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INTRODUCTION

Treatment is central to the reduction of harms incurred

by individuals and the community from opioid depen-

dence. Managed withdrawal, or detoxification, is not in

itself a treatment for dependence (Lipton & Maranda

1983; Mattick & Hall 1996). Rates of completion of with-

drawal tend to be low, and rates of relapse to opioid use

following detoxification are high (Vaillant 1988; Gossop

et al. 1989; Broers et al. 2000), but withdrawal remains

a required first step for many forms of longer-term treat-

ment (Kleber & Riordan 1982). It may also represent the

end point of an extensive period of substitution treatment

such as methadone maintenance. As such, the avail-

ability of managed withdrawal is essential to an effective

and comprehensive treatment system.

For many years, routine procedures involved suppres-

sion of withdrawal with methadone and gradual reduc-

tion of the methadone dose (Kleber & Riordan 1982). For

most of the past three decades, methadone has been the

© 2002 Society for the Study of Addiction to Alcohol and Other Drugs Addiction, 97, 49–58

a 2 -Adrenergic agonists in opioid withdrawal

Linda R. Gowing1, Michael Farrell2, Robert L. Ali1,3 & Jason M. White1,3

Drug and Alcohol Services Council, Parkside, Australia,1 National Addiction Centre, London, UK 2 and Department of Clinical and Experimental Pharmacology,

University of Adelaide, Australia3

Correspondence to:

Linda Gowing

Manager, Evidence-Based Practice Unit

Drug and Alcohol Services Council

161 Greenhill Road

Parkside SA 5063

Australia

Tel: + 61 88274 3388

Fax: + 61 88274 3320,

E-mail: [email protected]

Submitted 7 May 2001;

initial review completed 12 July 2001;

final version accepted 13 August 2001

ABSTRACT

Objectives This paper presents the main findings of a systematic

(Cochrane) review of the effectiveness of a2-adrenergic agonists in

managing opioid withdrawal.

Design The original systematic review included controlled trials that com-

pared a2-adrenergic agonists with another form of treatment (or placebo)

in participants who were primarily opioid-dependent.

Main findings Ten studies compared a treatment regime based on an

a2-adrenergic agonist with one based on reducing doses of methadone.

Withdrawal intensity is similar to, or marginally greater with a2-adrenergic

agonists, but signs and symptoms of withdrawal occur and resolve earlier in

treatment. Participants stay in treatment longer with methadone. The likeli-

hood of completing withdrawal is similar, or slightly less, with clonidine or

lofexidine. Clonidine is associated with more adverse effects than reducing

doses of methadone. Three studies compared the a2-adrenergic agonists,

clonidine and lofexidine. Lofexidine does not reduce blood pressure to the

same extent as clonidine, but is otherwise similar to clonidine.

Conclusions Participants stay in treatment longer with methadone

regimes, which may provide greater opportunity for psychosocial inter-

vention. Methadone regimes may be preferable for withdrawal in out-

patient settings where the risk of relapse to heroin use is high. The use of

methadone may also facilitate transfer to maintenance treatment should

completion of withdrawal become unlikely. For those who are well prepared

for withdrawal and seeking earlier resolution of withdrawal symptoms, a2-

adrenergic agonist treatment may be preferred. Clonidine and lofexidine

appear equally effective for inpatient settings, but the lower incidence of

hypotension makes lofexidine more suited to use in outpatient settings.

KEYWORDS Adrenergic alpha-agonists, opioid dependence, systematic

review, withdrawal syndrome.

RESEARCH REPORT



50 Linda Gowing et al.


main medication used within specialist withdrawal pro-

grammes. However, ambivalence to the use of a drug of

dependence to treat opioid dependence, government

restrictions on prescription of methadone and consumer

dislike of the protracted nature of methadone with-

drawal (Farrell 1994) have, to some extent, limited the

use of methadone in this way. Discovery of the capacity

of the a2-adrenergic agonist, clonidine, to ameliorate

some signs and symptoms of withdrawal led to wide-

spread use of this drug as a non-opioid alternative for

withdrawal treatment (Gossop 1988).

The use of clonidine in the management of opioid

withdrawal has been hampered by side effects of sedation

and hypotension. This, in turn, has led to the investiga-

tion of the effectiveness of other a2-adrenergic agonists

—lofexidine, guanfacine and guanabenz acetate—in the

management of opioid withdrawal, the aim being to find

a drug that has clonidine’s capacity to ameliorate the

signs and symptoms of opioid withdrawal but with fewerside effects.

A variety of other withdrawal treatment approaches

have also been explored in recent years. Approaches

involving the use of opioid antagonists to induce with-

drawal or the use of buprenorphine to suppress with-

drawal have been prominent. These approaches are not

discussed further in this review.

The diversity of withdrawal treatment approaches

and the lack of clear consensus on best practice provided

the basis for a series of systematic reviews relating to the

management of opioid withdrawal and prepared by the

authors under the aegis of the Cochrane Collaboration(Gowing et al. 2000a, b; 2001a; b). This paper presents

the main findings of one of those reviews (Gowing et al.

2001b). It focuses on comparison of the two withdrawal

treatments that are in widespread use, namely reducing

doses of methadone and use of a2-adrenergic agonists.

METHOD

Studies were located for the review by searching multiple

electronic databases and the reference lists of retrieved

studies, reviews and conference abstracts. The relevantpharmaceutical companies (Boehringer Ingelheim and

Britannia Pharmaceuticals) were also contacted.

Studies included in the Cochrane review were con-

trolled clinical trials that compared a2-adrenergic ago-

nists with another form of treatment, or placebo, or that

compared two or more different a2-adrenergic agonists,

for the management of withdrawal in participants who

were primarily opioid dependent.

Studies were analysed on the basis of:

1 Intensity of signs and symptoms and overall with-

drawal syndrome experienced;

2 duration of treatment;

3 completion of withdrawal, and

4 nature and incidence of adverse effects, particularly

hypotension or symptoms of hypotension.

DESCRIPTION OF STUDIES

Twenty-four studies (31 reports), involving 1956 partici-

pants, met the inclusion criteria for the Cochrane review.

This paper focuses on the comparison of a2-adrenergic

agonists with reducing doses of methadone (10 studies)

and lofexidine with clonidine (three studies). The major

characteristics of these 13 studies are summarized in

Table 1.

The requirements of clinical trials, particularly the

need to maintain double-blind conditions, can limit the

flexibility of dose regimens. The loss of flexibility is a

potential source of bias, particularly for comparisonsof a2-adrenergic agonists and reducing doses of

methadone. However, the 13 studies discussed in this

paper all indicated the use of procedures that enabled

the dose of a2-adrenergic agonist to be titrated against

withdrawal severity and side effects. In general, cloni-

dine was commenced at 0.1–0.2 mg/dose, increasing to

a maximum of around 1.0 mg/day, while lofexidine

was commenced at 0.4–0.6 mg/dose increasing to a

maximum of around 2 mg/day.

RESULTS AND DISCUSSION

a2-Adrenergic agonists compared with reducing doses

of methadone

Intensity and pattern of withdrawal

These two medications have very different mecha-

nisms of action and therefore may be expected to have

very different effects on opioid withdrawal. This issue

has been addressed in a number of the studies re-

viewed, with intensity, temporal pattern and/or specific

symptoms of withdrawal all being considered to some

extent.In one study (Senay, Tennant & Washton, Boehringer

Ingelheim GmbH report number U85–0844; unpub-

lished data) 13 of 30 participants treated with clonidine

and 13 of 31 treated with methadone gave ‘intolerable

withdrawal’ as the reason for leaving treatment. In a

related study (Kleber et al. 1985), five of 25 in the cloni-

dine group compared to two of 25 in the methadone

group cited ‘intolerable withdrawal’ as the reason for

dropout. In a third study (Washton & Resnick 1981), two

of 13 in each group gave physical withdrawal as the

primary reason for discontinuing detoxification.



a 2-Adrenergic agonists in opioid withdrawal 51


San et al. (1990) reported significantly higher mean

peak withdrawal scores for groups treated with clonidine

or guanfacine compared to the group treated with

methadone (scores were 8.1, 7.6 and 4.9, respectively, for

a scale with a maximum possible score of 21). Bearn et

al. (1996) reported similar mean peak withdrawal scores

for participants treated with lofexidine or methadone

(scores of 15 and 14, respectively, on a scale with a

maximum possible score of 30). In a second study by San

et al. (1994) scores for withdrawal rated by observers

were slightly higher for the two groups treated with

guanfacine compared to the methadone group on days

11 and 12 (methadone was ceased and guanfacine com-

menced on day nine of treatment). However, on the basis

of participant ratings the intensity of withdrawal was

similar in all three groups.

Kleber et al. (1985) reported 15 of 24 treated with

clonidine and 16 of 23 treated with reducing doses of

methadone used sleep medications during treatment.However, participants in the clonidine group reported

higher self-rated maximal withdrawal, a greater propor-

tion of days in treatment with a high level of withdrawal

and earlier emergence of a high level of withdrawal. San

et al. (1994) reported the average total dose of diazepam

prescribed during treatment was 19.0 mg for partici-

pants treated with methadone, compared to 20.3 mg and

16.3 mg for the two guanfacine groups (difference not

significant).

Data from Kleber et al. (1985) on the mean daily with-

drawal score shows a peak around day 3 in the clonidine

group and day 23 in the methadone group (administra-tion of active methadone ceased on day 20). Withdrawal

scores for the clonidine group had returned to baseline

levels by day 23, while scores remained elevated on day

30 (the last day of data collection) for the methadone

group. Washton & Resnick (1981) also noted that par-

ticipants treated with clonidine reported symptoms

during the first week of treatment, while those treated

with reducing doses of methadone reported symp-

toms following cessation of methadone on day 20 of

treatment.

Bearn, Gossop & Strang (1996) reported higher mean

withdrawal scores on days 2–12 for participants treatedwith lofexidine, and higher scores for participants treated

with methadone from days 13–21 (with methadone

ceased after day 10). The difference was not so clear-

cut in a later study comparing two different lofexidine

regimes with methadone (Bearn, Gossop & Strang 1998).

Around a third of participants in both studies were

concurrently withdrawing from benzodiazepines, which

may have confounded the pattern of withdrawal ob-

served; none the less, the data indicate that withdrawal

signs and symptoms emerged more quickly in partici-

pants treated with lofexidine.

Jiang (1993) reported mean daily withdrawal scores

to be significantly greater in the group treated with

clonidine from days 2–4, and in the group treated

with methadone from days 8–12 (the last 4 days of

methadone treatment). In both groups maximal with-

drawal occurred pretreatment, and declined steadily

during treatment.

San et al. (1990) reported the withdrawal scores for

groups treated with clonidine or guanfacine to be signif-

icantly higher than the group treated with methadone

from day 2 to day 4, with all three drugs being tapered

over 10 days.

Graphs of mean daily withdrawal scores reported by

Howells and colleagues (Howells et al., pers. comm.) show

a very small and progressive decrease in score for both

lofexidine and methadone groups over 10 days of treat-

ment, with mean scores for the lofexidine group consis-

tently 5–10% higher than scores for the methadone

group (the difference was not statistically significant).However, comparison with other studies is confounded by

the circumstances of treatment. The study was con-

ducted in a prison health centre with participants enter-

ing the study after 24–48 hours in custody. The interval

between last opioid use and study entry is uncertain; it is

possible that maximal withdrawal may have occurred

prior to study entry.

Kleber et al. (1985) reported higher levels of appetite

loss, low energy, muscle pains, drowsiness, yawning, dry

mouth and sneezing among participants treated with

clonidine compared with reducing doses of methadone.

However, Washton & Resnick (1981), using the sametreatment regime, reported that major symptomatic

complaints (specifically lethargy, restlessness and insom-

nia) were identical for both groups, and subjective ratings

were indistinguishable. Cami et al. (1985) reported sleep

disturbances and ‘weeping’ were more common in par-

ticipants treated with clonidine, while muscular aching,

flatulence and drowsiness were more common in par-

ticipants treated with methadone. San et al. (1990)

reported sleeplessness, restlessness, muscular pain and

insomnia as the most frequent signs and symptoms in

participants treated with methadone. In comparison, the

most frequent signs and symptoms in the clonidine andguanfacine groups were mydriasis and sleeplessness, fol-

lowed by chills, muscular pain and insomnia in the cloni-

dine group, or muscular pain and restlessness in the

guanfacine group. Howells and colleagues (1999, pers.

comm.) reported scores for feeling cold and aches/pains

were higher for participants treated with lofexidine,

whereas scores for drowsiness were higher for partici-

pants treated with methadone. However, the main items

contributing to scores in both groups were sleep prob-

lems, anxiety/nervousness, irritability, lack of energy,

aches/pains and feeling cold.



© 2 0 0 2 S oc i e t yf or t h e S t ud yof Ad d i c t i ont oAl c oh ol and O t h e r D r ugs

A d d i c t i o n, 9 7 ,4 9 –5 8

Table 1 Summary of characteristics of studies.

Study Methods and setting Participants Intervent

Bearn et al. 1996 Randomized controlled trial, double- n1 = 42, n2 = 44. Opioid dependent (1) Lofex

blind, inpatient by DSM-IV. Stabilized on methadone (2) meth

(around 60 mg/day) for 3 days 10 da

prior to withdrawal twice

Bearn et al. 1998 Non-randomized controlled trial n1 = 19, n2 = 20, n3 = 22. Opioid dependent (1) Meth

(participants able to choose by DSM-IV. Stabilized on methadone, mean (2) lofex

methadone or lofexidine), inpatient (1) 65.5 (2) 65.3 (3) 56.0 mg/day for 3 days (3) lofex

prior to withdrawal

Senay et al., unpublished data Randomized controlled trial, double- n1 = 30, n2 = 31. Al l stabil ized on methadone, (1) Clon

blind, outpatient 20 mg/day (2) meth

Cami et al. 1985 Controlled (nonrandomized?) trial, n1 = 26, n2 = 19. All heroin users, dependent (1) Clon

double-blind, inpatient. Analysis by DSM-III-R. Detoxification preceded 30–4

on 30/45 completing 12 days of admission to drug-free therapeutic community

treatment

Carnwath & Hardman 1998 Randomized controlled trial, double- n1 = 26, n2 = 24. All stabilized on methadone (1) Lofex

blind, home-based (40 mg/day or less) prior to study 0.1 m

last 3

Howells et al. 1999 Randomized controlled trial, double- n1 = 36, n2 = 38. Dependent on heroin or (1) Lofex

(pers. comm.) blind, prison health-care centre methadone 30 m

Jiang 1993 Randomized controlled trial. Not n1 = 100, n2 = 100. Heroin users dependent (1) Clon

all par ticipants had entered by DSM-III-R. ( 1) 67 (2) 80 using orally only (2) taper

treatment voluntarily. Inpatient



© 2 0 0 2 S oc i e t yf or t h e S t ud yof Ad d i c t i ont oAl c oh ol and O t h e r D r ugs

A d d i c t i o n, 9 7 ,4 9 –5 8

Kahn et al. 1997 Randomized controlled trial, double- n1 = 14, n2 = 14. Opiate dependent by history (1) Clon

blind, inpatient and urine screen 1.8 m

Kleber et al. 1985 Randomized controlled trial, double- n1 = 25, n2 = 25. All withdrawing from (1) Clon

blind, outpatient methadone maintenance (20 mg/day or less) (2) Meth

Lin et al. 1997 Randomized controlled trial, double- n1 = 40, n2 = 40. Heroin dependent by (1) Lofexblind, inpatient DSM-IV. 61 used i.v., 9 i.m., 10 by smoking 0.6 m

San et al. 1990 Randomized controlled trial, double- 170 entered study. Recruitment continued (1) Clon

blind, inpatient until 30 in each group had completed 12 over

or more days. Heroin dependent by DSM-III-R

San et al. 1994 Randomized controlled trial, n1 = 75, n2 = 43, n1 = 26. Heroin dependent (1) Cont

inpatient by DSM-III-R. Stabilized on methadone with guanf

dose reduced to (1) 10% or (2 & 3) 50%

of initial dose

Washton & Resnick 1981 Randomized controlled trial, double- n1 = 13, n2 = 13. 19 withdrawing from (1) Clon

blind, outpatient methadone maintenance, 7 withdrawing by 1

from heroin and/or methadone. All stabilized

for 3 weeks on 15–30 mg/day methadone

Abbreviations: max = maximum; i.v. = intravenous; i.m. = intramuscular.



Taken together, the above data indicates that, in

general, retention in treatment is greater for withdrawal

managed with reducing doses of methadone compared to

a2-adrenergic agonists. Two studies by Bearn et al. (1996,

1998) were exceptions to the trend. Both studies com-

pared lofexidine and methadone in an inpatient setting,

with detoxification followed by a period of residential

rehabilitation. The lower incidence of adverse effects with

lofexidine (see section ‘Adverse effects’) and the different

context of detoxification may be explanations for the

equivalent retention rates in this study.

Completion of withdrawal

For six studies, data were reported on the number of

participants who completed withdrawal. Completion of

withdrawal is not a clear-cut outcome, with the result

that studies differ considerably in definitions of comple-

tion (Gowing et al. 2000c). In three studies comple-tion was defined as 10 days opioid-free confirmed by

urine testing (Senay, Tennant & Washton, Boehringer

Ingelheim GmbH report number U85–0844; unpub-

lished data; Kleber et al. 1985), or a negative naloxone

challenge (Washton & Resnick 1981). In a further three

studies the defined outcome was completion of the sched-

uled treatment period (San et al. 1990; Bearn et al. 1996,

1998). Because of the variability in outcome definition,

an overall combined completion rate was not calculated.

In five of the six studies (Washton & Resnick 1981;

Senay, Tennant & Washton, Boehringer Ingelheim GmbH

report number U85–0844; unpublished data; Kleberet al. 1985; Bearn et al. 1996, 1998), the 95% confidence

interval for completion of withdrawal included an odds

ratio of 1. This indicates that, for these five studies, the

difference in rates of completion of withdrawal for

a2-adrenergic agonists compared to reducing doses of

methadone was not statistically significant. For the sixth

study (San et al. 1990) the difference was significant,

with completion of withdrawal being less likely for those

treated with a2-adrenergic agonists (Peto odds ratio 0.29,

95% confidence interval 0.13–0.63). However, lack of

information on the method used to allocate participants

to treatment group and the doubtful adequacy of alloca-tion concealment means that this study is at risk of bias.

Withdrawal from methadone potentially differs from

withdrawal from heroin or other short-acting opioids due

to the longer half-life of methadone, and consequent later

development of withdrawal symptoms. Furthermore,

some people withdrawing from methadone will have

been participating in a period of methadone mainte-

nance treatment, and hence are more likely to be

stabilized in health and social terms, which may facili-

tate successful completion of withdrawal (Gowing et al.



In summary, intensity of withdrawal seems to be

similar for a2-adrenergic agonists and methadone.

Despite their differing mechanisms of action, there do not

seem to be any consistent differences in the types of

symptoms reported. However, the temporal pattern of

withdrawal is very different, with peak intensity occur-

ring much earlier in subjects treated with clonidine or

lofexidine.

Retention in treatment

The duration of treatment was reported, or was able to

be calculated, for four studies. In all cases the mean dura-

tion of treatment was longer for the group treated with

reducing doses of methadone. However, two studies

(Senay, Tennant & Washton, Boehringer Ingelheim

GmbH report number U85–0844; unpublished data;

Kleber et al. 1985) were derived from the same multi-

centre randomized controlled trial in which the totalscheduled treatment period was 30 days, with active

methadone administered for 20 days and active clonidine

for 10 days. One study (Howells et al., pers. comm.)

occurred in a prison setting where cessation of treatment

was influenced by administrative factors more than indi-

vidual response to treatment. In the fourth study (Jiang

1993) only some of the participants in this study had

entered treatment voluntarily; in this context, most par-

ticipants would be constrained to complete treatment.

The differing contexts of the four studies confound inter-

pretation of the apparent difference in absolute duration

of treatment.For one of their studies, San et al. (1990) reported

mean days in treatment for ‘successes’ and ‘failures’ in

each of the treatment groups. While the mean duration

was similar for ‘successes’ in each group (14.7 days for

clonidine, 14.7 days for guanfacine and 14.2 days for

methadone), the mean duration for ‘failures’ was greater

in the group treated with reducing doses of methadone

(5.7 days for clonidine, 4.9 days for guanfacine and 7.3

days for methadone).

An alternative approach to assessing retention

in treatment is through the number of participants who

completed the scheduled period of administration of active medication. Such data were available for four

studies (Senay, Tennant & Washton, Boehringer Ingel-

heim GmbH report number U85–0844; unpublished

data; Kleber et al. 1985; Bearn et al. 1996; Howells et al.,

pers. comm.); in all four studies, participants who

received an a2-adrenergic agonist were less likely to be

retained in treatment until the scheduled period of

administration of active medication had been completed

(combined Peto odds ratio 0.23 with 95% confidence

interval 0.13–0.42).





2000d). The limited data available from the studies

included in this review did not support exploration of this

aspect.

Adverse effects

In addition to their efficacy in suppressing opioid with-

drawal, a2-adrenergic agonists and methadone are likely

to differ in their side effect profile. Of particular concern

are problems associated with blood pressure changes

following administration of a2-adrenergic agonists. Such

changes are unlikely to occur with methadone.

In the study by Senay, Tennant & Washton

(Boehringer Ingelheim GmbH report number U85–0844;

unpublished data) of 30 participants treated with cloni-

dine, 19 had one or more adverse experiences, including

seven who experienced orthostatic hypotension. In com-

parison, of 31 participants treated with reducing doses of

methadone, 11 had one or more adverse experienceswith three experiencing orthostatic hypotension. Other

adverse effects that were more frequent among partici-

pants treated with clonidine (compared to those treated

with methadone) were drowsiness (6/30 versus 0/31)

and fatigue (4/30 versus 1/31). One participant in the

clonidine group (but none from the methadone group)

was withdrawn from the study because of adverse effects

(dizziness, drowsiness and headache).

In the study by Kleber et al. (1985) of 25 participants

treated with clonidine, 18 had one or more adverse expe-

riences, including four who experienced orthostatic

hypotension. In comparison, of 25 participants treatedwith reducing doses of methadone, 10 had one or more

adverse experiences, with none experiencing orthostatic

hypotension. Other adverse effects that were more fre-

quent amongst those treated with clonidine were drowsi-

ness (8/25 versus 0/25), fatigue (6/25 versus 0/25), dry

mouth (3/25 versus 1/25) and insomnia (2/25 versus

0/25). Four participants in the clonidine group (but none

in the methadone group) were withdrawn from the study

because of adverse effects. One participant had their dose

of clonidine reduced because of low blood pressure. The

maximum mean side-effects score was 16.8 for the cloni-

dine group compared to 11.5 for the methadone group.Cami et al. (1985) reported four participants treated

with clonidine, compared with one participant treated

with methadone, experienced orthostatic hypotension.

A graph of daily adverse effects score shows a steady

decline and similar magnitude in the clonidine and

methadone groups from days 1–6 of a regime in which

both drugs were tapered over 10 days. After day six, the

adverse effects score for the methadone group increased,

while the score for the clonidine group continued to

decline.

Jiang (1993) reported 89 of 100 participants treated

with clonidine experienced dizziness on standing, mainly

in the second and third days of treatment when clonidine

doses were at their highest (around 1 mg/day). Both sys-

tolic and diastolic blood pressure decreased in the cloni-

dine group (by no more than 10 mmHg) during the first 4

days of treatment, whereas blood pressure was stable in

the methadone group. Overall scores of side effects were

significantly higher in the clonidine group from days 1–7

(both drugs were tapered over 10 days). The greatest dif-

ference occurred on the second day of treatment, when

the mean side effects score was 8.2 ± 5.5 in the clonidine

group and 1.95 ± 3.91 in the methadone group. The score

subsequently declined steadily in both groups. General

tiredness, weakness in walking, dizziness in standing, dry

mouth and lethargy were reported as the most common

adverse effects in those treated with clonidine.

San et al. (1990) reported significantly lower mean

blood pressure in participants treated with clonidine,compared to those treated with methadone. A significant

difference in mean side effects score was reported for par-

ticipants treated with clonidine on the second and third

days of treatment. The most common adverse effects in

the clonidine group were asthenia, dry mouth, flushing

and mental clouding.

In a comparison between lofexidine and reducing

doses of methadone, Bearn et al. (1996) reported no sig-

nificant difference in mean blood pressures. Two of 42

participants in the lofexidine group experienced dizziness

due to postural hypotension, but both continued treat-

ment on lower doses.Howells and colleagues (Howells et al., pers. comm.)

also compared lofexidine with reducing doses of

methadone. In this study there was no appreciable

change in either heart rate or blood pressure and there

was no significant difference in mean blood pressures for

the two groups.

In the study by Bearn et al. (1998) two different lofex-

idine treatment regimes were compared with reducing

doses of methadone. It was reported that there was no

significant difference in the mean blood pressure for the

two lofexidine groups. Two of 20 participants in the 10-

day group and three of 22 participants in the 5-daygroup experienced side effects, necessitating a reduction

in the dose of lofexidine. None were withdrawn from the

study because of adverse effects.

Comparison of lofexidine with clonidine

While clonidine has been the major a2-adrenergic

agonist used to treat opioid withdrawal, lofexidine has

received attention recently. One of the purported benefits

of lofexidine is a lesser effect on blood pressure.



number of participants who completed withdrawal. In

this study successful withdrawal was defined by an

opioid-free urine sample 4 weeks after the commence-

ment of treatment. On this basis, 17 of 26 (65%)

participants treated with lofexidine compared to 12 of 24

(50%) treated with clonidine successfully completed

withdrawal.

Adverse effects

In the study by Carnwath & Hardman (1998), lofexidine

was compared with clonidine for the management of

opioid withdrawal in a home setting. Significant differ-

ences were reported in three aspects relating to adverse

effects: participants in the lofexidine group received a

mean of 0.5 extra home visits, compared to 1.3 for the

clonidine group; the mean side-effects score was 3.9 in

the lofexidine group, compared to 4.6 for the clonidine

group; and the mean score for ‘feelings of control’ was4.2 for the lofexidine group compared to 3.7 for the cloni-

dine group. Between treatment days 8 and 10, signifi-

cantly more hypotension was reported in the group

treated with clonidine, compared to those treated with

lofexidine, but the incidence of hypotension in each

group was not quantified.

In the study by Kahn et al. (1997), there were 114

reports of adverse effects among participants treated

with lofexidine, compared to 226 reports among partici-

pants treated with clonidine. Significantly lower mean

blood pressure was reported for participants treated

with clonidine from days 5–8 of treatment. Eight of 14treated with lofexidine, compared to 13 of 14 partici-

pants treated with clonidine, experienced postural

hypotension. Drowsiness was experienced by 11 of 14

participants in the lofexidine group and 12 of 14 partic-

ipants in the clonidine group. Two treated with lofexi-

dine, compared to 12 treated with clonidine, felt ‘unwell’

(anergy or weak/tired). Physicians assessed the adverse

effects as interfering with functioning for four of the 14

participants treated with clonidine, but none of the par-

ticipants treated with lofexidine.

Lin et al. (1997) reported omitting doses of medica-

tion due to low blood pressure on 25 of 615 possibleoccasions in 14 participants treated with lofexidine, com-

pared with 45 of 508 occasions in 16 participants

treated with clonidine. Low blood pressure occurred in

19 of 188 patient days for the lofexidine group and 34

of 162 patient days for the clonidine group. The

differences in the number of doses omitted and the

number of patient days of low blood pressure were

statistically significant. However, there was no clinically

significant hypotension, with systolic and diastolic blood

pressure being reduced by around 10 mmHg in both

groups.



Intensity and pattern of withdrawal

Carnwath & Hardman (1998) reported no significant dif-

ference in any parameters for withdrawal managed with

lofexidine compared to clonidine. A graph of mean daily

symptom scores reported by Kahn et al. (1997) for groups

treated with clonidine or lofexidine show an almost

identical pattern of peak withdrawal on day 7 (aftercessation of methadone on day 4), a plateau for 3 days,

then a gradual reduction in the withdrawal score. No

participants in either group experienced severe with-

drawal and no significant differences were detected. Lin

et al. (1997) also recorded almost identical patterns of

withdrawal score for participants treated with lofexidine

and those treated with clonidine. In both groups peak

withdrawal occurred on the second day of treatment and

the score had largely subsided by the end of the fourth

day.

If it is assumed that adjunct medication is prescribed

in response to the presence of withdrawal symptoms,

then the amount of adjunct medication can be used as

an indicator of withdrawal intensity. These data were

available for one study: Kahn et al. (1997) reported

almost identical use of lorazepam as adjunct medication

by participants in the lofexidine and clonidine groups: 10

of 14 in each group used lorazepam on 72 (clonidine)

and 71 (lofexidine) occasions.

Kahn et al. (1997) stated the pattern of individual

signs and symptoms of withdrawal to be similar with

clonidine or lofexidine treatment, with bone pain and

insomnia not responding to either drug. Lin et al. (1997)

also reported no difference between groups treated

with clonidine or lofexidine in terms of predominant

signs and symptoms of withdrawal. They reported that

six items were rated either moderate or severe during the

period of peak withdrawal (days 2 and 3) by more

than 20% of participants. These items were irritability,

agitation, back pain, muscular cramp, yawning and

lacrimation.

Duration of treatment

Of the three studies that compared lofexidine and cloni-

dine, only one (Lin et al. 1997) reported data on the dura-

tion of treatment: participants treated with lofexidine

remained in treatment for a median of five days (range

1–9 days), while those treated with clonidine remained

in treatment for a median of 4 days (range 1–8 days).

This in the context of treatment scheduled to last for

around 10 days.

Completion of withdrawal

Of the three studies that compared lofexidine and cloni-

dine, only one (Carnwath & Hardman 1998) reported the





CONCLUSIONS

The overall intensity of withdrawal associated with a2-

adrenergic agonist treatment is similar to that associated

with reducing doses of methadone. With a2-adrenergic

agonist treatment, the signs and symptoms of with-

drawal occur earlier, within a few days of cessation

of opioid drugs, whereas with reducing doses of

methadone, the signs and symptoms of withdrawal do

not become apparent until methadone doses approach

zero. The signs and symptoms of withdrawal also resolve

at an earlier stage when withdrawal is managed with a2-

adrenergic agonists. Data are limited, but it appears that

clonidine and lofexidine have similar capacity to attenu-

ate the signs and symptoms of opioid withdrawal.

Management of withdrawal with clonidine is associ-

ated with more adverse effects than management

by reducing doses of methadone. Adverse effects are

most severe for the few days of peak withdrawalwhen maximal doses of clonidine are administered. The

adverse effects more commonly associated with clonidine

than with reducing doses of methadone were hypoten-

sion, drowsiness, fatigue, lethargy and dry mouth. There

is currently insufficient information available to compare

lofexidine and methadone in terms of overall adverse

effects, but available information indicates that blood

pressure changes associated with lofexidine are not

significantly greater than those associated with reduc-

ing doses of methadone. Direct comparison of lofexidine

and clonidine indicates that lofexidine is associated with

fewer adverse effects, particularly less hypotensive effects.Management of withdrawal with a2-adrenergic ago-

nists, compared to reducing doses of methadone, is asso-

ciated with similar or lower rates of completion of

withdrawal but those who drop out of treatment tend to

do so earlier, resulting in a shorter average duration of

treatment. Lofexidine treatment is probably associated

with rates of completion of withdrawal at least similar

to rates associated with clonidine withdrawal. Factors

potentially influencing the lower rates of retention in

treatment for a2-adrenergic agonist treatment, compared

to reducing doses of methadone, include the earlier

emergence of withdrawal symptoms, the occurrence of adverse effects (also at an early stage of treatment) and

patient preference for an opioid drug.

Overall, the studies included in this review indicate

that treatment regimes based on the a2-adrenergic ago-

nists clonidine and lofexidine, and those based on the

administration of methadone in reducing doses over a

period of around 10 days, have similar efficacy in the

management of withdrawal from heroin or metha-

done, but participants stay in treatment longer with

methadone regimes and experience fewer adverse effects.

Hence, the choice of treatment regime will be influenced

by patient preference and circumstance as well as the

treatment setting. In many countries, including the

United States, the capacity to prescribe methadone for

people who are opioid dependent is limited by govern-

ment regulations. The findings of this review indicate

that a2-adrenergic agonists provide a good alternative.

The longer average time in treatment associated with

reducing methadone regimes increases the opportunity

for psychosocial interventions during withdrawal. Even if

the withdrawal attempt is unsuccessful, the contact with

treating staff may help the client be better prepared for

subsequent attempts. Reducing methadone regimes may

also be preferable for withdrawal in outpatient settings to

help manage the risk of lapse to heroin use. Furthermore,

if it becomes apparent during a reducing methadone

regime that completion of withdrawal is unlikely, trans-

fer to methadone maintenance treatment would be

facilitated.

On the other hand, for those who are well prepared forwithdrawal and seeking earlier resolution of withdrawal

symptoms, a2-adrenergic agonist treatment may be pre-

ferred. If detoxification is to be followed by naltrexone

maintenance treatment, it is usually necessary for there

to be 5–10 days without opioid use if naltrexone is to be

commenced without significant withdrawal symptoms.

Hence, treatment with a2-adrenergic agonists would also

be preferred over reducing doses of methadone as a

prelude to naltrexone treatment. The demand for in-

patient treatment is often such that the average length of

stay is considerably less than 10 days. In this situation a2-

adrenergic agonist treatment is likely to be prefer red. Forthose clients not tolerant of clonidine or lofexidine,

methadone could still be administered for a few days in

low doses simply to ameliorate withdrawal symptoms,

but there is insufficient evidence to assess the effective-

ness of this approach.

Clonidine and lofexidine appear equally effective for

inpatient settings where the dose is adjusted on a daily

basis to reflect blood pressure and withdrawal severity.

The lower incidence of hypotension makes lofexidine

more suited to use in outpatient settings.

There is a need for further studies of the withdrawal

process both in terms of medications, settings and thelonger term outcomes of withdrawal, with particular ref-

erence to postwithdrawal morbidity and mortality. To this

end, the methodology of withdrawal studies deserves

more attention and greater use of comparable measures,

better description of mode of treatment allocation, stan-

dardization of time frames for measurement and better

descriptions of the psychosocial component of the treat-

ment input. Future meta-analytical studies would be sig-

nificantly assisted by the reporting of such information.

It is also highly desirable for there to be greater research

attention given to the management of withdrawal fol-





lowing methadone maintenance treatment, compared to

treatment following heroin use with or without a short

period of stabilization on methadone.

ACKNOWLEDGEMENTS

During the preparation of this systematic review com-

ments and information were provided by Richard Mattick

(National Drug and Alcohol Research Centre, Uni-

versity of New South Wales, Australia); Maria Chang

(Boehringer Ingelheim, Australia); and Len Cretney

and Jackie Akhurst (Britannia Pharmaceuticals, United

Kingdom). Financial assistance for the work was

provided by the Commonwealth Department of Health

and Aged Care (Australia). All support is gratefully

acknowledged.

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