RATIONALE FOR THE USE OF LOFEXIDINE IN OPIATE WITHDRAWAL

Opiates and 2 adrenergic agonists inhibit the sympathetic nervous system in the
midbrain
In a study of rats, both morphine and clonidine inhibit firing of noradrenergic
cells of the locus coeruleus and C1 adrenergic cells of the rostroventrolateral
medulla (an area thought to be involved in sympathetic tone maintenance:
inhibition leads to hypotension and bradycardia). Naloxone precipitated
opiate withdrawal activates these cells (Baraban et al 1995)
Clonidine, initially developed as a drug to treat hypertension, is a centrally acting 2
adrenergic agonist. It has been found to alleviate symptoms of opiate withdrawal
(Gold et al 1978)
The side effects of clonidine in opiate withdrawal include marked hypotension,
sedation and dry mouth.
Lofexidine, a vasoactive agent structurally related to clonidine and also a centrally
acting 2 adrenergic agonist was initially developed as a potential antihypertensive
agent. It has only a weak effect on lowering blood pressure, and so the possibility that
it might be more useful in opiate withdrawal was considered.
In a comparative study, it was confirmed that clonidine is associated with a higher
incidence of side effects (dry mouth, sedation and hypotension) than lofexidine (Lopez
& Mehta 1984)

LOFEXIDINE - BASIC PHARMACOLOGY

Lofexidine in opiate withdrawal

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Pharmacodynamics
Centrally and peripherally acting 2 adrenergic agonist
(?Also has 1 adrenergic agonist activity at higher doses)

Pharmacokinetics
Following one oral dose of 0.32mg given to 6 normal male subjects (Midgley et al
1982)
Peak plasma level

3 hours (range 2-5 hours)

Protein binding
Unchanged
Metabolites
Total

Extensive
40%
40-50%
80-90%

Half-lives
t1/2
t1/2

2.9 hours (range 1.3 - 3.7 hours)

14.8 hours (range 9.0 - 18.3 hours)

Metabolism
Unchanged
Major metabolites
Minor metabolite

12% of dose
2,6 dichlorophenol, in 2 glucuronide conjugates
Ethylenediamine derivative

Excretion
Urine

85% (71-94%)

Faeces

6hrs
12 hrs
24 hrs

28.7% of total dose

48.4% of total dose
66.9% of total dose

5% of total dose

LOFEXIDINE - CLINICAL PHARMACOLOGY

Actions

Lofexidine in opiate withdrawal

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Central 2 adrenergic agonist activity (sympathetic inhibition)

central hypotensive activity (weak)
inhibition of opiate withdrawal autonomic hyperactivity
Peripheral 2 adrenergic agonist activity
peripheral intestinal antisecretory activity
peripheral vascular involvement
reduces intraocular pressure in animals, via reduced arterial supply
may be effective in vasospasm of the menopause (hot flushes)
Indications
Management of opiate withdrawal
(hypertension)
(hot flushes)
Cautions

Severe coronary insufficiency

Recent myocardial infarction
Cerebrovascular disease
Marked bradycardia
Renal impairment
History of depression (if chronic use of lofexidine contemplated)
Pregnancy and breastfeeding

Withdraw gradually over 2-4 days to reduce the risk of rebound hypertension
Side effects
Drowsiness
Dry mucous membranes
dry mouth, throat, nose
Hypotension
Bradycardia
Sedation and coma in overdose

USE OF LOFEXIDINE IN OPIATE WITHDRAWAL

Lofexidine in opiate withdrawal

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Indication
Patient dependent on opiates wishing to detoxify
Starting on abrupt withdrawal of opiates
1.
Abrupt discontinuation
2.
Withdrawal syndrome induced by naloxone / naltrexone
Starting at the end of a methadone detoxification to alleviate residual symptoms
During methadone detoxification
As precursor of opiate abstinence assisted by naltrexone
Type of Patient
Highly motivated patient wishing to abstain for life from opiate use
Extremely ambivalent patient who wants a quick fix
Patient naive to opiate treatment / early on in opiate career, for whom a quick
detoxification might abort a drug-using career
Inpatient vs outpatient
Outpatient
Good social supprt
Patient highly motivated
Patient likely to be co-operative / reliable
Patient willing to tolerate discomfort
No medical complication

Inpatient
Poor social support
Ambivalent / unmotivated
Patient uncooperative/complaining
Patient reluctant to accept discomfort
Medical complication

Caution
There are reports of lofexidine diversion. There are several possible reasons:
Unscrupulous dealers are selling the drug under another name (eg ecstacy)
patients are carrying out their own detoxes
1. out of a false sense of control
2. because they are reluctant to engage statutory agencies
3. when supplies of the opiate of choice have dried up temporarily (eg run out of
money)
4. as a method of sensitizing themselves, so that the next hit will be more powerful

EFFECTS OF LOFEXIDINE ON OPIATE WITHDRAWAL SYMPTOMS

Lofexidine in opiate withdrawal

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Withdrawal symptoms against which lofexidine is effective

Effects mediated through the sympathetic nervous system

Lacrimation (watery eyes)

Rhinorrhoea (runny nose)
Sweating
Diarrhoea
Chills
Piloerection (gooseflesh)
Hypersalivation

Withdrawal symptoms against which lofexidine is not effective

Effects probably mediated through the endorphin systems
Bone and muscle pain
a.
Failure of gating mechanisms
b.
Naltrexone arthralgia
Insomnia
Effects mediated through the dopaminergic system
Anxiety
Dysphoria
Restlessness
Effects probably mediated through sensitization
Craving

STUDIES OF EFFICACY OF LOFEXIDINE IN OPIATE WITHDRAWAL

Gold et al 1981
Lofexidine in opiate withdrawal

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15 chronic methadone addicts

opiate addicts > 1 year
methadone addicts > 6 months
all expressed interest in discontinuation
only methadone in urine
inpatient study
36 hours abstinent
Given 3g/kg lofexidine
Reduction in withdrawal symptoms 120 mins after dose of lofexidine
No reduction in bp
All 15 completed detox
Main complaint was difficulty falling and / or staying asleep

Washton et al 1981
15 Methadone dependent patients
Doses 0.1mg bd, increasing to 0.4mg qds
Methadone stopped on day 2
10/15 completed detox
Drug reported as decreasing insomnia, pain and lethargy
Side efects of dry mouth and mild drowsiness

STUDIES OF EFFICACY OF LOFEXIDINE IN OPIATE WITHDRAWAL

Washton et al 1983
30 healthy adult male volunteers
Addicted > 2 years
26 subjects on methadone 10-45mg/day (mean 22.1)
4 subjects on LAAM
Lofexidine in opiate withdrawal

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Self-administered regime lofexidine 0.1mg qds increasing as required to 2.0mg/day

(0.5mg qds)
Reports of reduced lacrimation, rhinorrhoea, sweating, diarrhoea, chills, myalgia,
stomach cramps
Some reports of reduced anxiety and restlessness
21 completed (70%)
7/9 dropouts cited opiate craving or not ready to detoxify as the reason
Side effects of dry mouth and mild drowsiness
No lowering of bp (mean 115/76 before lofexidine; 114/76 at maximum doses)
no dizziness, lightheadedness, oversedation
Wylie & Stewart 1995
Specialist unit, outpatient detox
Group A
Lofexidine regime - pilot study
Lofexidine 0.2mg bd, by 0.2mg bd to 1.2mg bd
+ chlordiazepoxide 25mg 6hrly prn
+ chloral hydrate 2g nocte prn
16/30 patients offerred it took it, 13 entered
7/13 (54%) completed ( 2 iv heroin users + temaz; 3 methadone; 2 df118)
Group B
Retrospective casenote review of 24 pts who had undergone detox with standard
regime
chlordiazepoxide 25mg qds + cophenotrope i tds (diphenoxylate 2.5mg, atropine
25g)
4/24 (17%) completed
Comparison of 7/13 in lofexidine group with 4/24 in standard group is misleading
NB ALL THESE STUDIES ARE OPEN UNCONTROLLED STUDIES
ASPECTS OF USE OF LOFEXIDINE IN CLINICAL PRACTICE

Tendency to use a protocol

Standard treatment, can be carried out by nurses and inexperienced doctors
Inflexible

Lofexidine in opiate withdrawal

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 Rationale not necessarily soundly based in science or even good clinical practice
Not clear how to proceed when patients clinical experience deviates from the
protocol

Preparation for lofexidine detoxification

Substance misuse assessment
Ensure that the patient is dependent on opiates
history of opiate use and withdrawal symptoms; urine drug screen shows the
presence of an opiate
Physical examination
assess cardiovascular, renal and hepatic function status with physical
examination (esp pulse and bp) and blood tests; ECG if necessary
Assess whether detox should be carried out as outpatient or inpatient
Clarify the role of the detox in the treatment of the patient
ie assess motivation of the patient and devise an aftercare plan

Initiation of treatment
Unclear whether to start at low or high dose
Tendency to start with 0.2mg bd.
a.
Low dose allows early detection of hypotension.
Also may be appropriate if long acting opiate such as methadone has
not been cleared from the body
b.
High dose allows the patient to gain early relief from symptoms
Unclear whether should reduce to low dose methadone (around 20mg) prior to
starting or stop abruptly from high dose (50-100mg)
Unclear whether should change from methadone to diamorphine for 3 days prior to
initation of treatment, or from diamorhine to methadone
Adopt optimistic therapeutic stance

ASPECTS OF USE OF LOFEXIDINE IN CLINICAL PRACTICE

During treatment
Titrate dose to appearance of symptoms: currently up to a maximum of 2.4mg daily
(?risk of aggravating withdrawal symptoms at higher doses, if 1 adrenergic
agonist activity)
Lofexidine in opiate withdrawal

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 Monitor pulse and blood pressure daily

Be willing to treat symptoms that would not be expected to respond to lofexidine
with adjunctive, non-opiate therapy
a.
anxiety:
oxazepam;
b.
bone pain:
paracetamol or a NSAID
c.
muscle cramps:
quinine sulphate
d.
diarrhoea:
imodium
Monitor for illicit opiate use

After treatment completed

Reduce dose of lofexidine slowly over 2-3 days to avoid risk of rebound
hypertension
Encourage the patient to persist with aftercare arrangements

Lofexidine in opiate withdrawal

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