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Clonidine and the treatment of the opiate withdrawal syndrome
Drug and Alcohol Dependence, 21(1988) 253-259 Elsevier Scientific Publishers Ireland Ltd.
253
Clonidine and the treatment of the opiate withdrawal syndrome M. Gossop Drug Dependence
Clinical Reeearch and Treatment Unit. The Bethlem Royal Hospital and The Maudsby Beckenham, Kent BRS SBX 07.K.1
Hospital
(Received March 14th, 1988) Clonidine is a central alpha adrenergic agonist which can be used to treat the opiate withdrawal syndrome. It has been used in many controlled trials and a substantial body of research evidence is available about its effectiveness in this role. This paper reviews the literature regarding its introduction in the Yale studies, its effectiveness relative to gradual methadone reduction treatments, its side effects, and touches briefly upon its use in conjunction with opiate antagonists. It is concluded that clonidine produces marked reduction of withdrawal symptoms but does not eliminate them; that the pattern of withdrawal symptoms differs from that associated with methadone reduction schemes; that there is some disagreement about the clinical significance of hypotensive and other side effects; and that the drug has interesting possibilities for rapid withdrawal programmes when combined with naltrexone. Key worde: clonidine; opiates; withdrawal; antagonists
Introduction Although first introduced as a nasal decongestant, clonidine has been used principally for its antihypertensive effects. A further, and more recently described property of the drug is its capacity to reduce or suppress withdrawal opiate symptoms. Clonidine appears to alter the opiate withdrawal syndrome by decreasing central nervous system noradrenergic activity. Opiates decrease central noradrenergic activity by depressing the firing rate of the locus coeruleus (LC), but prolonged administration of opiates and LC depression produces an increase in the numbers of alpha-2 and beta-adrenergic binding sites in LC projection areas. Opiate withdrawal is associated with central noradrenergic hyperactivity as reflected by decreased brain noradrenaline levels and increased noradrenaline metabolite levels. Clonidine diminishes noradrenalin release by binding presynaptically to alpha-2 receptors and
reverses the increased noradrenalin turnover during withdrawal. Opiates and clonidine both act at the LC to decrease central noradrenergic function; but whereas opiates bind to opioid receptors and are antagonised by naloxone, clonidine’s actions are mediated by alpha adrenergic receptors and are not antagonised by opioid antagonists. In the first clinical study of clonidine’s effects on withdrawal 5 methadone addicts were given either clonidine followed by placebo, or placebo followed by clonidine. A single dose of 5 rg/kg of clonidine was found to produce a rapid and substantial reduction in observed withdrawal symptoms. Similar reductions were noted in subjective distress ratings and in systolic and diastolic blood pressure [l]. This paper was immediately followed by others with samples of methadone [2] and heroin [3] addicts. Again, 5 pg/kg of clonidine or a placebo was administered in double blind, after the onset of the withdrawal syndrome.
0375-8716/88/$03.50 0 1988 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
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In both the heroin- and methadone dependent groups clonidine produced ‘a rapid, prolonged and significant reduction of opiate signs and symptoms’ [3]. Clonidine was also found to be effective in eliminating withdrawal symptoms and relieving subjective distress within a 2week detoxification programme [4 - 61. One of the largest samples reported by the Yale group is that of Gold and Kleber [7]. As in other studies methadone was abruptly discontinued and the withdrawal syndrome was allowed to develop. At this point, patients were given blind doses of either clonidine or a placebo. The results confirm the earlier findings of a rapid and significant decrease in symptoms after clonidine. Clonidine also reduced (irritability, self-rated distress nervousness and anger). After the experimental blind dose, 100 patients were withdrawn in an open trial over a 14-day period. All but one of the 100 patients completed the 14 day trial. As such, this trial stands as the most successful withdrawal trial to be completed on a sample size of this magnitude and under controlled conditions. Clonidine dose schedules
The drug administration schedule for the treatment of the withdrawal syndrome in the early Yale studies [4,6] is shown below. It gives a clonidine ‘plateau’ between days 1 and 10. On days 11, 12 and 13 the dose of clonidine is reduced by 50% per day and on day 14 no clonidine is given. On day 1,6 rg/kg is given as a test dose followed by 6 pg/kg at bedtime. Between days 2 and 10, the drug is given in doses of 7 I.cg/kg at 08:OO h, 3 pg/kg at 15:00 h and 7 rg/kg at 22:00 h; on day 11, doses of 3 pg/kg, 1 pglkg and 4 pgikg at these times: on day 12, 2 pglkg at 08:OO h and 2 rg/kg at 22:00 h; on day 13, 2 rg/kg at 08:OO h. On day 14 the patient receives no clonidine. The application of such dose schedules should allow for individual variation in response. Washton and Resnick [8], for instance, caution that sensitivity to clonidine’s
hypotensive, sedative and withdrawal-suppressing effects varies widely among individuals. Comparisons of clonidine and methadone
One of the most widely used procedures for withdrawing opiate addicts involves giving gradually reducing doses of oral methadone. This has been described as one of the most effective, safest and most humane methods currently being used [9,10], and it has been suggested that there may be as many as 10 000 patients withdrawing from methadone at any one time in the U.S.A. [6]. Methadone is, therefore the yardstick against which clonidine will be measured, and studies which have been designed to compare clonidine and methadone withdrawal are of particular interest. In one such trial [11,12] subjects who were eligible for the study were randomly assigned to one of two conditions. In the clonidine group, the active drug was given for 16 days followed by 14 days placebo. In the methadone group, the active drug was given for 20 days followed by 10 days placebo. The results showed no difference in success rates for the two conditions. Forty-two percent of the clonidine group were successes, with 39% of the sample in the methadone group achieving abstinence. However, patients receiving clonidine experienced a higher self-rated level of maximum withdrawal symptoms and a higher percentage of days on which self-rated symptoms were high. In nurses’ ratings, the clonidine group scored higher on appetite loss, low energy, muscle pains, drowsiness, yawning, dry mouth and sneezing. Also, the clonidine group tended to drop out during the first week whereas the methadone drop-outs tended to stay until the third week. This may relate to the finding that with clonidine, withdrawal symptoms started earlier but then faded, whereas with methadone, symptoms tend to peak as the drug reaches doses less than 10 mg. In a double blind trial, 4 out of 13 patients completed withdrawal on clonidine vs. 6 out
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of 13 on methadone, with similar ‘major withdrawal complaints’ (lethargy, restlessness and insomnia1 in both groups [13]. The authors conclude that clonidine was not superior to methadone in the numbers of patients able to achieve abstinence. Clonidine has also been compared with methadone in a study of Spanish opiate addicts [14]. Results are given for 30 patients out of a sample of 45 who were originally admitted to the study. The 15 missing patients failed to complete detoxification. Of these, 12 left because ‘they did not want to continue with the research study’, and 8 of these 12 were in the clonidine condition. The other 3 drop-outs completed detoxification only after being transferred to methadone. Of the 15 drop-outs, 11 were from the clonidine condition. The treatment comparison showed no overall difference between groups with regard to withdrawal symptoms, though some differences in the pattern of withdrawal are described. The reduction in symptoms appeared to be greater in the methadone group during the first half of the treatment period, and greater in the clonidine group during the second half. Special groups In many studies, the subjects were not representative of the addict population in treatment. The patients in the study of Charney et al. [15] had been on a methadone maintenance programme for at least 2 years, and each was said to be ‘a member in good standing’ on the programme. The selection of relatively stable and compliant patients also occurred in other studies [2,4,5,15-1181. The good rates of compliance found in these studies may have been influenced by the subject selection processes [19]. Among the stated exclusion criteria noted by Kleber et al. [11] are: current alcohol abuse; current use of sedative/hypnotic drugs, MAO inhibitors, neuroleptics or other antihypertensive drugs; pregnancy; and medical or psychiatric illness that ‘in the judgement of
the investigator’ might put the subject at risk or compromise the trial (examples given include certain cardiovascular conditions, renal or metabolic diseases, schizophrenia and severe affective disorders). Similar criteria are described by others [4,5], and Washton et al. [20] conclude that ‘the low incidence of clonidine side-effects in (their own) study can be attributed to our careful selection of candidates.’ Elsewhere it has been suggested that clonidine may be more effective for patients using methadone than for those addicted to heroin, and for those dependent on relatively low doses [21]. Devenyi et al. [22] recommended that clonidine should be used ‘only in relatively wellmotivated in-patients.’ In one study dose reductions of methadone occurred prior to the beginning of the trial, and all subjects who took part in the study had already successfully been reduced to a dose of 20 mg of methadone at entry; ‘only subjects who were comfortable at this dose were entered into detoxification’ [ll]. It is not known how many patients failed to achieve the considerable reduction (on average, more than half the daily dose), or in what ways they differed from the subjects who were successfully reduced to 20 mg. This sort of selection process is clearly described by the Yale investigators, and Charney et al. [23] acknowledge that the processes operating so as to select certain subjects prior to their trial may have contributed towards the high success rate of detoxification. Hypotensive effects In many studies, clonidine was found to produce significant reductions in both systolic and diastolic blood pressure. Gold et al. have reported drops in mean levels of 124- 106 (systolic), and 85-69 (diastolic) [2], and drops of 130 - 102, and 91- 70. [5]. Decreases of 10 15 mmHg in both systolic and diastolic blood pressure have been reported [8]; and Kleber et al. [24] found that in a group of heroin
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addicts mean levels fell from 111 to 85 (systolic) and 74 to 61 (diastolic). Charney et al. [15] conelude that ‘clonidine had statistically significant - - - - . but clinically negligible effects on systolic and diastolic BP with patients sitting. Clonidine did have clinically important effects upon BP during standing, with 10 out of the 20 patients having at least two doses withheld because systolic pressure during standing was less than 85 mm Hg.’ Other papers describe ‘Unacceptable dizziness and/or sedation while taking only 0.3 mg/kg,’ [21] and it has been reported that ‘most patients’ experienced dizziness on standing 1241,with doses of clonidine needing to be decreased on several occasions to compensate for over-sedation or hypotension [5]. In the Spanish study there were three episodes on which systolic BP dropped to 50 mmHg, and one patient receiving clonidine suffered a transient loss of consciousness [141* There is agreement that clonidine’s hypotensive effects can be successfully managed in a hospital setting [5,20]. It has also been suggested that tolazoline, a clonidine antago nist, as well as intravenous fluids, should be available if blood pressure drops too low [S]. There is less agreement about clonidine’s potential for treating addicts in an out-patient rather than a hospital setting. Washton and Resnick [8] suggest that in some in-patient studies, the dose of clonidine was sufficiently high to reduce withdrawal symptoms but only at the cost of profound hypotension and sedation in certain cases [4], and that in some patients it may be difficult to achieve a balance between a dose level adequate for the relief of withdrawal symptoms and one which avoids introducing undesirable side-effects. There is also a need for caution because of the safety implications for non-hospitalised patients, e.g. driving, operating machinery, and in clonidine’s interactive effects with other drugs, including alcohol 1151. Earlier reports acknowledged that clonidine’s sideeffects may present dangers of traffic accidents and recommended that it should be
used ‘on an in-patient basis only if possible’ [6,25]. However, in one trial, hypotension was said ‘not to be a notable problem’ in outpatient clonidine detoxification, and Kleber et al. [ll] suggest that the medical risks associated with clonidine treatment can be well managed within routine clinical practice by the following procedures: 1. The hy~tensive response requires monitoring of blood pressure and dosage adjustments based on the blood pressure. 2. Sedation necessitates supervision of transport to and from the detoxification site. 3. The use of illicit drugs and their interaction with clonidine should be monitored by history and the use of daily urine screening. Other side-effects of clonidine Of the unpleasant effects described in the early elonidine withdrawal studies the most common are lethargy and insomnia [7,13]. Dry mouth, sluggishness, depression and bone pain have also been noted during opiate withdrawal trials [5]. More recent investigations have listed appetite loss, low energy, muscle pains, drowsiness, yawning, dry mouth and sneezing [12]. In a comparison of methadone and clonidine, 7 out of 14 patients in the clonidine group were removed from the study because they were rated as ‘experiencing unacceptable side-effects’ compared to 1 out of 11 in the methadone group [ll]; 2 of the clonidine subjects experienced immediate severe side-effects that prevented them from continuing beyond a couple of days. Many of these side-effects are also components of the opiate withdrawal syndrome itself, and it is difficult to differentiate between side-effects of clonidine and underlying withdrawal symptoms which have not been fully suppressed, Several studies report that clonidine reduced, but did not completely remove withdrawal symptoms 181. However, certain symptoms may be directly attributable to clonidine since sedation, inhibition of rhinorrhea and laerimation, hypotension, bra-
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dycardia and hypothermia have been demonstrated in both humans and animals not receiving opiates [26 - 281. The most common complaints made by addicts are of lethargy and insomnia. Patients ‘almost invariably’ complain of these [29]. Insomnia should be regarded as a comparatively serious side-effect since addicts find sleep difficulties one of the most distressing aspects of withdrawal from drugs [30,31], and it may often lead to patients prematurely discharging themselves from treatment with a greatly increased risk of relapse. One attempt to cope with this problem of insomnia has been the use of hypnotics, including flurazepam [14], and chloral hydrate and flurazepam [24]. Other studies refer less specifically to the valuable role of supplementary sedative-hypnotic medication [8,11]. When used as an antihypertensive drug, clonidine has been anecdotally reported to induce hallucinations [32], and hypermania after abrupt discontinuation [33]. Psychotic symptoms were exacerbated by the drug during an experimental antipsychotic treatment [34]. One of the few opiate withdrawal studies to report the occurrence of such sideeffects is by Kleber [S]: ‘Because of the occurrence of serious psychiatric symptoms in 6 patients early in our research, all of whom had previous psychiatric histories of major disorders’, such patients were specifically excluded from this and most other Yale studies. Perhaps more worrying is the suggestion that clonidine may in itself be a potential drug of abuse. Clonidine has been shown to have opiate-like effects in animal studies [35], and to support intravenous self-administration in primates [36]. There have also been suggestions that clonidine might produce euphoria and lead to dependence in humans [37,38], though this was strongly denied by other workers [39,40]. One interesting study that allowed addicts to self-administer the drug found that clonidine did not differ from placebo either in the number of choices or in total capsules taken, though the absolute difference was in the
direction of greater self-administration of the active drug [41]. There is no evidence in this study to that clonidine has suggest euphoriant effects or that it is likely to be attractive as a drug of abuse. Clonidine in combination with opiate antagonists
One advantage that clonidine has over its opioid competitors is that it can be used in combination with opioid antagonist drugs [4,5]. The use of post-withdrawal naltrexone was found to produce a significantly higher rate of continued abstinence in the immediate postwithdrawal period than clonidine withdrawal alone [42]. The authors suggest that the high post-withdrawal relapse rate among clonidine subjects should serve as a caution to those who have unrealistic expectations about the role of this drug in the treatment of drug addiction. Naltrexone after-care has also been found to be highly effective with certain highly motivated patients such as addicted business executives and physicians [43]. Clonidine alone does not reduce the duration of the opiate withdrawal syndrome, and 10 days of clonidine administration may be required to suppress the withdrawal symptoms produced by longer-acting opiates such as methadone [44]. The combined (simultaneous) use of clonidine and naltrexone has been used to achieve a more rapid detoxification [45]. In a further study, combined clonidine and naltrexone treatment was used to withdraw patients from methadone in 4-5 days: 38 out of 40 completed the withdrawal programme successfully, though the majority were also given flurazepam for night-time sedation [23]. More recently, combined clonidine and naltrexone treatment was used to withdraw 14 heroin addicts over 5 days in an out-patient day setting [24]. Subjects experienced some degree of withdrawal discomfort, especially during the first 2 days of treatment. For all patients the most persistent symptoms were restlessness, anxiety, muscular aches, craving,
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insomnia, and hot and cold flushes. In one case muscular aching was treated with diazepam. Patients also noted sedation on the second and third day. Conclusions In both open- and double-blind trials clonidine has been found to produce a rapid and prolonged reduction of withdrawal symptoms. This reduction in symptoms is sufficiently acceptable to addicts for many to complete detoxification. However, although clonidine reduces withdrawal severity, it does not completely eliminate symptoms. In many studies patients were given additional medication (usually hypnotics1 to modify residual symptoms. Also, although clonidine produces an improvement in self-rated withdrawal distress, this may be less marked than the improvement shown by observer ratings. When compared to existing methadone withdrawal procedures, clonidine and methadone produce similar overall reductions in withdrawal symptomatology. There are, however, differences in the pattern of withdrawal response to the two drugs. Patients experience more withdrawal symptoms in the first few days of clonidine treatment, whereas methadone patients experience more discomfort at a later stage. Although several authors refer to the superiority of clonidine as a withdrawal option, this general assertion is not supported by the evidence. In certain specific respects, clonidine may have advantages over methadone. For instance, it may be used in conjunction with antagonist drugs in a way which methadone cannot. The use of clonidine as a detoxification agent followed immediately by naltrexone after-care has been shown to be useful with some patients, though it is unclear how many addicts would find this acceptable. Perhaps more interestingly, there is evidence to suggest that combined naltrexonelclonidine treatment may permit a more rapid detoxification than either clonidine alone or methadone alone. Clonidine has hypotensive effects which
may restrict the manner in which it can be used. There is some disagreement in the literature as to the extent and severity of these effects. Some papers suggest that the hypotensive effects are either unimportant or can be easily managed; other papers have reported marked difficulties in some patients. The potential problems associated with hypotensive side-effects are sufficiently worrying as to suggest a need for caution in interpreting these results. Associated with this is that clonidine detoxification requires a considerable degree of medical back-up. There appears to be marked individual variation in response to the drug. In order to achieve a balance between adequate suppression of withdrawal symptoms and an avoidance of sedation or hypotensive side-effects, treatment requires relatively close medical supervision. This may limit the range of situations in which clonidine can be safely used. Clonidine is an interesting addition to the available treatments for the opiate withdrawal syndrome, and it seems likely that it will establish an important place for itself in this role. However, it has not shown itself to be clearly superior to existing treatments, and it carries its own disadvantages. Acknowledgments The author would like to thank Professor Herbert Kleber for his helpful comments on the uses of clonidine, and the British Medical Research Council who made available financial support for this review of the literature. The material presented and opinions expressed, however, are those of the author and not of the British Medical Research Council. References M.S. Gold, D.E. Redmond and H.D. Kleber. Lancet, i (1978) 929. M.S. Gold, D.E. Redmond and H.D. Kleber, Lancet, ii (1978) 599. M.S. Gold, D.E. Redmond and H.D. Kleber, Psycbiatry, 136 (1979) 100. M.S. Gold et al., J. Am. Med. Assoc., 243 (1980) 343.
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M.S. Gold et al., Drug Alcohol Depend., 6 (19801201. H.D. Kleber, M.S. Gold and C.E. Riordan, U.N. Bull. Narcot., 32 (19801 1. M.S. Gold and H.D. Kleber, in: L. Harbans and S. Fielding (Eds.1. Psychopharmacology of Clonidine, Allan Ft. Liss, New York, 1981, pp. 299-306. A.K. Washton and R.S. Resnick, in: L. Harbans and S. Fielding fEds.1, Psychopharmacology of Clonidine. Allan R. Liss, New York, 1981, pp. 277-284. M. Gossop, A. Johns and L. Green, Br. Med. J., 293 (19881 103. H.D. Kleber, in: J.H. Lowinson and P. Ruiz (Eds.1, Substance Abuse: Clinical Problems and Perspectives, Williams and Wilkins. Baltimore, 1981. H.D. Kleber et al., Arch. Gen. Psychiatry, 42 (19851 391. B.J. Rounsaville, T. Kosten and H. Kleber. J. Nerv. Ment. Dis., 173(21(19851 103. A.M. Washton and R.B. Resnick, Lancet, i (19801 1297. J. Cami et al., Clin. Pharmacol. Ther., 38 (1985) 336. D.S. Charney et al., Arch. Gen. Psychiatry, 38(111 (19811 1273. M.S. Gold et al. Am. J. Psychiatry, 137 (19801375. T.W. Uhde, D.E. Redmond and H.D. Kleber Psychiatr. Res., 2 (1980137. M.S. Gold et al., N. Engl. J. Med., 302 (19801 1421. H. Agren, Acta Psychiatr. Stand., 73 (1986) 91. A.M. Washton, R.B. Resnick and R.A. Rawson, Lancet, i (19801 1078. A.M. Washton and R.B. Resnick, Am. J. Psychiatr., 137 (19801 1121. P. Devenyi, A. Mitwalli and W. Graham, Can. Med. Assoc. J. 127 (19821 1009. D.S. Charney, G.R. Heninger and H.D. Kleber, Am. J. Psychiatr., 143 (19861831. H.D. Kleber et al., Am. J. Drug Alcohol Abuse, 13 (1987) 1.
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M.S. Gold et al., Drug Alcohol Depend., 8 (19811307. C.T. Dollery et al., Clin. Pharmacol. Ther., 19 (1975) 11. W.B. Pickworth, L.G. Sharpe and V.N. Gupta, Eur. J. Pharmacol., 81 (19821 551. R. Laverty and K.M. Taylor, Br. J. Pharmacol., 356 (19691253. M.S. Gold and A. Dackis, Arzneim. Forsch., (1983) 155. M.R. Gossop, B.P. Bradley and R.K. Brewis, Drug Alcohol Depend., 10 (19821 177. M.R. Gossop and B.P. Bradley, Drug Alcohol Depend., 13 (19841 191. M.J. Brown, D. Salmon and M. Rendell. Ann. Int. Med., 93 (19801456. G.D. Tollefson, J. Clin. Psychopharmacol., 1 (1981193. L.E. Adler et al., Am. J. Psychiatry., 139 (19821 110. L. Paalzow, J. Pharmacy Pharmacol., 26 (19741361. W.L. Woolverton, W.D. Wessinger and R.L. Balster. Psychopharmacology, 77 (1982117. J.S. Yudkin, Lancet, i (1977) 546. Treatment of Opiate-Withdrawal Symptoms (Editorial), Lancet, ii (19801349. A. Korczyn, Lancet, ii (19801649. M.S. Gold et al. Lance& ii (19801 1078. K.L. Preston, G.E. Bigelow and Y.A. Liebson. Clin. Pharmacol. Ther., 38 (19851 219. R.A. Rawson et al., Clonidine Hydrochloride Detoxification from Methadone Treatments: The Value of Naltrexone Aftercare. California Community Health Projects, 1980. A.M. Washton, M.S. Gold and A.C. Pottash, (19841 Naltrexone in addicted physicians and business executives. in: L.S. Harris (Ed), Problems of Drug Dependence. NIDA, Rockville, MD, 1984, pp. 185- 190. D.S. Charney et al., Arch. Gen. Psychiatry., 38 (1981) 1273. C.E. Riordan and H.D. Kleber, Lancet, i (19801 1079.
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Clonidine and the treatment of the opiate withdrawal syndrome M. Gossop Drug Dependence
Clinical Reeearch and Treatment Unit. The Bethlem Royal Hospital and The Maudsby Beckenham, Kent BRS SBX 07.K.1
Hospital
(Received March 14th, 1988) Clonidine is a central alpha adrenergic agonist which can be used to treat the opiate withdrawal syndrome. It has been used in many controlled trials and a substantial body of research evidence is available about its effectiveness in this role. This paper reviews the literature regarding its introduction in the Yale studies, its effectiveness relative to gradual methadone reduction treatments, its side effects, and touches briefly upon its use in conjunction with opiate antagonists. It is concluded that clonidine produces marked reduction of withdrawal symptoms but does not eliminate them; that the pattern of withdrawal symptoms differs from that associated with methadone reduction schemes; that there is some disagreement about the clinical significance of hypotensive and other side effects; and that the drug has interesting possibilities for rapid withdrawal programmes when combined with naltrexone. Key worde: clonidine; opiates; withdrawal; antagonists
Introduction Although first introduced as a nasal decongestant, clonidine has been used principally for its antihypertensive effects. A further, and more recently described property of the drug is its capacity to reduce or suppress withdrawal opiate symptoms. Clonidine appears to alter the opiate withdrawal syndrome by decreasing central nervous system noradrenergic activity. Opiates decrease central noradrenergic activity by depressing the firing rate of the locus coeruleus (LC), but prolonged administration of opiates and LC depression produces an increase in the numbers of alpha-2 and beta-adrenergic binding sites in LC projection areas. Opiate withdrawal is associated with central noradrenergic hyperactivity as reflected by decreased brain noradrenaline levels and increased noradrenaline metabolite levels. Clonidine diminishes noradrenalin release by binding presynaptically to alpha-2 receptors and
reverses the increased noradrenalin turnover during withdrawal. Opiates and clonidine both act at the LC to decrease central noradrenergic function; but whereas opiates bind to opioid receptors and are antagonised by naloxone, clonidine’s actions are mediated by alpha adrenergic receptors and are not antagonised by opioid antagonists. In the first clinical study of clonidine’s effects on withdrawal 5 methadone addicts were given either clonidine followed by placebo, or placebo followed by clonidine. A single dose of 5 rg/kg of clonidine was found to produce a rapid and substantial reduction in observed withdrawal symptoms. Similar reductions were noted in subjective distress ratings and in systolic and diastolic blood pressure [l]. This paper was immediately followed by others with samples of methadone [2] and heroin [3] addicts. Again, 5 pg/kg of clonidine or a placebo was administered in double blind, after the onset of the withdrawal syndrome.
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In both the heroin- and methadone dependent groups clonidine produced ‘a rapid, prolonged and significant reduction of opiate signs and symptoms’ [3]. Clonidine was also found to be effective in eliminating withdrawal symptoms and relieving subjective distress within a 2week detoxification programme [4 - 61. One of the largest samples reported by the Yale group is that of Gold and Kleber [7]. As in other studies methadone was abruptly discontinued and the withdrawal syndrome was allowed to develop. At this point, patients were given blind doses of either clonidine or a placebo. The results confirm the earlier findings of a rapid and significant decrease in symptoms after clonidine. Clonidine also reduced (irritability, self-rated distress nervousness and anger). After the experimental blind dose, 100 patients were withdrawn in an open trial over a 14-day period. All but one of the 100 patients completed the 14 day trial. As such, this trial stands as the most successful withdrawal trial to be completed on a sample size of this magnitude and under controlled conditions. Clonidine dose schedules
The drug administration schedule for the treatment of the withdrawal syndrome in the early Yale studies [4,6] is shown below. It gives a clonidine ‘plateau’ between days 1 and 10. On days 11, 12 and 13 the dose of clonidine is reduced by 50% per day and on day 14 no clonidine is given. On day 1,6 rg/kg is given as a test dose followed by 6 pg/kg at bedtime. Between days 2 and 10, the drug is given in doses of 7 I.cg/kg at 08:OO h, 3 pg/kg at 15:00 h and 7 rg/kg at 22:00 h; on day 11, doses of 3 pg/kg, 1 pglkg and 4 pgikg at these times: on day 12, 2 pglkg at 08:OO h and 2 rg/kg at 22:00 h; on day 13, 2 rg/kg at 08:OO h. On day 14 the patient receives no clonidine. The application of such dose schedules should allow for individual variation in response. Washton and Resnick [8], for instance, caution that sensitivity to clonidine’s
hypotensive, sedative and withdrawal-suppressing effects varies widely among individuals. Comparisons of clonidine and methadone
One of the most widely used procedures for withdrawing opiate addicts involves giving gradually reducing doses of oral methadone. This has been described as one of the most effective, safest and most humane methods currently being used [9,10], and it has been suggested that there may be as many as 10 000 patients withdrawing from methadone at any one time in the U.S.A. [6]. Methadone is, therefore the yardstick against which clonidine will be measured, and studies which have been designed to compare clonidine and methadone withdrawal are of particular interest. In one such trial [11,12] subjects who were eligible for the study were randomly assigned to one of two conditions. In the clonidine group, the active drug was given for 16 days followed by 14 days placebo. In the methadone group, the active drug was given for 20 days followed by 10 days placebo. The results showed no difference in success rates for the two conditions. Forty-two percent of the clonidine group were successes, with 39% of the sample in the methadone group achieving abstinence. However, patients receiving clonidine experienced a higher self-rated level of maximum withdrawal symptoms and a higher percentage of days on which self-rated symptoms were high. In nurses’ ratings, the clonidine group scored higher on appetite loss, low energy, muscle pains, drowsiness, yawning, dry mouth and sneezing. Also, the clonidine group tended to drop out during the first week whereas the methadone drop-outs tended to stay until the third week. This may relate to the finding that with clonidine, withdrawal symptoms started earlier but then faded, whereas with methadone, symptoms tend to peak as the drug reaches doses less than 10 mg. In a double blind trial, 4 out of 13 patients completed withdrawal on clonidine vs. 6 out
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of 13 on methadone, with similar ‘major withdrawal complaints’ (lethargy, restlessness and insomnia1 in both groups [13]. The authors conclude that clonidine was not superior to methadone in the numbers of patients able to achieve abstinence. Clonidine has also been compared with methadone in a study of Spanish opiate addicts [14]. Results are given for 30 patients out of a sample of 45 who were originally admitted to the study. The 15 missing patients failed to complete detoxification. Of these, 12 left because ‘they did not want to continue with the research study’, and 8 of these 12 were in the clonidine condition. The other 3 drop-outs completed detoxification only after being transferred to methadone. Of the 15 drop-outs, 11 were from the clonidine condition. The treatment comparison showed no overall difference between groups with regard to withdrawal symptoms, though some differences in the pattern of withdrawal are described. The reduction in symptoms appeared to be greater in the methadone group during the first half of the treatment period, and greater in the clonidine group during the second half. Special groups In many studies, the subjects were not representative of the addict population in treatment. The patients in the study of Charney et al. [15] had been on a methadone maintenance programme for at least 2 years, and each was said to be ‘a member in good standing’ on the programme. The selection of relatively stable and compliant patients also occurred in other studies [2,4,5,15-1181. The good rates of compliance found in these studies may have been influenced by the subject selection processes [19]. Among the stated exclusion criteria noted by Kleber et al. [11] are: current alcohol abuse; current use of sedative/hypnotic drugs, MAO inhibitors, neuroleptics or other antihypertensive drugs; pregnancy; and medical or psychiatric illness that ‘in the judgement of
the investigator’ might put the subject at risk or compromise the trial (examples given include certain cardiovascular conditions, renal or metabolic diseases, schizophrenia and severe affective disorders). Similar criteria are described by others [4,5], and Washton et al. [20] conclude that ‘the low incidence of clonidine side-effects in (their own) study can be attributed to our careful selection of candidates.’ Elsewhere it has been suggested that clonidine may be more effective for patients using methadone than for those addicted to heroin, and for those dependent on relatively low doses [21]. Devenyi et al. [22] recommended that clonidine should be used ‘only in relatively wellmotivated in-patients.’ In one study dose reductions of methadone occurred prior to the beginning of the trial, and all subjects who took part in the study had already successfully been reduced to a dose of 20 mg of methadone at entry; ‘only subjects who were comfortable at this dose were entered into detoxification’ [ll]. It is not known how many patients failed to achieve the considerable reduction (on average, more than half the daily dose), or in what ways they differed from the subjects who were successfully reduced to 20 mg. This sort of selection process is clearly described by the Yale investigators, and Charney et al. [23] acknowledge that the processes operating so as to select certain subjects prior to their trial may have contributed towards the high success rate of detoxification. Hypotensive effects In many studies, clonidine was found to produce significant reductions in both systolic and diastolic blood pressure. Gold et al. have reported drops in mean levels of 124- 106 (systolic), and 85-69 (diastolic) [2], and drops of 130 - 102, and 91- 70. [5]. Decreases of 10 15 mmHg in both systolic and diastolic blood pressure have been reported [8]; and Kleber et al. [24] found that in a group of heroin
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addicts mean levels fell from 111 to 85 (systolic) and 74 to 61 (diastolic). Charney et al. [15] conelude that ‘clonidine had statistically significant - - - - . but clinically negligible effects on systolic and diastolic BP with patients sitting. Clonidine did have clinically important effects upon BP during standing, with 10 out of the 20 patients having at least two doses withheld because systolic pressure during standing was less than 85 mm Hg.’ Other papers describe ‘Unacceptable dizziness and/or sedation while taking only 0.3 mg/kg,’ [21] and it has been reported that ‘most patients’ experienced dizziness on standing 1241,with doses of clonidine needing to be decreased on several occasions to compensate for over-sedation or hypotension [5]. In the Spanish study there were three episodes on which systolic BP dropped to 50 mmHg, and one patient receiving clonidine suffered a transient loss of consciousness [141* There is agreement that clonidine’s hypotensive effects can be successfully managed in a hospital setting [5,20]. It has also been suggested that tolazoline, a clonidine antago nist, as well as intravenous fluids, should be available if blood pressure drops too low [S]. There is less agreement about clonidine’s potential for treating addicts in an out-patient rather than a hospital setting. Washton and Resnick [8] suggest that in some in-patient studies, the dose of clonidine was sufficiently high to reduce withdrawal symptoms but only at the cost of profound hypotension and sedation in certain cases [4], and that in some patients it may be difficult to achieve a balance between a dose level adequate for the relief of withdrawal symptoms and one which avoids introducing undesirable side-effects. There is also a need for caution because of the safety implications for non-hospitalised patients, e.g. driving, operating machinery, and in clonidine’s interactive effects with other drugs, including alcohol 1151. Earlier reports acknowledged that clonidine’s sideeffects may present dangers of traffic accidents and recommended that it should be
used ‘on an in-patient basis only if possible’ [6,25]. However, in one trial, hypotension was said ‘not to be a notable problem’ in outpatient clonidine detoxification, and Kleber et al. [ll] suggest that the medical risks associated with clonidine treatment can be well managed within routine clinical practice by the following procedures: 1. The hy~tensive response requires monitoring of blood pressure and dosage adjustments based on the blood pressure. 2. Sedation necessitates supervision of transport to and from the detoxification site. 3. The use of illicit drugs and their interaction with clonidine should be monitored by history and the use of daily urine screening. Other side-effects of clonidine Of the unpleasant effects described in the early elonidine withdrawal studies the most common are lethargy and insomnia [7,13]. Dry mouth, sluggishness, depression and bone pain have also been noted during opiate withdrawal trials [5]. More recent investigations have listed appetite loss, low energy, muscle pains, drowsiness, yawning, dry mouth and sneezing [12]. In a comparison of methadone and clonidine, 7 out of 14 patients in the clonidine group were removed from the study because they were rated as ‘experiencing unacceptable side-effects’ compared to 1 out of 11 in the methadone group [ll]; 2 of the clonidine subjects experienced immediate severe side-effects that prevented them from continuing beyond a couple of days. Many of these side-effects are also components of the opiate withdrawal syndrome itself, and it is difficult to differentiate between side-effects of clonidine and underlying withdrawal symptoms which have not been fully suppressed, Several studies report that clonidine reduced, but did not completely remove withdrawal symptoms 181. However, certain symptoms may be directly attributable to clonidine since sedation, inhibition of rhinorrhea and laerimation, hypotension, bra-
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dycardia and hypothermia have been demonstrated in both humans and animals not receiving opiates [26 - 281. The most common complaints made by addicts are of lethargy and insomnia. Patients ‘almost invariably’ complain of these [29]. Insomnia should be regarded as a comparatively serious side-effect since addicts find sleep difficulties one of the most distressing aspects of withdrawal from drugs [30,31], and it may often lead to patients prematurely discharging themselves from treatment with a greatly increased risk of relapse. One attempt to cope with this problem of insomnia has been the use of hypnotics, including flurazepam [14], and chloral hydrate and flurazepam [24]. Other studies refer less specifically to the valuable role of supplementary sedative-hypnotic medication [8,11]. When used as an antihypertensive drug, clonidine has been anecdotally reported to induce hallucinations [32], and hypermania after abrupt discontinuation [33]. Psychotic symptoms were exacerbated by the drug during an experimental antipsychotic treatment [34]. One of the few opiate withdrawal studies to report the occurrence of such sideeffects is by Kleber [S]: ‘Because of the occurrence of serious psychiatric symptoms in 6 patients early in our research, all of whom had previous psychiatric histories of major disorders’, such patients were specifically excluded from this and most other Yale studies. Perhaps more worrying is the suggestion that clonidine may in itself be a potential drug of abuse. Clonidine has been shown to have opiate-like effects in animal studies [35], and to support intravenous self-administration in primates [36]. There have also been suggestions that clonidine might produce euphoria and lead to dependence in humans [37,38], though this was strongly denied by other workers [39,40]. One interesting study that allowed addicts to self-administer the drug found that clonidine did not differ from placebo either in the number of choices or in total capsules taken, though the absolute difference was in the
direction of greater self-administration of the active drug [41]. There is no evidence in this study to that clonidine has suggest euphoriant effects or that it is likely to be attractive as a drug of abuse. Clonidine in combination with opiate antagonists
One advantage that clonidine has over its opioid competitors is that it can be used in combination with opioid antagonist drugs [4,5]. The use of post-withdrawal naltrexone was found to produce a significantly higher rate of continued abstinence in the immediate postwithdrawal period than clonidine withdrawal alone [42]. The authors suggest that the high post-withdrawal relapse rate among clonidine subjects should serve as a caution to those who have unrealistic expectations about the role of this drug in the treatment of drug addiction. Naltrexone after-care has also been found to be highly effective with certain highly motivated patients such as addicted business executives and physicians [43]. Clonidine alone does not reduce the duration of the opiate withdrawal syndrome, and 10 days of clonidine administration may be required to suppress the withdrawal symptoms produced by longer-acting opiates such as methadone [44]. The combined (simultaneous) use of clonidine and naltrexone has been used to achieve a more rapid detoxification [45]. In a further study, combined clonidine and naltrexone treatment was used to withdraw patients from methadone in 4-5 days: 38 out of 40 completed the withdrawal programme successfully, though the majority were also given flurazepam for night-time sedation [23]. More recently, combined clonidine and naltrexone treatment was used to withdraw 14 heroin addicts over 5 days in an out-patient day setting [24]. Subjects experienced some degree of withdrawal discomfort, especially during the first 2 days of treatment. For all patients the most persistent symptoms were restlessness, anxiety, muscular aches, craving,
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insomnia, and hot and cold flushes. In one case muscular aching was treated with diazepam. Patients also noted sedation on the second and third day. Conclusions In both open- and double-blind trials clonidine has been found to produce a rapid and prolonged reduction of withdrawal symptoms. This reduction in symptoms is sufficiently acceptable to addicts for many to complete detoxification. However, although clonidine reduces withdrawal severity, it does not completely eliminate symptoms. In many studies patients were given additional medication (usually hypnotics1 to modify residual symptoms. Also, although clonidine produces an improvement in self-rated withdrawal distress, this may be less marked than the improvement shown by observer ratings. When compared to existing methadone withdrawal procedures, clonidine and methadone produce similar overall reductions in withdrawal symptomatology. There are, however, differences in the pattern of withdrawal response to the two drugs. Patients experience more withdrawal symptoms in the first few days of clonidine treatment, whereas methadone patients experience more discomfort at a later stage. Although several authors refer to the superiority of clonidine as a withdrawal option, this general assertion is not supported by the evidence. In certain specific respects, clonidine may have advantages over methadone. For instance, it may be used in conjunction with antagonist drugs in a way which methadone cannot. The use of clonidine as a detoxification agent followed immediately by naltrexone after-care has been shown to be useful with some patients, though it is unclear how many addicts would find this acceptable. Perhaps more interestingly, there is evidence to suggest that combined naltrexonelclonidine treatment may permit a more rapid detoxification than either clonidine alone or methadone alone. Clonidine has hypotensive effects which
may restrict the manner in which it can be used. There is some disagreement in the literature as to the extent and severity of these effects. Some papers suggest that the hypotensive effects are either unimportant or can be easily managed; other papers have reported marked difficulties in some patients. The potential problems associated with hypotensive side-effects are sufficiently worrying as to suggest a need for caution in interpreting these results. Associated with this is that clonidine detoxification requires a considerable degree of medical back-up. There appears to be marked individual variation in response to the drug. In order to achieve a balance between adequate suppression of withdrawal symptoms and an avoidance of sedation or hypotensive side-effects, treatment requires relatively close medical supervision. This may limit the range of situations in which clonidine can be safely used. Clonidine is an interesting addition to the available treatments for the opiate withdrawal syndrome, and it seems likely that it will establish an important place for itself in this role. However, it has not shown itself to be clearly superior to existing treatments, and it carries its own disadvantages. Acknowledgments The author would like to thank Professor Herbert Kleber for his helpful comments on the uses of clonidine, and the British Medical Research Council who made available financial support for this review of the literature. The material presented and opinions expressed, however, are those of the author and not of the British Medical Research Council. References M.S. Gold, D.E. Redmond and H.D. Kleber. Lancet, i (1978) 929. M.S. Gold, D.E. Redmond and H.D. Kleber, Lancet, ii (1978) 599. M.S. Gold, D.E. Redmond and H.D. Kleber, Psycbiatry, 136 (1979) 100. M.S. Gold et al., J. Am. Med. Assoc., 243 (1980) 343.
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M.S. Gold et al., Drug Alcohol Depend., 6 (19801201. H.D. Kleber, M.S. Gold and C.E. Riordan, U.N. Bull. Narcot., 32 (19801 1. M.S. Gold and H.D. Kleber, in: L. Harbans and S. Fielding (Eds.1. Psychopharmacology of Clonidine, Allan Ft. Liss, New York, 1981, pp. 299-306. A.K. Washton and R.S. Resnick, in: L. Harbans and S. Fielding fEds.1, Psychopharmacology of Clonidine. Allan R. Liss, New York, 1981, pp. 277-284. M. Gossop, A. Johns and L. Green, Br. Med. J., 293 (19881 103. H.D. Kleber, in: J.H. Lowinson and P. Ruiz (Eds.1, Substance Abuse: Clinical Problems and Perspectives, Williams and Wilkins. Baltimore, 1981. H.D. Kleber et al., Arch. Gen. Psychiatry, 42 (19851 391. B.J. Rounsaville, T. Kosten and H. Kleber. J. Nerv. Ment. Dis., 173(21(19851 103. A.M. Washton and R.B. Resnick, Lancet, i (19801 1297. J. Cami et al., Clin. Pharmacol. Ther., 38 (1985) 336. D.S. Charney et al., Arch. Gen. Psychiatry, 38(111 (19811 1273. M.S. Gold et al. Am. J. Psychiatry, 137 (19801375. T.W. Uhde, D.E. Redmond and H.D. Kleber Psychiatr. Res., 2 (1980137. M.S. Gold et al., N. Engl. J. Med., 302 (19801 1421. H. Agren, Acta Psychiatr. Stand., 73 (1986) 91. A.M. Washton, R.B. Resnick and R.A. Rawson, Lancet, i (19801 1078. A.M. Washton and R.B. Resnick, Am. J. Psychiatr., 137 (19801 1121. P. Devenyi, A. Mitwalli and W. Graham, Can. Med. Assoc. J. 127 (19821 1009. D.S. Charney, G.R. Heninger and H.D. Kleber, Am. J. Psychiatr., 143 (19861831. H.D. Kleber et al., Am. J. Drug Alcohol Abuse, 13 (1987) 1.
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