Neuropsychiatric aspects of sedative drug withdrawal

HUMAN PSYCHOPHARMACOLOGY, VOL. 3, 171-180 (1988)

Neuropsychiatric Aspects of Sedative Drug Withdrawal JOHN DUNCAN, MA, MRCP, Research Fellow INSEG (Institute of Neurology, National Hospital, National Society for Epilepsy Research Group), Institute of Neurology, London WCI N 3BG; and Chalfont Centre f o r Epilepsy, Buckinghamshire, UK

The withdrawal syndromes after discontinuance of alcohol, barbiturates, benzodiazepines and other sedative drugs, such as chloral and paraldehyde, are all similar. The severity of a withdrawal reaction is largely determined by the daily dose, the duration of administration and the rate of fall of the drug levels after withdrawal, as well as the propensity of the individual patient. The time course of a withdrawal reaction is determined by the drug’s clearance. Alcohol has a half-life of a few hours; withdrawal symptoms may develop within 6-8 hours of abstinence and convulsions in 12-48 hours. After discontinuance of short- or medium-acting barbiturates (half-life 8-40 hours) symptoms may develop in 1-3 days, followed by convulsions and delirium after 3-8 days. Symptoms and seizures may develop in the 1-10 days after withdrawal of benezodiazepines.

In patients with no prior history of epilepsy the types of seizures most commonly induced by drug withdrawal are generalized convulsions, but partial seizures are not uncommon if there is a focal cerebral lesion, or a previous history of partial seizures. Paroxysmal activity and photosensitivity may occur after barbiturate withdrawal in non-epileptics, more commonly in severe withdrawal reactions. Similar EEG changes may be seen after alcohol and benzodiazepine withdrawal, but photosensitivity does not appear to have been shown to be a feature of the benzodiazepine withdrawal syndrome.

K E Y woRDs-Alcohol, benzodiazepines, barbiturates, withdrawal symptoms, seizures, electroencephalogram.

INTRODUCTION

The withdrawal symptoms from sedative drugs have received considerable attention in recent years, but withdrawal seizures and the EEG features of sedative drug withdrawal have been studied less.

This review considers the symptoms, seizures and EEG features that may occur on the withdrawal of alcohol, barbiturates and benzodiazepines, and the similarities and differences between the withdrawal syndromes of these agents.

ALCOHOL

Symptoms of alcohol withdrawal

The clinical features of alcohol withdrawal were in- vestigated in a detailed experimental study by Isbell et al. (1955). Symptoms developed within 12 hours of a significant drop in alcohol intake. Minor symptoms, occurring after cessation of regular alcohol intake for 16 days, included tremor, gastric upset, sweating, anxiety and weakness. A more severe clinical picture was seen in patients who drank more alcohol for longer, before discontinu-

ance. The above symptoms were more intense, and vomiting, insomnia, fever, tachycardia, hyper- tension, increased reflexes, visual and auditory hallucinations, delirium and seizures were noted, resolving over 1-8 days.

Other reported symptoms and signs have included anorexia; pruritus; headache; muscle pains; myoclonic jerks; palpitations; depression; disordered visual, auditory and tactile perception; dizziness; restlessness; agitation; nystagmus and inability to walk (Klett et al., 1971; Gross et al . , 1974; Bjorkquist et al., 1976; Thompson, 1978; Drake, 1983; Flygenring et al., 1984). Alcohol has a half-life of a few hours and the alcohol withdrawal syndrome evolves gradually. Minor symptoms appear 6-8 hours after a substantial fall in blood alcohol level, and in the mild case resolve over the next day or so. More severe cases worsen over the following 24 hours with the development of hallucinations, delirium tremens and seizures. It is estimated that 80 per cent of alcohol withdrawals result in only mild symptoms, 15 per cent are of moderate severity and 5 per cent develop delirium tremens. Delirium tremens develops 1-6 days after alcohol withdrawal, lasts 2-4 days and has a mortality of 5-10 per cent (Hillbom and Hjelm- .lager, 1984; Lerner and Fallon, 1985).

0885-6222~88/030171-10$05.00 0 1988 by John Wiley & Sons, Ltd. Accepted 29 April 1988

172 J. DUNCAN

Alcohol withdrawal seizures

In a person who is not epileptic, a seizure occurring after alcohol withdrawal is an indication of a major withdrawal reaction. Usually this only occurs after continuous intoxication for several days, but occasionally is noted after alcohol intoxication for less than 24 hours (Hillbom, 1980). The overall incidence of seizures amongst patients attending an inpatient alcohol withdrawal unit has been estimated at 10 per cent (Hilllbom and Hjelm-Jager, 1984). Other estimates very from 1 per cent, in a community-based study, to 15 per cent (Whitfield et al., 1978; Chan, 1985). Such figures obviously depend critically on the criteria for admission and the definition of alcohol withdrawal. If seizures occur after alcohol withdrawal they commonly do so at 24-48 hours (Kalinowsky, 1942; Isbell et al., 1955; Giove and Gastaut, 1965; Hillbom and Hjelm-Jager, 1984). In a study of 241 patients with alcohol withdrawal seizures, in 50 per cent the onset of seizures was between 13 and 24 hours after drinking stopped, and in 90 per cent the onset was between 7 and 48 hours (Victor and Brausch, 1967).

Up to 40 per cent of patients with alcohol withdrawal seizures develop delirium tremens (Thompson, 1978). In Hillbom’s study (1980) the incidence being 21 of 277 patients (7.6 per cent). The seizure onset usually precedes, but may occur during or even after, the delirium (Pohlisch, 1928; Kalinowsky, 1942; Thompson, 1978). In Victor and Brausch’s study of 241 cases, 100 had a single seizure, 133 had repeated seizures (usually two to four) and eight developed status epilepticus.

Alcohol abuse is commonly associated with seizures. In one study, about 40 per cent of patients with seizures presenting to city hospital emergency rooms had a history of alcohol abuse, and in 24 per cent the seizures were thought due to alcohol withdrawal (Earnest and Yarnell, 1976). In the remainder, head injuries sustained as a consequence to intoxication and poor compliance with prescribed antiepileptic drugs (AEDs) appeared to be important mechanisms (Earnest and Yarnell, 1976; Hillbom, 1980). In other studies the proportion of seizures caused by alcohol withdrawal ranged from 0 to 24 per cent (Chan, 1985). This wide range is a result of studying different populations and differing selection criteria. In patients with a pre- existing seizure disorder, alcohol abuse, especially withdrawal, is associated with an exacerbation of seizures (Victor and Brausch, 1967; Mattson et al., 1975; Chan, 1985). In these cases poor compliance

with prescribed medication is often an additional fact or.

The type of seizure occurring on alcohol withdrawal is usually a generalized convulsion (Kalinow- sky, 1942; Isbell et al., 1955; Victor and Brausch, 1967; Deisenhammer et al., 1984; Chan, 1985). Focal seizures occurred in 12 of 241 cases studied by Victor and Brausch (1967). Eight of these 12 had known focal cerebral lesions, and the remaining four had had numerous head injuries. Other studies confirm that focal seizures may be precipitated by alcohol withdrawal if there is a prior history of such seizures or a focal cerebral lesion (Giove and Gastaut, 1965; Earnest and Yarnell, 1976; Dauben and Adams, 1977; Nai-Shin, 1980; Deisenhammer et al., 1984).

Electroencephalographic findings in alcohol withdrawal

The electroencephalograms (EEGs) of most patients who have seizures only after alcohol withdrawal are normal. In the study of Victor and Brausch (1967) 21 of 130 EEGs were abnormal. Four of these 21 returned to normal in under 2 weeks, two had a previous history of unprovoked seizures and three had a history of head injury, leaving 12 patients with persistently abnormal records. Other studies agree with this finding of interictal epileptiform activity (IEA) in less than 10 per cent of the EEG records of persons with seizures occurring only after alcohol withdrawal, in contrast with IEA in the EEG records of 50 per cent of patients with seizures not precipitated by alcohol withdrawal (Giove and Gastaut, 1965; Deisen- hammer et al., 1984; Chan, 1985).

EEG abnormalities after alcohol withdrawal may be only short-lived. Spikes, sharp waves (SSW) and rhythmic paroxysmal discharges were noted 15-19 hours after alcohol withdrawal (Wikler et al., 1956). In a study of 14 volunteers, with IEA apparent on their EEGs, there was a suppression of activity while blood alcohol levels were rising or at a peak and, in two cases, a rebound increase in IEA 12 hours later (Mattson et al., 1975). Patients with pre- existing focal cerebral lesions who develop focal motor seizures on alcohol withdrawal have been found to have focal epileptiform discharges which do not persist after recovery from the alcohol withdrawal period (Chatrian et al., 1964; Dauben and Adams, 1977; Nai-Shin, 1980).

SEDATIVE DRUG WITHDRAWAL 173

Photosensitivity has been found to occur transiently after alcohol withdrawal (Lloyd-Smith and Gloor, 1961; Karpati et al., 1963; Victor and Brausch, 1967). In Victor and Brausch’s study, 35 of 84 patients developed photosensitivity after withdrawal of alcohol, compared with one of 50 of a control group with cryptogenic epilepsy. In the alcoholic group the development of photosensitivity was not a significant risk factor for the development of withdrawal seizures. In this investigation photosensitivity was rather loosely defined as photomyoclonus, photoconvulsions or paroxysmal EEG activity, and the incidence of strictly defined photoconvulsive response was not given. Environmental photic stimulation from television sets has been reported to precipitate generalized convulsions in alcoholics, after one or two days abstinence (De Keyser et al., 1984).

BARBITURATES

Symptoms of barbiturate withdrawal

Barbiturates were introduced in 1903 and were quickly established as drugs of addiction. Experi- mental studies have elucidated the features of the barbiturate withdrawal syndrome. Isbell et al. (1950) administered maximally tolerated doses of short-acting barbiturates to five volunteer prisoners for 90-144 days and then stopped the drug abruptly. Within 12 hours the subjects developed anxiety, weakness, insomnia, anorexia, tremor and muscle twitching. These symptoms worsened over the next day with postural hypotension, nausea and vomiting. Four subjects developed increasing insomnia and, after 4 days, a delirium of varying severity that lasted 3-5 days and was characterized by extreme agitation, fever, auditory and visual hallucinations, disorientation and confusion. After large doses of barbiturate were taken for 7- 12 days, withdrawal was followed by insomnia, tremor, hyperacusis and, in 10 per cent, delirium (Alex- ander, 195 1).

Fraser et al. (1958) gave smaller amounts of secobarbital or pentobarbital to 50 volunteers for 32-365 days before abrupt withdrawal. Two patients on 200mg daily had no significant symptoms. One of 18 subjects on 400mg daily developed insomnia. Nine of 18 on 600 mg daily noted insomnia, tremor, weakness and anxiety. All of five subjects withdrawn from 800 mg daily had

these symptoms and two developed hallucinations. Eighteen patients took maximally tolerated doses (0.9-2.2 g daily) and all developed these symptoms and 12 became psychotic.

Wulff (1959) did not find any withdrawal symptoms on recovery from acute barbiturate poisoning in nine patients. Six of eight volunteers who received moderate doses of barbiturate for 2 weeks developed minor, transient withdrawal symptoms. Eighty-five instances of withdrawal from chronic barbiturate abuse were also studied. In this group, symptoms only occurred if short- or medium-acting barbiturates were taken, and if the rate of elimination exceeded 20 per cent per day. Symptoms developed 1-3 days after withdrawal and included insomnia, restlessness, anxiety, tension, tremor, sweating, nausea, weakness and reflex hyperirritability. In 25 per cent of cases these symptoms were the only features, and resolved in about 3 days. Delirium supervened in 21 patients (25 per cent), with onset at 4-6 days and a duration of 3-8 days. The deliria were characterized by clouding of consciousness, disorientation, auditory and visual hallucinations, abnormalities of smell and taste, agitation, insomnia and fever. Other reported barbiturate withdrawal symptoms include headache, dizziness, distorted visual perception, hyperacusis and weight loss (Gardner, 1967; Khantzian and McKenna, 1979).

These studies indicate that a withdrawal syndrome is most likely to occur after abrupt discontinuance of a large dose of short-acting barbiturate taken for a long time. Withdrawal symptoms are unlikely to occur if a long-acting barbiturate (e.g. phenobarbitone-half-life 96 hours) is stopped, and if doses are decreased over a number of days. The barbiturate withdrawal syndrome has an evolving pattern; minor symptoms develop first, after a significant fall in barbiturate levels. A minor reaction will resolve spontaneously, but in more severe reactions the symptoms intensify and delirium, seizures and death may occur (Khantzian and McKenna, 1979).

Barbiturate withdrawal seizures

Convulsions associated with barbiturate abuse were first reported by Kress in 1905 and delirium after barbiturate withdrawal was documented by Laehr in 1912 (Wulff, 1959). Pohlisch (1928) reported a series of patients, with no previous history of seizures, who developed generalized convulsions

174 J. DUNCAN

and a psychosis 6-10 days after withdrawal of barbital. Convulsions occurred in 11 of 30 cases of withdrawal psychosis. Similar findings were reported by other German workers (citations by Kalinowsky, 1942; Isbell et al., 1950). Kalinowsky (1942) reported seven patients who had a generalized convulsion 4-5 days after abrupt withdrawal of soluble barbital that had been administered for at least I8 months. There have been many other series of case reports of generalized convulsions occurring a few days after either withdrawal or a marked reduction of barbiturate dose (Dunning, 1940; Brownstein and Pacella, 1943; Osgood, 1947; Alexander, 195 1; Gardner, 1967).

In an experimental study, four of five subjects had generalized convulsions 30-60 hours after discontinuance of a short-acting barbiturate that had been taken in maximally tolerated doses for 90-144 days (Isbell et al., 1950). Two subjects had a single convulsion and one subject each had two and three convulsions. Withdrawal of maximally tolerated doses of short-acting barbiturate taken for only 7-12 days resulted in a major withdrawal reaction, with convulsions and delirium in 10 per cent of cases (Alexander, 1951). Fourteen of 18 subjects abruptly withdrawn from maximally tolerated doses of secobarbital or pentobarbital (0.9 to 2.2g daily), taken for 32-365 days, developed convulsions. In contrast, only two of 18 subjects withdrawn from 600mg daily, and one of five withdrawn from 800 mg daily, had convulsions (Fraser et al., 1958).

Patients recovering from acute barbiturate poisoning did not develop convulsions, and neither did volunteers who stopped barbiturates after taking moderate doses for 2 weeks (Wulff, 1959). In contrast, 29 per cent of patients (25 of 85) withdrawn after chronic barbiturate abuse developed convulsions, with onset generally 4-7 days later. A single convulsion occurred in 18 patients (72 per cent), six had two to six convulsions, one had 11 and one case developed psychomotor seizures. Psychomotor seizures where also noted after barbiturate withdrawal in a patient with no prior history of seizures, but who had previously had a prefrontal leucotomy (Malcolm, 1972). Focal and generalized seizures occur after barbiturate withdrawal in dogs with focal cerebral lesions (Essig, 1962).

As with alcohol, barbiturate withdrawal seizures usually take the form of generalized convulsions if there is no focal lesion, but focal seizures may

develop if there is such an abnormality. Risk factors for seizures after barbiturate withdrawal include a long duration of use, a high dose and rapid withdrawal. Nearly all reports of seizures following barbiturate withdrawal in non-epileptics involve discontinuation of short- or medium-acting barbiturates. However, Pohlisch (1928) reported a case of four convulsions 9-1 1 days after abrupt withdrawal of phenobarbitone (half-life 96 hours).

EEG findings in barbiiurate withdrawal

Isbell et al. (1950) noted paroxysmal bursts of high- amplitude waves of four to six cycles per second appearing 24-48 hours after abrupt withdrawal of large doses of short-acting barbiturate. Two weeks later an increase in slow waves was still apparent, and by 4 weeks the EEG had returned to normal. Wikler et al. (1955) recorded EEGs after abrupt withdrawal of large doses of barbiturates; 79 per cent of their subjects developed convulsions, and random slow waves and spikes, mixed spike and slow wave or four cycles per second spike and wave paroxysms appeared after 2-3 days, and abated over the following week. There was no absolute correlation, but convulsions were commonly associated with such EEG changes. Essig and Fraser (1958) withdrew seco- or pentobarbital from 18 subjects after they had taken 400 mg daily for 90 days. Only mild withdrawal symptoms were noted and just two subjects’ EEGs showed high-voltage, bilateral sharp wave paroxysms at five to eight cycles per second. Three other subjects’ EEGs developed lesser abnormalities. The abnormalities appearing 24-35 hours after withdrawal and had resolved by 36-1 13 hours.

Wulff (1959) performed EEGs, with and without photic stimulation, after barbiturate withdrawal. Twelve per cent of those withdrawn from short- acting barbiturates had paroxysms of single or multiple spikes, with or without slow waves, in the resting EEG, and this increased to 62 per cent after photic stimulation. These paroxysmal abnormalities usually receded over the following 2 weeks, 17 per cent lasted up to 4 weeks and in one case they persisted for 1 12 days. Paroxysmal abnormalities were seen in 80 per cent of patients with delirium and/ or convulsions, in 62 per cent of patients with only minor symptoms and in 44 per cent of asymp- tomatic patients. No paroxysmal activity was seen after withdrawal of long-acting barbiturates. Photosensitivity, however, may develop after withdrawal of a long-acting barbiturate. Brillman et al.


(1974) described a patient who took an overdose of primidone. The drug was not continued and photosensitivity was noted from the 17th to 23rd day after withdrawal.

In summary, paroxysmal activity, slow waves and photosensitivity are often noted, transiently, after barbiturate withdrawal with a time course that matches the clinical features. In general the most severe EEG abnormalities are Heen in major withdrawal reactions, after abrupt withdrawal of large doses of short-acting barbiturates.

BENZODIAZEPINES

Symptoms of benzodiazepine withdrawal

Since the first report (Hollister et al., 1961), an extensive literature of benzodiazepine withdrawal has developed (Ayd, 1979; Lader, 1983; Marks, 1983; Schopf, 1983; Petursson and Lader, 1984; Higgitt et al., 1985). Most of the reported cases follow diazepam withdrawal, but similar problems have been noted following withdrawal of lorazepam (Stewart et al., 1980; Einarson, 1980; De La Fuente et al., 1980; Howe, 1980), temazepam (Ratna, 1981), clobazam (Petursson and Lader, 1981a), chlordiazepoxide (Hollister et al., 1961; Covi et al., 1973) and alprazolam (Levy, 1984). The half-life of benzodiazepines varies from 3 to 100 hours (Goodman and Gilman, 1975) and this wide ragne explains the differing time course of withdrawal reactions from different benzodiazepines.

Nearly all case reports and investigations of benzodiazepine withdrawal symptoms have involved patients who have been prescribed the drugs to alleviate psychological or psychiatric difficulties, and have not been of patients prescribed the drugs for other reasons, such as spasticity or seizure control. There has been considerable debate about whether symptoms occurring on benzodiazepine withdrawal are true withdrawal symptoms or a recurrence of pre-existing complaints. The con- sensus, from a number of case reports (Barten, 1965; Bant, 1975; Haskell, 1975; Preskorn and Denner, 1977; Dysken and Chan, 1977; Pevnick et al., 1978; De Bard, 1979; Khan et al., 1980; Stewart el al., 1980; Winokur et al., 1980; Petursson and Lader, 198 1 a; Ratna, 198 1) and from trials of benzodiazepine withdrawal, is that there is an identifiable symptom complex associated with withdrawal of these drugs.

Ten of 11 psychiatric inpatients developed new symptoms when large doses of chlordiazepoxide (300-600mg daily), taken daily for 2-6 months, were abruptly replaced with placebo. Depression, worsening of psychosis, insomnia, agitation, anorexia, nausea, sweating and generalized convulsions were noted. Symptoms appeared 2-9 days after withdrawal and had largely resolved by 10 days (Hollister et al., 1961). Covi et al. (1973) stopped chlordiazepoxide, 45 mg daily, abruptly after treatment for 10 weeks and, in the next 2 weeks, many patients complained of anorexia, trembling, nausea, insomnia, numbness, paraesthesiae, dizziness, weakness and lethargy. Adam et al. (1976) gave 5mg of nitrazepam at night to 10 healthy volunteers for 10 weeks, and noted increased nocturnal wakefulness in the following 1-2 weeks. Rebound insomnia was also found after usage of nitrazepam, flunitrazepam and triazolam for a few nights (Kales et al., 1979).

Rickels (1981) reported on 100 anxious patients who had received diazepam for up to 6 months and who were then switched to a matching placebo. Eleven developed withdrawal reactions, mainly gas- trointestinal disturbance, lethargy, tremor, weakness, insomnia, anxiety and hypersensitivity to light and sound. These symptoms developed on the second day and resolved in 2 weeks. In an un- blinded study, 27-45 per cent of patients treated with benzodiazepines for more than 4 months developed withdrawal symptoms when the medication was stopped abruptly (Tyrer et al., 1981). Symptoms included insomnia, dysphoria, impaired perception of movement, headache, muscle twitching, vomiting, difficulty focusing, depersonalization and derealization, disordered sensory perception and a seizure. Petursson and Lader (1981b) conducted a double-blind, placebo-controlled study of gradual withdrawal of benzodiazepines over 2 weeks, in 16 patients, after therapy for at least 1 year. All complained of insomnia, anxiety, tension, agitation, restlessness and bodily symptoms of anxiety. More than 50 per cent noted tremor, headache, distortion of taste, muscle pains and twitching, irritability, anorexia, nausea, photophobia, incoordination and depression. Lesser numbers were troubled by excess sweating, lack of energy, hyperacusis, paraesthesiae, impaired memory and concentration, depersonalization, derealization, tactile hypersensitivity and paranoia. Tyrer et al. (1983) studied 41 ambulant patients who had taken 5-20 mg of diazepam daily for at least 3 months. Gradual, double-blind, placebo-controlled

176 J. DUNCAN

withdrawal took place over 3 months. Forty-four per cent of patients developed withdrawal symptoms, including insomnia, depersonalization, derealization, depression, anorexia, anxiety, difficulty concentrating, tension, tiredness, memory impair- ment, agitation, muscle twitching, abnormal sensa- tions of movement and distorted sensory perception.

Twelve patients, who took benzodiazepines for 3-22 years, had the drug withdrawn over 2-3 weeks. Withdrawal symptoms peaked at about 5-7 days and improved over the following 1-6 months. Perceptual distortion, hallucinations, paranoia, insomnia, derealization, depression, excitability, paraesthesiae, altered taste, myalgia, tremor, jerks, unsteadiness, visual blurring, nausea, flu-like symptoms, anorexia and weight loss were all noted (Ashton, 1984). Fontaine et al. (1984) conducted a double-blind, placebo-controlled comparison of abrupt and gradual withdrawal of benzodiazepines over 3 weeks in 48 anxious outpatients. Anxiety scores increased in 44 per cent of patients who had abrupt withdrawal, and in none of those who had gradual withdrawal. Insomnia developed more commonly after abrupt withdrawal, but agitation more commonly during gradual withdrawal. In another study, symptoms were more severe after abrupt changeover to placebo than if diazepam was tailed off over 8 weeks, and generally resolved over 4 weeks (Busto et al., 1986). Withdrawal symptoms do not only occur after prolonged use, but have been noted after abrupt discontinuation of 6 weeks benzodiazepine therapy (Murphy et al., 1984; Power et al., 1985).

There are several case reports of psychosis developing after abrupt withdrawal of therapeutic doses of benzodiazepines taken for a long time, usually at least 6 months (Hollister et al., 1961; Barten, 1965; Fruensgaard, 1976; Dysken and Chan, 1977; Preskorn and Denner, 1977; De Bard, 1979; Levy, 1984). Psychosis generally develops 3-8 days after stopping the drug, is self-limiting and responds to the administration of a benzodiazepine. However, psychosis may also follow gradual reduction of benzodiazepines over several days (De Bard, 1979).

Benzodiazepine withdrawal seizures

This review is confined to benzodiazepine withdrawal seizures in non-epileptics. There have been many reports of generalized convulsions occurring in persons with no prior history of epilepsy, after

benzodiazepine withdrawal (Hollister et al., 1961, 1963; Barten, 1965; Vyas and Carney, 1975; Rifkin et al., 1976; Preskorn and Denner, 1977; Acuda and Muhangi, 1979; De Bard, 1979; De la Fuente et al., 1980; Einarson, 1980; Howe, 1980; Khan et al., 1980; Le Bellec el al., 1980; Levy, 1984). A convulsion is a symptom of a major withdrawal reaction, and in many cases psychosis and a seizure occurred contemporaneously. The period of great- est risk for a convulsion is 1-10 days after withdrawal. A long duration of treatment and an abrupt withdrawal are positive risk factors for a serious reaction (Marks, 1983) although generalized convulsions have been reported 5 days after diazepam 30mg daily, taken for 3 months, was stopped abruptly (Rifiin et al., 1976).

Serial convulsions have been noted after lorazepam withdrawal (De La Fuente et al., 1980) and status epilepticus reported after abrupt withdrawal of diazepam, 200-250 mg daily, taken for at least 7 months (Zaccara et al., 1986). Abrupt withdrawal of benzodiazepines, alcohol and barbiturates may also precipitate non-convulsive status epilepticus in patients with no history of seizures (Emre et al., 1985).

EEG findings in benzodiazepine withdrawal

The most prominent feature of the EEG after benzodiazepine withdrawal is reduction of the activity in the beta and theta wavebands that is associated with benzodiazepine administration (Petursson and Lader, 1981b; Lader, 1983; Petursson and Lader, 1984). EEGs recorded from non-epileptics with benzodiazepine withdrawal reactions, including seizures, usually do not show paroxysmal activity (Hollister et al., 1961; Rifkin et al., 1976; Howe, 1980; De La Fuente et al., 1980; Le Bellec et al., 1980; Petursson and Lader, 1981b; Levy, 1984). In some severe caes, however, generalized paroxysmal activity (sharp and slow waves, spike and polyspike discharges) may be noted transiently during the withdrawal reaction (Hollister et al., 1961; Le Bellec et al., 1980; Zaccara et al., 1986).

OTHER DRUGS

A similar syndrome to that seen after withdrawal of barbiturates, benzodiazepines and alcohol may be seen after discontinuance of chloral and paraldehyde (Pohlisch, 1928). In several cases of paraldehyde withdrawal, seizures occur after 2-3 days

SEDATIVE DRUG WITHDRAWAL

Table 1. Clinical features of drug withdrawal

177

Alcohol Barbiturates

Anxiety Agitation Restlessness Depression Weakness Pruritus Delirium Increased reflexes Insomnia Anorexia Nausea Vomiting Sweating Tremor Dizziness Head ache Twitching Muscle pain Fever Impaired perception:

Visual Auditory Tactile

Hallucinations: Visual Auditory

Tachycardia Palpitations Nystagmus Seizures

Anxiety Agitation Restlessness

Weakness Disorientation Delirium Increased reflexes Insomnia Anorexia Nausea Vomiting Sweating Tremor Dizziness Headache Twitching Muscle pain Fever Impaired perception:

Visual H yperacusis Olfactory Gustatory


Seizures

Benzodiazepines

Anxiety Agitation Restlessness Depression Weakness Impaired memory Depersonalization Derealization Insomnia Anorexia Nausea Vomiting Sweating Tremor Dizziness Headache Twitching Muscle pain Numbness Paraesthesiae Photophobia Impaired perception:

Hyperacusis Tactile Gustatory


Paranoia Incoordination Flu-like symptoms Seizures

abstinence, and chloral withdrawal seizures generally occur after 3-4 days (Merry, 1968). Similar syndromes have been noted after the withdrawal of meprobamate (Haizlip and Ewing, 1958; Hollister and Glazener, 1960) and glutethimide (Essig, 1963).

CONCLUSIONS

There is a great deal of similarity between the profiles of symptoms that may occur on the withdrawal of alcohol, barbiturates and benzodiazepines (Table 1) . The evolving pattern of the withdrawal syndromes is also similar for these agents. Anxiety, sweating and tremor commonly pre-

dominate early; in a mild reaction these symptoms abate spontaneously, but in a more severe case may intensify and be accompanied by delirium and seizures. The natural history of the majority of drug withdrawal reactions is to remit spontaneously, but severe cases may prove fatal.

The severity of a withdrawal reaction is determined largely by the dose and duration of drug ingestion, and by the rate of withdrawal. The greater the dose, the longer the usage and the quicker the withdrawal, the more likely there is to be a serious reaction. If discontinuation of a drug is abrupt, significant reactions are more likely to occur if the drug has a short half-life (e.g. alcohol) than if the drug has a long half-life (e.g. phenobarbitone).

178 J. DUNCAN

A seizure, in a patient without a prior history of epilepsy, indicates a major withdrawal reaction, necessitating urgent treatment. Single or multiple seizures can occur and may develop into status epilepticus. The most common type of withdrawal seizure is a generalized convulsion, but partial seizures may be precipitated in patients with a prior history of such seizures, or a focal cerebral lesion.

The EEG changes associated with sedative drug withdrawal include spikes, sharp and slow waves, and photosensitivity. Epileptiform activity develops more commonly in patients with severe withdrawal reactions and is transient, with a time course that is similar to the clinical features. As with withdrawal seizures, the EEG abnormalities are usually generalized unless there is a pre-existing focal lesion, in which case focal EEG epileptiform activity may be a prominent feature.

ACKNOWLEDGEMENTS

I am very grateful to Drs S. D. Shorvon and M. R. Trimble for encouragement and critical review of this article. These studies were supported by grants from Ciba Geigy Pharmaceuticals and the Brain Research Trust.

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Neuropsychiatric aspects of sedative drug withdrawal