Information about use of clonidine in the treatment of narcotic withdrawal.

Fråga: Information about use of clonidine in the treatment of narcotic withdrawal.

Sammanfattning: In summary, clonidine is effective in the treatment of narcotic withdrawal, especially if patients are carefully selected for this method of narcotic detoxification. Results of in-patients studies are better than those of out-patients studies. Clinicians and patients should be aware that even the smoothest expectable detoxification is not entirely symptom free.

Svar: Clonidine, an alpha-adrenergic agonist has been used to suppress symptoms of opiate withdrawal since 1978 (1). Both in-patient (1-5) and out-patient (6,7) methods of opiate detoxification were studied. Clonidine has been found very effective in rapid detoxification from narcotics before starting treatment with naltrexone (8). Hypothesis for mechanism of action are discussed by Gold in reference number 9.

IN-PATIENT STUDIES: There are 2 basic protocols that have been followed, with some modifications, in the studies or case reports to-date. One protocol, developed by Kleber and Gold (2) for methadone detoxification is as follows:

Day 0: usual dose of methadone;

Day 1: 6 ug/kg test dose, 6 ug/kg at bedtime;

Day 2-10: 17 ug/kg/day divided as follows: 7 ug/kg in the morning, 3 ug/kg in the afternoon and 7 ug/kg in the evening;

Day 11: 8 ug/kg/day divided as follows: 3 ug/kg in the morning, 1 ug/kg in the afternoon and 4 ug/kg at bedtime;

Day 12: 4 ug/kg/day divided as follows: 2 ug/kg in the morning and 2 ug/kg at bedtime;

Day 13: 2 ug/kg in the morning.

Note for Day 2-10: 1) If systolic blood pressure (BP) drops bellow 90 or diastolic BP below 60 mmHg, clonidine should be held until the pressure rises. The patient should rest in the supine position. 2) In general, the peak drop in BP occurs 2-3 hours after clonidine dose. 3) If hypotension is persistent or if patient is excessively drowsy, clonidine dose might have to be reduced. 4) Additional prn doses of clonidine may be given up to 0.4 ug/day in 2-4 divided doses.

The other protocol was reported by Charney (3) is as follows: Day 1 (24-48 hrs after the last dose of methadone): clonidine 5 ug/kg: 2 doses

Day 5-10: individualized doses 3 times daily up to 10-20 ug/kg/day.

Day 8-13 (last 2-3 days): gradual decrease to "no clonidine".

Doses of clonidine and duration of treatment can be reduced when treating withdrawal from shorter acting narcotics such as hydrocodone, oxycodone, and others (10).

OUT-PATIENT STUDIES: Washton et al (6) treated 59 patients wihtdrawing from methadone (5-40 mg/day) with clonidine. Twenty of the patients received clonidine in conjunction with gradual methadone dose reduction and the remaining 39 patients received clonidine after abrupt termination of the methadone. All patients were instructed to take clonidine 0.1 mg every 4-6 hours and gradually increase it up to 1.2 mg/day. Patients actually took 0.3-1.2 mg/day (average 0.8 mg/day). Methadone was decreased by 5-10 mg/week in the clonidine-methadone group. The duration of clonidine treatment in the group where methadone was discontinued abruptly was 10 days. The duration of treatment in the other group is not stated. Washton concluded that clonidine is a safe and effective method of treatment of narcotic withdrawal. He reported 80 per cent success rate following abrupt withdrawal of 5-40 mg of methadone. This success rate was much higher than that reported for gradual methadone withdrawal. However, the success rate was measured only in terms of the patient´s ability to stay off narcotics for the 10 days since the methadone was stopped.

Kleber et al (7) reported a study of 49 patients withdrawing from 20 mg of methadone. Twenty five of those were treated with gradual reduction (1 mg/day) of methadone. The remaining 24 of patients were instructed to take clonidine according to the following schedule (after abrupt discontinuation of methadone): Day 1: clonidine 0.3 mg; Day 2: clonidine 0.4-0.6 mg; Day 3: clonidine 0.4-0.7 mg; Day 4: clonidine 0.5-0.8 mg; Day 5-10: clonidine 0.6-1 mg; Day 11-15: 20-25 per cent decrease in dose of clonidine daily; Day 16-30: placebo. In this study success rate was measured by being drug free for 10 days after the end of the study. It was about equal for the 2 groups, about 40 per cent. One third of the 40 per cent were reported to be drug free at 6 months follow up.

The most commonly reported SIDE EFFECTS in all studies are: difficulty in falling asleep, dry mouth and sedation. Systolic and diastolic BPs were decreased in most patients and dose of clonidine had to be reduced or held in some of the patients. It is therefore important to check the BP before each dose is given. It was also observed in the early studies that clonidine can precipitate serious psychiatric symptoms in patients who had history of psychiatric disorders (11). In the later studies, history of psychiatric problems became one of the exclusion criteria (2-8). The other exclusion criteria (in most studies) were: chronic or acute cardiac disorders, renal or metabolic diseases, moderate to severe hypertension and pregnancy. Patients on tricyclic antidepressants were also excluded (7), probably after Haggerty´s report (12) of a case of "unsuccessfull" meperidine withdrawal using clonidine in a patient on amitriptyline. Eventhough this is only a case report it is not unlikely that amitriptyline can antagonize the action of clonidine in the treatment of narcotic withdrawal.

The one situation in which clonidine has been shown to be most effective, is the rapid detoxification from narcotics before treatment with naltrexone (8,13). In a double blind study Charney et al (8) observed 11 patients in whom methadone was abruptly discontinued and who were given clonidine followed by naltrexone. Seven patients remained drug free and 3 patients chose to continue on naltrexone after discharge. At 4 and 12 months follow-up only 1 patient reverted to narcotic use. Another study by Gold et al (13) of clonidine-naloxone treatment confirmed the usefulness of this approach.

In order to maximize the effectiveness of clonidine treatment of narcotic withdrawal, it is essential to select patients carefully and to provide non-drug support during and after the withdrawal from narcotics. Rounsaville (14) examined characteristics and behaviours of 49 patients during withdrawal, 25 of whom were randomly assigned to methadone and 24 to clonidine withdrawal. In this study only about 40 per cent of those who entered the study were able to successfully complete the detoxification program using either regimen. During the detoxification phase very few patients experienced no symptoms or medication side effects, and most patients experienced difficulty sleeping, feeling "blah" and craving on at least one occasion. Thus Rounsaville urges clinicians to be aware that addicts with even the smoothest expectable withdrawal course will not be entirely symptom free and that the patients should be informed of this before undergoing detoxification. In the clonidine group the differences between patients in the "successfull" and the "failure " groups were evident in the first week of treatment. Thus if a patient is unable to tolerate the clonidine withdrawal after a week, the clinician should concider an alternate treatment. In addition, the patients whose last dose of methadone was 10 mg or less did considerably better than patients on higher dose. Thus it might be beneficial to reduce methadone to 10 mg before starting clonidine withdrawal. 1 Gold MS, Redmond DE Jr, Kleber HD: Clonidine in opiate withdrawal. Lancet 1978; I: 929-930 2 Kleber HD, Gold MS, Riordan CE: The use of clonidine in detoxification from opiates. Bull Narc 1980; 32: 1-10 3 Charney DS, Sternberg DE, Kleber HD, Heninger GR, Redmond E Jr: The clinical use of clonidine in abrupt withdrawal from methadone. Effects on blood pressure and specific signs and symptoms. Arch Gen Psychiatry 1981; 38: 1273-1277 4 Gold MS, Pottash AC, Sweeney DR, Kleber HD: Opiate withdrawal using clonidine. A safe, effective and rapid nonopiate treatment. JAMA 1980; 243: 343-346 5 Uhde TW, Redmond DE Jr, Kleber HD: Clonidine suppresses the opioid abstinence syndrome without clonidine-withdrawal symptoms: a blind inpatient study. Psychiatry Res 1980; 2: 37-47 6 Washton AM, Resnick RB: Clonidine for opiate detoxification: outpatient clinical