doses producing addiction for four and a half to six months.

 

After withdrawal, a definite abstinence syndrome ensued in all fifteen cases. The manifestations of this syndrome, though milder than those seen after the withdrawal of morphine, were consistently observed in all men and at the same time. Subjectively, the men made no complaints in the first two days of abstinence and said that they were still under the influence of the drug (were "loaded"). On the third day of abstinence they began to complain of anxiety, insomnia, vague gastric distress, headache and occasionally, tinnitus. The men did not suffer from the muscle aches and cramps which are so troublesome after the withdrawal of morphine. The subjective symptoms increased in intensity until the sixth day of abstinence, after which they gradually declined. Some patients continued to complain of weakness for sixty days after withdrawal. Thirteen of the fifteen subjects considered the subjective symptoms less severe than those following the abrupt withdrawal of morphine, but all agreed that the symptoms were sufficiently severe to cause them to return to the use of the drug had it been obtainable. Nearly all complained bitterly about the slowness in improvement. A typical comment on the tenth day of abstinence was 'This stuff seems like it never will turn a man loose. When I stop a morphine habit I start getting better on the third day and keep getting better every day after that. I didn't start to get sick until the third day off, and I'm still half sick all the time and not getting better. If I were on the street I'd have a shot within five minutes.'

 

The general appearance and behavior of fourteen of the men were not greatly altered. They appeared to be tired and mildly irritable. They made frequent requests for either methadone or morphine after the third day of abstinence but did not lose emotional control when their requests were refused" (Isbell et al, 1948)

 

CONCLUSION

 

Narcotic addiction is both a psycho-social and physiological condition. The high percentage of Vietnam veterans addicted to heroin while in Vietnam who were not addicted a year later when back in the United States, as well as the overwhelming majority of medically addicted individuals who cease narcotic use once the underlying painful condition is treated, all bear witness to the important role of psychological and social factors. Conversely, the existence of the opiate receptor sites, the endorphins, and the protracted abstinence syndrome, are significant reminders of the potential role which biological factors play. Our clinical experience with clonidine to date supports the necessity of adequate psychological supports during and after the withdrawal process. The patients in many cases have been on a daily drug,

whether heroin or methadone, for 5 to 15 years. Sudden cessation of this daily drug intake, around which many of their daily activities were scheduled, is often felt as an acute loss or disorienting factor with resultant depression, confusion, and, finally, return to drug use. We have learned through painful experience that during clonidine administration, patients should have a daily opportunity to talk about what they are going through with a knowledgeable clinician, and they should remain in treatment afterwards for at least one to three months. Where the size of the program permits, it may be useful to establish a clonidine group where patients who have undergone clonidine-aided withdrawal can meet at least once a week and discuss with a skilled group leader the problems involved in remaining abstinent and the experiential psychological loss. Although this support can be crucial, it is too often spurned by patients who feel that once they are clean they wish no further program contact.

 

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