ABSTRACT
Introduction
Experience to date
Results
Ten-day study
Precautions and side-effects
Follow-up
The role of psychological support
Scientific rationale
Comments
Author: H. D. KLEBER , M. S. GOLD, C. E. RIORDAN
Pages: 1 to 10
Creation Date: 1980/01/01
Use of clonidine hydrochloride in detoxification from opiates has demonstrated that this substance can rapidly suppress the signs and symptoms associated with opiate withdrawal. Clonidine hydrochloride, an alpha-adrenergic agoinst, is a non-opiate substance. Studies to date indicate that clonidine is useful for withdrawal from methadone maintenance, where it can help in detoxifying the patient in less than 14 days (instead of the usual three to six months) with a high rate of success in achieving zero dosage. The results of a clinical investigation of clonidine are presented and discussed in this paper. It has been shown to suppress signs and symptoms of opiate withdrawal in patients taking up to 75 mg of methadone daily. Shorter-acting narcotics may be withdrawn in less than a week. To prevent relapse, post-detoxification counselling and the use of the narcotic antagonist, naltrexone, are recommended.
Detoxification from opiates has probably been a problem 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 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 [ 1] . Examples of the former include the use of injectable morphine to cure opium eating [ 2] and the use of heroin to treat morphine addiction [ 3] ; while examples of the latter include the Towns-Lambert belladonna mixture [ 4] , Narcosan [ 1] , sodium thiocyanate [ 1] , and electroconvulsive therapy [ 5] .
Approximately 30 years ago, methadone was used in this country to treat the heroin withdrawal syndrome and, approximately 15 years ago, its use was extended to serve as a maintenance agent in treating the narcotic addict [ 6] . In the United States alone there are currently about 80,000 individuals on methadone maintenance programmes, and over 10,000 of these are in the process of withdrawing from methadone at any one time [ 7] . 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 per cent of the patients attempting detoxification are able to achieve zero dosage at any one time and of those that do, only about 50 per cent are able to maintain it [8, 9]. In the classic withdrawal study done by Senay [ 10] , 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 per cent 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 [10, 11]. Physiological dependence upon methadone may be at least partially responsible for the low rates, but the extent of its role is unclear [ 12] . Detoxification becomes more difficult when the dose gets below 20 mg per day [10, 13].
Thus, while methadone maintenance, when given in the overall context of a treatment programme, 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. Although the history of attempts to improve detoxification as mentioned above require caution in announcing any new treatment method, it appears that clonidine may indeed be a useful new technique for detoxification from narcotics. Acupuncture, which has also been invoked as a promising new method, while diminishing withdrawal symptoms, appears to have too many practical difficulties associated with its application to be routinely useful on a clinical basis [ 14] . Clonidine, on the other hand, an alpha-adrenergic agonist and a widely available agent for the treatment of hypertension, appears to be a simple but very effective tool for such use [15, 16].
Our first clonidine experiment used a double-blind placebo methodology and demonstrated that a single dose of 5 μg/kg of clonidine caused a rapid and significant decrease in opiate withdrawal signs and symptoms in patients addicted to methadone [ 15] . Continuation of the work in an open outpatient study suggested that clonidine could be useful in the rapid detoxification of patients addicted to methadone [ 17] or heroin [ 18] . Similar confirmatory findings were later reported by others [ 19] . However, the interpretation of these outpatient studies was complicated by the difficulty in getting patients to follow exactly the outpatient protocol, their use of other drugs and the small number of subjects. We have, therefore, concentrated since then on using clonidine on an in-patient basis on a larger number of subjects to determine the most effective dose and frequency of administration, particularly with regard to the amount of opiate use preceding withdrawal and the existence of side-effects. Over 100 patients have been successfully detoxified so far, either at the facilities of the Yale University Department of Psychiatry and the Connecticut Mental Health Center or at the Research Unit at Fair Oaks Hospital in New Jersey. An example of our findings on 10 of the patients, recently described in detail [ 16] , follows.
The patients were members in good standing of methadone maintenance treatment programmes and had been maintained on methadone for at least six months prior to detoxification. Most, in fact, had been on methadone for 1-5 years, with some as long as 10 years, and had been on heroin before that for up to 15 years. The average methadone dose was 35 mg a day with a range from 10 to 70 mg. Exclusion criteria included cardiac arrhythmia, hypotension, vaso-motor instability and serious psychiatric illness. All of these subjects were men, all expressed interest in discontinuing use of opiates and gave informed consent for the study which included abrupt narcotic withdrawal and at least 36 hours without opiates. All the subjects had prior attempts at detoxifying from narcotics and had demonstrated objective signs of opiate withdrawal.
During the first day of treatment, all patients were rated for the presence or absence of withdrawal signs and symptoms by a research nurse/clinician every hour from 8 a.m. on. Following Day 1 the ratings were reduced to three times a day before each clonidine dose. The withdrawal rating scale consisted of 22 items which were rated as present (1) or absent (0) with the total score being added up to give a measure of withdrawal severity. Items rated were opiate craving, anxiety, yawning, perspiration, lacrimation, rhinorrhea, frequently interrupted sleep, mydriasis, goose-flesh, tremors, hot and cold flushes, aching bones and muscles, anorexia, increased blood pressure, insomnia, increased temperature, increased respiratory rate and depth, increased pulse rate, restlessness, nausea and vomiting, diarrhea and spontaneous orgasm. In addition to this nurse-completed form, patients completed the Addiction Research Center Inventory (ARCI) and Weak Opiate Withdrawal (WOW) scales to assess self-rated opiate withdrawal. These were completed every hour on the first day of clonidine and then three times a day thereafter. Finally, patients completed self-rating analogue scales to assess changes in nervousness, being high, unpleasantness, energy, irritability, fear and anger. These were done hourly from 9 a.m. on Day 1 and three times a day after clonidine administration thereafter.
On the first day, to document more fully the clonidine effect, patients took 6 μg/kg of clonidine or placebo orally in matching vehicles to demonstrate the acute effect of clonidine on opiate withdrawal signs and symptoms and to measure the changes in blood pressure produced by this dose of clonidine. If the clonidine response was positive in terms of the effect on the opiate withdrawal symptoms, and if the blood pressure drop was not too precipitous, the patients were then given clonidine for at least nine additional days at a level of 17 μ/kg per day.
As predicted, the number of opiate withdrawal signs increased during the baseline period to a peak of 15.4 ± 0.5 standard error of mean (sem). Clonidine, 6 μg/kg, produced a rapid and significant decrease in opiate withdrawal signs and symptoms from 15.4 ± 0.5 sem to 0.7 ± 0.3 sem paired t test, P<.01 at 120 minutes. Opiate withdrawal signs and symptoms were 0.3 ± 0.2 sem at 180 minutes, 0.2 ± 0.1 sem at 240 minutes, 0.5 ± 0.2 sem at 300 minutes, and 0.8 ± 0.3 sem at 360 minutes. Systolic blood pressure was significantly reduced ( P<.01) from a pre-treatment mean of 128.5 ± 3.6 to 104.4 ± 4.0 mm Hg, as was diastolic blood pressure which decreased from a pre-treatment mean of 88.6 ± 3.7 to 67.4 ± 3.2 mm Hg at 120 minutes after clonidine administration. Diastolic blood pressure was reduced to less than 60 mm Hg at 180 minutes after clonidine administration in two patients. The ARCI ratings were also significantly ( P<.01) reduced from a pre-treatment mean of 12.4 ± 1.l to 6.8 ± 0.6 sem at 120 minutes after clonidine administration.
Relief from subjective distress was significant. On self-rating analogue scales where 70 is the highest score, there were significant ( P<.01) decreases in self-rated nervousness (59.5 ± 2.5 sem to 32.0 ± 2.0 sem at 120 minutes) and irritability (51.5 ± 2.5 to 27.5 ± 2.3 sem at 120 minutes). There were no significant changes noted in self-rating analogue scales for energy or euphoria. There was a significant ( P<.01) decrease in scores reported for the "uninvolved" and "angry" scales. At 120 minutes after clonidine administration, none of the 10 patients stated that they felt the need for methadone or like they were kicking. Placebo had no significant effects on any of the previously mentioned measurements or ratings.
All 10 patients continued to receive clonidine in an in-patient hospital setting. None of the patients chose a return to methadone after their first dose of clonidine. On the first day of clonidine administration, the patients were given 6 μg/kg as a test dose and then 6 μg/kg at bedtime. On the next day and then for nine days, patients were given 17 μg/kg of clonidine in divided doses of 7 μg/kg at 8 a.m., 3 μg/kg at 4 p.m., and 7 μg/kg at 11 p.m. Each day vital signs and nurses' abstinence ratings and self-ratings were carried out. Clonidine doses were held in some cases until the diastolic blood pressure was above 60 mm Hg. There were no significant changes in the abstinence ratings during this 10-day in-patient trial. Six patients, however, complained of difficulty in falling asleep. Dry mouth, sluggishness and occasional bone pain were more infrequent complaints. Mean opiate withdrawal symptoms and signs were 1.8 ± 0.4 sem on Day 2, 0.8 ± 0.2 sem on Day 3, 0.6 ± 0.2 sem on Day 4, 0.2 ± 0.1 sem on Day 5, and 0.1 ± 0.1 sem on Day 6.
Systolic and diastolic blood pressures remained significantly decreased from pre-treatment values throughout the 10 days of 17 μg/kg of clonidine administration. There were no significant increases or decreases in self-rated nervousness, irritability, uninvolvement, anger, fear, euphoria or energy. When necessary, the clonidine dose was decreased to compensate for oversedation or hypotension. All of the 10 patients completed both the acute and 10-day in-patient study. On Days 11, 12 and 13, the clonidine dose was decreased daily by 50 per cent. On Day 14, the patients received no clonidine whatsoever. None of the patients showed any increase in opiate withdrawal signs or symptoms or had the emergence of clonidine withdrawal symptoms using this protocol. On Day 14, all patients were given 1.2 mg of naloxone hydrochloride intravenously to assess residual opiates or dependence. All naloxone tests were negative.
In another paper it was indicated that the 17 μg/kg daily dose of clonidine would block withdrawal effects from maintenance doses of methadone as high as 75 mg/day [ 20] . Most recently we have shown that in treating iatrogenic addiction to drugs such as percodan, the duration of clonidine administration could be reduced by one half [ 21]
With these clinical studies completed we are proposing the following protocol:
Recommended procedure for methadone withdrawal
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Day 0
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Usual dose of methadone
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Day 1
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Clonidine:
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6 μg/kg as test done
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6 μg/kg at bedtime
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Note:
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A smaller and less frequent dosage of clonidine is used on the First day because the long-acting nature of methadone leads to less severe withdrawal symptoms on this day.
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Days 2-10
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Clonidine:
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17 μg/kg divided as follows:
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8 a.m.-7 μg/kg
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3 p.m.-3 μg/kg
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10 p.m.-7 μg/kg
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Note:
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1. A higher dosage is used at bedtime because of the frequency of insomnia as a withdrawal symptom which is not totally controlled by clonidine.
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2. If systolic blood pressure drops below 90 or diastolic below 60 mm Hg, the clonidine dose may be held until the pressure rises and the patient put at bed rest in the supine position.
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3. In general, the peak drop in blood pressure has occurred by two or three hours after the clonidine dose.
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4. It may be necessary in the presence of persistent hypotension or excessive sedation to reduce the clonidine dose.
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5. Additional p.r.n. doses of clonidine may be given up to 0.4 mg/day divided into 2-4 doses.
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Day 11
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Clonidine:
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8 μg /kg divided as follows:
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8 a.m.-3 μg/kg
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3 p.m.-1 μg/kg
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10 p.m.-4 μg/kg
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Day 12
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Clonidine:
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4 μg /kg divided as follows:
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8 a.m.-2 μg /kg
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10 p.m.-2 μg/kg
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Day 13
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Clonidine:
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2 μg/kg at 8 a.m.
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Note:
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Although rebound hypertension does not usually occur even with abrupt clonidine cessation until it has been used for 30 days, we have tapered its use as a precaution.
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Day 14
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No clonidine
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Note:
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If the patient is to be started on a narcotic antagonist such as naltrexone, it would be useful to check at this time for residual opiate dependency by giving naloxone, i.m. or i.v., 1.2-2.0 mg.
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The above protocol can be shortened to six days and the dose of clonidine made somewhat lower in treating withdrawal from shorter-acting narcotics such as heroin, dilaudid or percodan.
The most common symptom reported during the withdrawal regime was difficulty in falling and remaining asleep. Less common complaints were dry mouth, sluggishness, irritability and bone pain. Sedation was common during the first few days but was not usually a problem thereafter. Because of the occurrence of serious psychiatric symptoms in six patients early in our research, all of whom had previous psychiatric histories of major disorders, we have now excluded such patients from the study [ 22] .
Blood pressure should be checked immediately before each clonidine dose and at hourly intervals for two to three hours, or until it stabilizes, after each clonidine dose. Tolazolidine, a clonidine antagonist, as well as i.v. fluids, should be available if the pressure drops too low.
Clonidine has been noted to have mild analgesic effects [ 23] . Thus in withdrawing "medical addicts", there may be no need for analgesia during the withdrawal period, even though the original painful condition persists to some extent. Pain usually returns 24-48 hours after the last clonidine dose but may now be treated with a milder analgesic or lowered doses of the original one.
Our experience to date in following patients after clonidine withdrawal is limited. Preliminary results on a small sample indicate that at six months almost half have returned either to methadone maintenance or to illicit narcotic use. We do not know yet whether clonidine withdrawal affects the development of the protracted abstinence syndrome [ 24] .
Narcotic addiction is both a psycho-social and physiological condition. The high percentage of Viet Nam veterans addicted to heroin while in Viet Nam 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 programme 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 programme contact.
The most frequent question asked by physicians is why we tested clonidine. We originally tested the efficacy of clonidine in opiate withdrawal as a result of studies of the major noradrenergic nucleus, the locus coeruleus (LC) in monkeys and earlier studies by Gold and Zornetzer in rodents [ 25] . The effects of electrical or pharmacological activation of this nucleus was demonstrated to produce changes that resembled those seen in opiate withdrawal [26-28]. Morphine and clonidine blocked the effects of the electrical and pharmacological activation of the LC in primates [26-28]. This suggested that opiate withdrawal may be due, in part, to increased noradrenergic neural activity in areas such as the LC, which are inhibited by both opiates through opiate receptors and clonidine through alpha-adrenergic receptors [ 15] . However, we never directly tested clonidine's efficacy in primate opiate withdrawal. This LC hypothesis is also supported by the similarity of clonidine and opiate withdrawal with respect to effects on vital signs and mood and the noradrenergic hyperactivity reported in clonidine withdrawal [ 29] .
Opiates administered systemically and microiontophoretically turn off the LC by stimulation of inhibitory opiate-receptor sites, causing a reversal of this effect by the opiate antagonist Naloxone [30,31]. Clonidine also inhibits the LC, but by stimulation of a different receptor. This effect is reversed by specific alpha-adrenergic antagonists [ 32] . These data have suggested that opiate interactions with noradrenergic areas such as the LC, regulated by both alpha-adrenergic and opiate receptors, may become activated in opiate withdrawal related panic states and possibly naturally occurring panic states. Although morphine and endogenous opiates and clonidine seem to act on independent receptors within the LC, they have in common a similar depressant effect on overall LC cell activity [30-32]. These and other observations by Aghajanian [ 33] provide support for the hypothesis that the alpha-agonist clonidine suppresses certain signs and symptoms of opiate withdrawal by means of a parallel but independent action on LC cell activity and reverses the critical symptom-generating neurobiological event in withdrawal.
Clonidine is a non-opiate drug which suppresses the signs and symptoms associated with opiate withdrawal. In less than two weeks, suitable patients can be detoxified from methadone maintenance at a rate approaching 100 per cent, whereas the existing method of gradual methadone withdrawal commonly takes three to six months and only about 50 per cent of patients achieve zero dosage. However, as our brief follow-up experience demonstrated, the relapse rate after detoxification with clonidine was about the same as with conventional techniques. We strongly advocate, therefore, the continuation and improvement of post-detoxification counselling techniques accompanied wherever possible by the use of the long-acting narcotic antagonist, naltrexone. Naltrexone provides the blocking effect that may be crucial while the individual is learning to live with no narcotic effect in his or her system. Detoxification with clonidine makes it possible to administer naltrexone to the patient immediately after his or her withdrawal without having to wait the 5 to 10 days usually required for total abstinence after methadone withdrawal. Clonidine can also be useful in treating the medical addict where the need for the narcotic has diminished or where the dose has been increased because of gradually developing tolerance.
Clonidine-aided withdrawal can be also useful for narcotic addicts not going onto methadone maintenance. The patient going into a drug-free programme can begin with detoxification with clonidine without the necessity of undergoing gradual methadone withdrawal which may be discouraging or not available in some residential therapeutic communities. The patient going onto naltrexone can begin this after five days on clonidine without having to wait the additional 5 to 10 days after withdrawal which is necessary if he or she were detoxified with a narcotic. There is therefore a possibility to interrupt relapse episodes. Finally, clonidine may make the steps approach [ 34] easier and encourage methadone programmes to get heroin addicts on the street away from needles and out to work on a stable dose of methadone and, when ready, rapid detoxification with clonidine can lead to the next step, naltrexone.
It would be very advantageous in terms of cost and patient convenience to be able to use clonidine for withdrawal on an outpatient basis, and we are currently about to launch such a study in collaboration with three other centres. Our experience to date indicates that the primary problems are patient compliance with the protocol and the dangers of mixing clonidine in high doses with other drugs. For example, combined use of clonidine and opiates potentiates such effects as sedation, dizziness and postural hypotension. Therefore, such use presents the danger of possible traffic accidents, and physicians using the drug for withdrawal would be advised to use it on an in-patient basis only if possible.
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