M
Mac DS, Kumar R, Goodwin DW.
Anterograde Amnesia with Oral Lorazepam.
Journal of Clinical Psychiatry 1985; 46: 137-138.

" These results support findings by other investigators that lorazepam has a deleterious effect on
short-term recall of verbal material. This has implications for students and other preparing for
tests or doing mental work while taking therapeutic doses of lorazepam. " [p. 137]

[Key words; Ativan, lorazepam, amnesia, memory impairment]

Maletzky BM, Klotter J.
Addiction to Diazepam.
International Journal of the Addictions 1976; 11: 95-115.

" Indeed, the "Warnings" section of the Valium package insert admitting to the occurrence of
withdrawal symptoms leads one to believe that addiction can only occur should the usual doses
be exceeded or the user be an alcoholic, drug addict, or "addiction-prone", a state further
undefined. " [p. 96]

" Of 27 articles (Constant and Gruver, 1963; Grayson, 1962; Katz, Aldes, and Rector, 1962;
Kelley, 1962: Cromwell, 1963; Levy, 1963; Burdine, 1963: Dorfran, 1964; Fowlkes, Strickland,
and Peirson, 1964; Bowes, 1965; Burnett and Holman, 1965; Vilkin and Lom as, 1962; Randall
et al., 1961; Susses, Linton, and Herlihy, 1961; Chesrow et al., 1962; Feldman, 1962; Kelley,
1962; Kerry and Jenner, 1962; Merliss, Turner, and Krumholz, 1962; Pignataro, 1962; Proctor,
1962; Cromwell, 1963; Dorfman, 1963; Love, 1963; McGovern et al., 1963; Rathbone, 1963;
Ryan, 1963;) reviewed in which diazepam was claimed to be free of addicting properties, n o n e
conducted sufficient controls to merit dismissing this question. " [p. 96]

" Diazepam may be vulnerable to self-manipulation because of its capacity to produce immediate
positive effects, a trait it shares with addicting substances, such as alcohol or amphetamines, as
opposed to nonaddicting psychotropic drugs, such as chlorpromazine and imipramine. " [p. 109]

" When asked, 14 of these 25 replied they increased their dose because the prescribed amount
was not as helpful as before. " [p. 109]

" Of 24 subjects who attempted discontinuance, 22 were unsuccessful and returned to the drug. "
[p. 109]

" ... several subjects complained of extreme anxiety upon abstinence, yet had been free of anxiety
when the drug was initially prescribed. in addition, symptoms such as tremor, diaphoresis, and
even insomnia, which had been rare prior to taking diazepam, emerged when the drug was
stopped. " [p. 110]

" It would seem logical to assume that... these symptoms developed d e n o v o upon abstinence."
[p. 110]

"... neither age, sex, psychiatric history, nor the presence of current psychiatric problems have the
slightest relationship to drug use and abuse variables. It is disappointing to find no individual
characteristics predictive of potential danger with diazepam. " [p. 110]

" In addition, many subjects not thought to be "addiction-prone" developed what appeared to be
both tolerance and withdrawal. These subjects, given the drug for medical reasons and without a
psychiatric history, were just as likely as psychiatric patients to develop tolerance and withdrawl."
[p. 111]

" While this sample was not taking excessively high doses, nor using the drug great lengths of
time, many had extreme difficulty in decreasing or discontinuing their dose, rather finding it easier
to increase. Most who increased felt they required more to achieve the same benefits as
previously. " [p. 112]

" ... age, sex, and the presence or absence of a history of psychiatric, alcoholic, or drug-related
problems had no bearing on development of tolerance or withdrawal, thus raising the question
about the validity of the "addiction-prone" concept. " [p. 112]

[Key words; Valium, diazepam, addiction, abuse, dependence, withdrawal, drug manufacturers]

Marcus A, Bahro M, Sartoris J, Schmidt MH.
Acute Exogenic Psychosis Following Oral Ingestion of 2 mg Lormetazepam
in an Eleven-Year-Old Boy.
Pharmacopsychiatry 1993; 26: 102-103.

After oral ingestion of 2 mg lormetazepam given by his mother, an 11-year-old boy suffered from
severe adverse effects.

Main symptoms were disorientation, restlessness, amnesia, anxiety, hostility, and rage reactions.
Paranoid ideation and impaired perception were concluded from strange reactions and remarks
of the child. Symptoms are similar to the van der Kroef syndrome described after the use of
rapidly eliminated high-potency benzodiazepines. This case demonstrates drug abuse on the part
of parents wishing to induce sleep in their children. [ SUMMARY p. 102 ]

[Key words; Noctamid, lormetazepam, aggression, paranoia, psychosis, paradoxical effects,
children]

Martin CD, Chan SC.
Distribution of Temazepam in Body Fluids and Tissues in Lethal Overdose.
Journal of Analytical Toxicology 1986; 10: 77-78.

Two cases of lethal overdose by temazepam re presented. In both cases, temazepam was the
only drug detected, and there was no involvement of alcohol. The drug concentrations in blood,
urine, and liver were measured. [ABSTRACT p. 77]

[Key words; Euhypnos, Normison, temazepam, poisoning]

Matthews HP, Drummond LM.
Obsessive-Compulsive Disorder - A Complication of Benzodiazepine
Withdrawal.
British Journal of Psychiatry 1987; 150: 272.

"There has been increased awareness in recent years of the symptoms of benzodiazepine
withdrawal. Although obsessional symptoms have been described as part of this withdrawal
syndrome, obsessive-compulsive disorder has not previously been reported.

Case Report: The patient, a 32-year-old married woman, had a history of recurrent depression
treated by diazepam (6 mg daily) for the previous 7 years. She discontinued this abruptly in June
1985 on her general practitioners advice as she was planning a pregnancy. Two weeks after
discontinuing medication she developed symptoms of anxiety, insomnia, night mares, and
hyperacusis, similar to those reported by Tyrer et al (1983), which persisted for several weeks.
Four weeks after discontinuing diazepam, however, she also developed obsessive-compulsive
symptoms related to a fear that she might inadvertently reveal information to other people which
would lead to the loss of her home and family. This resulted in her hoarding rubbish and avoiding
going out alone. When outside her home she would stop and collect any rubbish on the road or
pavement. She repeatedly checked the contents of her dustbin and also her own and other
people's clothes, shoes, pockets, and money. She frequently asked her family for reassurance
and help with her checking rituals. She refused to be left alone in the house for fear that she might
throw "evidence" out of the window, ultimately required a family member to accompany her to
the toilet or bath. During the night she would wake her husband and request him to go into the
garden to check that she had not thrown anything out of the window. Her symptoms temporarily
abated when in September 1985 she recommenced diazepam for a two-week period but they
returned and increased in intensity on its cessation. In December 1985 she developed a severe
depressive illness and was admitted to hospital in February 1986 following her general
practitioner's request for psychiatric opinion. As an in-patient she was treated with clomipramine
(150\~mg daily) and after 4 weeks was free of depressive symptoms. However, her
obsessive-compulsive symptoms remained until April 1986 when a treatment programme of
graded exposure in real life with self-imposed response-prevention was instituted. In July she was
discharged from active behavioural treatment with marked improvement in her
obsessive-compulsive symptoms. She has continued to improve with homework practice and at
follow-up in September 1986 was able to perform home-management tasks with little fear,
although remaining anxious when walking alone outside her home.

As well as suggesting a previously unreported psychiatric complication of benzodiazepine
withdrawal, the case demonstrates that when depression coexists with obsessive-compulsive
disorder, treatment of the depressive symptoms may not lead to resolution of the obsessional
symptoms."

[Key words; Valium, diazepam, addiction, dependence, withdrawal, depression, OCD]

Mellman TA, Uhde TW.
Withdrawal Syndrome with gradual Tapering of Alprazolam.
American Journal of Psychiatry 1986; 143: 1464-1466.

The clinical and biological correlates of gradual alprazolam withdrawal were investigated in 10
patients in a double-blind, placebo-controlled trial. During gradual alprazolam withdrawal, anxiety
and plasma cortisol levels were higher than during a postwithdrawal medication-free period.
[SUMMARY p. 1464]

In fact, eight of our 10 patients, whose alprazolam doses were decreased at approximately
one-third rate, had both clinical (increased ratings of anxiety) and biological (increased pulse rates
or plasma cortisol level) evidence of benzodiazepine withdrawal. Although the withdrawal
syndrome was without marked autonomic hyperactivity or serious sequelae, four patients
demonstrated substantial increases in mean anxiety ratings, and an overlapping subgroup reported
headaches, muscle tension, and motor restlessness during the withdrawal but not during the
post-withdrawal period. [p. 1465]

[Key words; Xanax, alprazolam, addiction, dependence, withdrawal, anxiety]

Mendelson G.
Withdrawal Reactions after Oxazepam.
Lancet 1978; i: 565.

" Major withdrawal reactions, including psychotic episodes and grand-mal seizures, have been
described in patient who abruptly stopped taking diazepam or chlordiazepoxide in "therapeutic"
doses. The effects of such withdrawal may not appear for several days and may take up to 14
days to become apparent. I Have seen a withdrawal reaction in a patient who suddenly stopped
taking oxazepam.

A 24-year old man, in good physical health, had taken oxazepam for 2 years (15 mg every h,
with 30 mg at night). He began psychotherapy 18 months after starting the drug. About 6 months
later, without consulting either his local doctor or the psychiatrist, he stopped taking the drug.

On the following day he became aware of gradually increasing restlessness: his description was
similar to that given by patients experiencing akathisia. He also noted rigidity of all limbs and
stiffness of joints. He reported "having great energy" with impaired concentration, symptoms quite
different from the feelings of tension and anxiety he had experienced before taking oxazepam.
Later that day he resumed taking oxazepam and after a dose of 30 mg became drowsy and slept
for about 4 h. When he awoke, his symptoms had completely resolved.

The patient subsequently stopped oxazepam by taking gradually decreasing doses and had no
symptoms of withdrawal. The recommendation that if benzodiazepines are given continuously for
months they should be withdrawn gradually, needs to be stressed to the patient taking the drug as
well as to the prescribing doctor. "

[Key words; Serax, Serenid, Serepax, oxazepam, addiction, dependence, withdrawal]

Michelini S, Cassano GB, Frare F, Perugi G.
Long-Term Use of Benzodiazepines: Tolerance, Dependence and Clinical Problems in Anxiety and Mood Disorders.
Pharmacopsychiatry 1996; 29: 127-134.

"Long-term use of BZ seems to induce chronic dysphoric mood, with persistence of anxiety, irritability, difficulty in concentration and memory impairment." [p. 130]

"...anterograde amnesia, irritability, anger, hostility, depression and the impulse dyscontrol with high suicidal risk are clinically relevant findings in a well-defined number of long-term users with mood and anxiety disorders. In spite of this, these symptons are often interpreted as an exacerbation or as a natural evolution of previous disorders and the chronic use of sedatives is overlooked." [p. 131]

Miller F, Nulsen J.
Diazepam (Valium) Detoxification.
Journal of Nervous and Mental Disease 1979; 167: 637-638.

In the chronic abuser, diazepam (Valium) withdrawal can be a protracted event. In this report a
case is presented of a 37-year-old Caucasian female who had been ingesting 60 to 80 mg of
diazepam daily for 8 years. Twelve days following discontinuation of the drug, the patient
continued to experience diarrhea, restlessness, emotional lability, and anxiety. (---) The
prolonged period needed for detoxification in this patient raises important questions regarding the
appropriate length of hospitalisation or close supervision required to withdraw the diazepam
addict. [SUMMARY p. 637]

[Key words; Valium, diazepam, addiction, dependence, withdrawal, detoxification]

Miller NS, Gold SA.
Benzodiazepines: Reconsidered.
Advances in Alcohol and Substance Abuse 1990; 8: 67-84.

" The DAWN data reveal that 51% of the emergency room diazepam mentions involve a "suicidal
attempt or gesture". Other reports emphasise the importance of the combination of
benzodiazepines with alcohol and other drugs. "

" The toxic effect of alcohol and drugs is to produce depression, especially after chronic use.
Depressants such as alcohol, barbiturates and benzodiazepines produce depression of the mood
by the intoxicating effects on the brain ..."

" Closer observations with clear criteria for addiction, tolerance, and dependence for
benzodiazepines may reveal that they are not as safe as once considered and benzodiazepines
may be contributing to the effects that lead to suicide. " [p. 79]

[Key words; Valium, diazepam, addiction, dependence, withdrawal, depression, suicide]

Miller NS, Gold MS.
Introduction Benzodiazepines: A Major Problem.
Journal of Substance Abuse Treatment 1991; 8: 3-7.

Benzodiazepine use is prevalent. Moreover, benzodiazepine abuse, addiction, tolerance, and
dependence occur commonly with benzodiazepine use. Confusion arises in assessing the nature
and magnitude of benzodiazepine use and its consequences. Abuse, addiction, tolerance, and
dependence occur in medical and nonmedical populations, but the studies do not clearly
differentiate the benzodiazepine use between these two populations. The nonmedical use in
medical populations is underestimated and underdiagnosed. The nonmedical use is also
misdiagnosed in nonmedical populations as medical use. Clearer definitions and usage of the
terms of abuse, addiction, tolerance, and dependence would result in accurate diagnosis and
proper treatment of the disorders associated with benzodiazepine use, that is, anxiety and
depressive disorders, alcoholism, and other drug addictions. [ABSTRACT p. 3]

[Key words; addiction, abuse, dependence, withdrawal, tolerance, depression, long-term effects]

Misra PC.
Nitrazepam (Mogadon) Dependence.
British Journal of Psychiatry 1975; 126: 81-82.

A case of nitrazepam dependence has been described. This drug dependence could not be
relieved by substituting other tranquillisers. [SUMMARY p. 82]

[Key words; Mogadon, nitrazepam, addiction, dependence, withdrawal]

Moore C.
Oxazepam Withdrawal Syndrome.
Medical Journal of Australia 1982; 2: 220.

" This case illustrates two lessons: (a) a careful drug history should be sought in any person
suspected of suffering from dementia. (b) the withdrawal from benzodiazepines can be late,
spectacular, and as life-threatening as barbiturate withdrawal. " [p. 220]

[Key words; Serax, Serenenid, Serepax, oxazepam, addiction, dependence, withdrawal, the
elderly]

Morgan K, Dallosso H, Ebrahim S, Arie T, Fentem PH.
Prevalence, Frequency, and Duration of Hypnotic Drug Use among the
Elderly Living at Home.
BMJ 1988; 296: 601-602.

" These results suggest that for most elderly users of hypnotic drugs, patterns of consumption
encourage the development of cumulative effects and benzodiazepine dependence. " [p. 601]

" Estimates of the effective "life-span" of hypnotic drugs vary, with the Committee on the Review
of Medicines supporting the suggestion that "most hypnotics tend to lose their sleep promoting
properties within three to 14 days of continuous use." From our data, therefore, it seems that
many, perhaps most, elderly users of hypnotic drugs are unnecessarily exposed to the risks of
drug accumulation or daytime withdrawal effects. Furthermore, the overall pattern of use of
hypnotic drugs in this representative sample was consistent with the development of
benzodiazepine dependence in a substantial number of elderly patients. " [p. 602]

[Key words; addiction, dependence, drug accumulation, hypnotics, the elderly]

Murphy SM, Owen RT, Tyrer PJ.
Withdrawal Symptoms after Six Weeks Treatment with Diazepam.
Lancet 1984; ii: 1389.

" Fontaine et al have noted rebound anxiety after abrupt withdrawal of bromazepam and
diazepam after only 4 weeks of treatment. Our findings suggest that the symptoms exhibited after
stopping benzodiazepines constitute true pharmacological dependence as they are absent after
withdrawal from buspirone - a finding that contradicts the argument that such symptoms are a
return to pre-drug state. "

[Valium, Lexotan, diazepam, bromazepam, addiction, dependence, withdrawal]

Murray D, O'Leary D.
Recommendations for Data Sheets on Benzodiazepines Ignored.
BMJ 1984; 288: 717.

" The Committe on Review of Medicines, in its guidelines for data sheets on 10 named
benzodiazepines, "considered that an appropriate warning regarding long-term efficacy be
included... particularly in view of the high proportion of patients receiving prescriptions for
extended periods of time." In conjunction with a survey on prescribing patterns we examined the
Association of the British Pharmaceutical Industry's Data Sheet Compendium 1983-1984. We
found the 10 named compounds represented by 17 proprietary preparations. Although 16 warn
that "prolonged" or "excessive" use may lead to dependence, only one carries a caution regarding
long term efficacy.

If the pharmaceutical industry is allowed such latitude in the data sheets we can hardly expect
higher standards in their advertising literature. "

[Key words; addiction, dependence, drug manufacturers]

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