A date rape drug is any drug that incapacitates another person and renders that person vulnerable to a sexual assault, including rape. The substances are associated with date rape
because of reported incidents of their use in the context of two people
dating, during which the victim is sexually assaulted or raped or
suffers other harm. The substances are not exclusively used to
perpetrate sexual assault or rape, but are the properties or
side-effects of substances normally used for legitimate medical
purposes. One of the most common incapacitating agents for date rape is alcohol, administered either surreptitiously[1] or consumed voluntarily,[2] rendering the victim unable to make informed decisions or give consent.
No comprehensive data exists on the frequency of drug-facilitated sexual assaults
involving the use of surreptitious drug administration, due to the
report rate of assaults and because rape victims who do report are often
either never tested for these drugs, are tested for the wrong ones, or
the tests are administered after the drug has been metabolized and left
their body.[3]
A 1999 study of 1,179 urine specimens from victims of suspected
drug-facilitated sexual assaults in 49 American states found six (0.5%)
positive for Rohypnol, 97 (8%) positive for other benzodiazepines, 48 (4.1%) positive for GHB, 451 (38%) positive for alcohol and 468 (40%) negative for any of the drugs searched for.[4]
A similar study of 2,003 urine samples of victims of suspected
drug-facilitated sexual assaults found less than 2% tested positive for
Rohypnol or GHB.[5]
The samples used in these studies could only be verified as having
been submitted within a 72-hour time frame or a 48-hour time frame.
A three-year study in the UK detected sedatives or disinhibiting
drugs that victims said they had not voluntarily taken in the urine of
two percent of suspected drug-facilitated sexual assault victims. In 65%
of the 1,014 cases included in this study, testing could not be
conducted within a time frame that would allow detection of GHB.[6][7]
A 2009 Australian study found that of 97 instances of patients admitted
to hospital believing their drinks might have been spiked, illicit
drugs were detected in 28% of samples, and nine cases were identified as
"plausible drink spiking cases". This study defined a "plausible drink
spiking case" in such a way that cases where (a) patients believed that
their drink had been spiked, and (b) lab tests showed agents that
patients said they had not ingested would still be ruled out as
plausible if the patient did not also (c) exhibit "signs and symptoms"
that were considered "consistent with agents detected by laboratory
screening."[8]
Researchers agree that the drug most commonly involved in drug-facilitated sexual assaults is alcohol,[2]
which the victim has consumed voluntarily in most cases. In most
jurisdictions, alcohol is legal and readily available and is used in the
majority of sexual assaults.[10]
Many perpetrators use alcohol because their victims often drink it
willingly, and can be encouraged to drink enough to lose inhibitions or
consciousness. Sex with an unconscious victim is considered rape in most
jurisdictions and some assailants have committed "rapes of
convenience", assaulting a victim after he or she had become unconscious
from drinking too much.[13]
Alcohol consumption is known to have effects on sexual behavior and aggression.
During social interactions, alcohol consumption causes more biased
appraisal of a partner’s sexual motives while impairing communication
about and enhancing misperception of sexual intentions, effects
exacerbated by peer influence about how to behave when drinking.[14]
The effects of alcohol at the point of forced sex
commonly include an impaired ability to rectify misperceptions and a
diminished ability to resist sexual advances and aggressive sexual
behavior.[14]
The Blade
released a special report, "The Making of an Epidemic," criticizing a
study conducted in the 1990s that concluded that 55% of rape victims had
been intoxicated. According to The Blade, the study specifically
ignored an Ohio statute that excluded "situations where a person plies
his intended partner with drink or drugs in hopes that lowered
inhibition might lead to a liaison." The author of the study later
admitted that the wording of the survey had been ambiguous.[15]
The increase of sexual assaults on college campuses has been
attributed to the social expectations of students to participate in
alcohol consumption; social norm dictate that students drink heavily and engage in casual sex.[16]
Various studies have concluded the following:
On average, at least 50% of college sexual assault cases are associated with alcohol use.[14]
On college campuses, 74% of the perpetrators and 55% of the victims had been drinking alcohol.[14]
In 2002, more than 70,000 students between the ages of 18 and 24 were victims of alcohol-related sexual assault in the U.S.[17][failed verification]
In violent incidents recorded by the police in which alcohol was a
factor, about 9% of the offenders and nearly 14% of the victims were
under age 21.[17][failed verification]
Benzodiazepines (tranquilizers), such as Valium, Librium, Xanax, and Ativan, are prescribed to treat anxiety, panic attacks, insomnia,
and several other conditions, and are also frequently used
recreationally. Benzodiazepines are often used in drug-facilitated
sexual assaults, with the most notorious being flunitrazepam (chemical name) or Rohypnol (proprietary or brand name), also known as "roofies," "rope," and "roaches."[19][20]
The benzodiazepines midazolam and temazepam were the two most common benzodiazepines utilized for date rape.[21]
Benzodiazepines can be detected in urine through the use of drug
tests administered by medical officials or sold at pharmacies and
performed at home. Most tests will detect benzodiazepines for a maximum
of 72 hours after it was taken. Most general benzodiazepine detection
tests will not detect Rohypnol: the drug requires a test specifically
designed for that purpose. One new process can detect a 2 mg dose of
Rohypnol for up to 28 days post-ingestion.[11][22]
Other tests for Rohypnol include blood and hair tests. Because the most
commonly used drug tests often yield false negatives for Rohypnol,
experts recommend use of gas chromatography-mass spectrometry analysis.[1][5][23]
Rohypnol
This
drug is also known as Whitleys, Trip-and-Fall, Ruffies, Rophies, Rope,
Roopies, Roofies, Roches, Roach-2, Roach, Mind Erasers, Rib, Lunch
Money, R-2, Poor Man’s Quaalude, Mexican Valium, LA Rochas, Forget Pill,
and Circles. Rohypnols comes as a pill that dissolves in liquids. Some
are small, round, and white. Newer pills are oval and green-gray in
color. When slipped into a drink, a dye in these new pills makes clear
liquids turn bright blue and dark drinks turn cloudy. But this color
change might be hard to see in a dark drink, like cola or dark beer, or
in a dark room.[24]
In one 2002 survey of 53 women who used Rohypnol recreationally,
10% said they were physically or sexually assaulted while under its
influence.[5] If enough of the drug is taken, a person may experience a state of automatism
or dissociation. After the drug wears off, users may find themselves
unable to remember what happened while under its influence (anterograde amnesia),
and feeling woozy, hung-over, confused, dizzy, sluggish and
uncoordinated, often with an upset stomach. They may also have some
difficulty moving their limbs normally.[1][5][23]
Rohypnol is believed to be commonly used in drug-facilitated
sexual assaults in the United States, the United Kingdom, and throughout
Europe, Asia and South America.[25]
Although Rohypnol's use in drug-facilitated sexual assaults has been
covered extensively in the news media, researchers disagree about how
common such use actually is. Law enforcement manuals describe it as one
of the drugs most commonly implicated in drug-facilitated sexual
assaults,[1] but according to research conducted by Michael Robertson from the San DiegoMedical Examiner's office and Dr. Mahmoud El Sohly of El Sohly Laboratories,[26]
test results indicated that flunitrazepam was only used in around 1% of
reported date rapes according to Robertson and 0.33% according to urine
lab tests done by El Sohly, of the rape-kits that actually get tested
in time. Despite having a long half-life (18–28 hours) an incorrect
belief is that Rohypnol is undetectable 12 hours after administration
which may result in victims failing to get a blood or urine test the
following day.
GHB is used recreationally to stimulate euphoria, to increase sociability, to promote libido and lower inhibitions.[29] It is sold under names such as Rufies, Liquid E and Liquid X. It is usually taken orally, by the capful or teaspoon.[30]
From 1996 to 1999, 22 reports of GHB being used in drug-facilitated sexual assaults were made to the United States Drug Enforcement Administration.
A 26-month study of 1,179 urine samples from suspected drug-facilitated
sexual assaults across the United States found 4% positive for GHB.[29] The National Drug Intelligence Center
(NDIC) says that in the United States GHB had surpassed Rohypnol as the
substance most commonly used in drug-facilitated sexual assaults,
likely because GHB is much more easily available, cheaper and leaves the
body more quickly.[29][31] GHB is only detectable in urine for six to twelve hours after ingestion.[31]
3,4-Methylenedioxymethamphetamine (MDMA)
MDMA
is a stimulating psychedelic. Although it is not sedating like other
date rape drugs, it has been used to facilitate sexual assault.[32][33] It is empathogenic and can increase disinhibition and sexual desire.[34] Often Ecstasy is combined with amphetamines or other drugs.
Detection
Several devices have been developed to detect date rape drugs.[35][36][37][38]
Media coverage
There were three stories in the media about Rohypnol in 1993, 25 in 1994 and 854 in 1996. In early 1996, Newsweek
magazine published "Roofies: The date-rape drug" which ended with the
line "Don't take your eyes off your drink." That summer, researchers say
all major American urban and regional newspapers covered date rape
drugs, with headlines such as "Crackdown sought on date rape drug" (Los Angeles Times),[39] "Drug zaps memory of rape victims" (San Francisco Chronicle).[40] In 1997 and 1998, the date rape drug story received extensive coverage on CNN, ABC's 20/20 and Primetime Live, as well as The Oprah Winfrey Show.
Women were instructed to never drink from punch bowls, never leave a
drink unattended, try no new drinks, drink nothing with an unusual taste
or appearance, take their own drinks to parties, and drink nothing
opened by another person.
News media has been criticized for overstating the threat of
drug-facilitated sexual assault, for providing "how to" material for
potential date rapists and for advocating "grossly excessive protective
measures for women, particularly in coverage between 1996 and 1998.[41][42]
Law enforcement representatives and feminists have also been
criticized for supporting the overstatements for their own purposes.[43]
Craig Webber states that this extensive coverage has created or amplified a moral panic[44] rooted in societal anxieties about rape, hedonism and the increased freedoms of women in modern culture. Goode et al say it has given a powerful added incentive for the suppression of party drugs,[42] has inappropriately undermined the long-established argument that recreational drug use is purely a consensual and victimless crime.
By shining a spotlight on premeditated criminal behavior, Philip
Jenkins states that it has relieved the culture from having to explore
and evaluate more nuanced forms of male sexual aggression towards
people, such as those displayed in date rapes that were not facilitated
by the surreptitious administration of drugs.[45]
For similar moral panics around social tensions manifesting via
discussion of drugs and sex crime, researchers point to the opium scare
of the late 19th century, in which "sinister Chinese" were said to use
opium to coerce white women into sexual slavery. Similarly, in the Progressive Era, a persistent urban legend
told of white middle-class women being surreptitiously drugged,
abducted and sold into sexual slavery to Latin American brothels.[46][47]
This analysis doesn't contradict instances when date rape drugs are
used or sexual trafficking occurs; its focus is on actual prevalence of
certain crimes relative to media coverage of it.
The core structure of benzodiazepines. "R" labels denote common locations of side chains, which give different benzodiazepines their unique properties.
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal or BZD withdrawal —is the cluster of signs and symptoms that emerge when a person who has been taking benzodiazepines, either medically or recreationally, and has developed a physical dependence,
undergoes dosage reduction or discontinuation. Development of physical
dependence and the resulting withdrawal symptoms, some of which may last
for years, may result from taking the medication as prescribed.
Benzodiazepine withdrawal is characterized by sleep disturbance,
irritability, increased tension and anxiety, panic attacks,
hand tremor, shaking, sweating, difficulty with concentration,
confusion and cognitive difficulty, memory problems, dry retching and
nausea, weight loss, palpitations, headache, muscular pain and stiffness, a host of perceptual changes, hallucinations, seizures, psychosis, and increased risk of suicide
(see "signs and symptoms" section below for full list). Further, these
symptoms are notable for the manner in which they wax and wane and vary
in severity from day to day or week by week instead of steadily
decreasing in a straightforward monotonic manner. This phenomenon is often referred to as "waves" and "windows".
It is a potentially serious condition, and is complex and often protracted in its course. Long-term benzodiazepine use, defined as daily use for at least three months, is not desirable because of the associated increased risk of dependence, dose escalation, loss of efficacy, increased risk of accidents and falls, particularly for the elderly, as well as cognitive, neurological, and intellectual impairments. Use of short-acting hypnotics, while being effective at initiating sleep, worsens the second half of sleep due to withdrawal effects.
Benzodiazepine withdrawal can be severe and can provoke life-threatening withdrawal symptoms, such as seizures, particularly with abrupt or overly rapid dosage reduction from high doses or long-time use.
A severe withdrawal response can nevertheless occur despite gradual
dose reduction, or from relatively low doses in short-time users; even after a single large dose in animal models. A minority of individuals will experience a protracted withdrawal syndrome,
whose symptoms may persist at a sub-acute level for months or years
after cessation of benzodiazepines. The likelihood of developing a
protracted withdrawal syndrome can be minimized by a slow, gradual
reduction in dosage.
Chronic exposure to benzodiazepines causes neural adaptations that counteract the drug's effects, leading to tolerance and dependence.
Despite taking a constant therapeutic dose, long-term use of
benzodiazepines may lead to the emergence of withdrawal-like symptoms,
particularly between doses, when patients are treated with
shorter-acting benzodiazepines.
When the drug is discontinued or the dosage reduced, withdrawal
symptoms may appear and remain until the body has reversed the long-term
physiological adaptations.
These [[Rebound effect|rebound symptoms may be identical to the
symptoms for which the drug was initially taken, or may be part of
discontinuation symptoms. In severe cases, the withdrawal reaction may exacerbate or resemble serious psychiatric and medical conditions, such as mania, schizophrenia, and, especially at high doses, seizure disorders.
Failure to recognize discontinuation symptoms can lead to false
evidence for the need to take benzodiazepines, which in turn leads to
withdrawal failure and reinstatement of benzodiazepines, often at higher
doses.
Awareness of the withdrawal reactions, individualized taper
strategies according to withdrawal severity, the addition of alternative
strategies such as reassurance and referral to benzodiazepine
withdrawal support groups, all increase the success rate of withdrawal.
Signs and symptoms
Withdrawal effects caused by sedative-hypnotics discontinuation, such as benzodiazepines, barbiturates, or alcohol, can cause serious medical complications. They are cited to be more hazardous to withdraw from than opioids. Users typically receive little advice and support for discontinuation. Some withdrawal symptoms are identical to the symptoms for which the medication was originally prescribed, and can be acute or protracted in duration. Onset of symptoms from long half-life
benzodiazepines might be delayed for up to three weeks, although
withdrawal symptoms from short-acting ones often present early, usually
within 24–48 hours.
There may be no fundamental differences in symptoms from either high or
low dose discontinuation, but symptoms tend to be more severe from
higher doses.
Daytime reemergence and rebound withdrawal symptoms, sometimes
confused with interdose withdrawal, may occur once dependence has set
in. 'Reemergence' is the return of symptoms for which the drug was
initially prescribed, in contrast, 'rebound' symptoms are a return of
the symptoms for which the benzodiazepine was initially taken, but at a
more intense level than before; whereas 'interdose withdrawal' is when a
prior dosage of drug wears off and beginnings of an entirely new cycle
of withdrawal sets in, the symptoms of which dissipate upon taking the
next dosage but after which yet another entirely new cycle of withdrawal
begins when that dosage wears off, a new onset of withdrawal between
each dosage thus called 'interdose withdrawal' and if not
properly treated can recur indefinitely in a vicious circle (for which a
benzo with a long half life, e.g. diazepam, can be substituted so the drug does not wear off between doses).
Withdrawal symptoms may appear for the first time during dose
reduction, and include insomnia, anxiety, distress, weight loss,
dizziness, night sweats, shakes, muscle twitches, aphasia, panic
attacks, depression, derealization, paranoia, indigestion, diarrhea,
photo phobia etc., and are more commonly associated with short-acting
benzodiazepines discontinuation, like triazolam. Daytime symptoms can occur after a few days to a few weeks of administration of nightly benzodiazepines or z-drugs such as zopiclone; withdrawal-related insomnia rebounds worse than baseline, and for rapidly eliminated benzodiazepines, including triazolam and temazepam, this may occur even when used briefly and intermittently, according to a small 1991 study (n=18).
The following symptoms may emerge during gradual or abrupt dosage reduction:
As withdrawal progresses, patients often find their physical and
mental health improves with improved mood and improved cognition.
Mechanism
The neuroadaptive processes involved in tolerance, dependence, and
withdrawal mechanisms implicate both the GABAergic and the glutamatergic
systems. Gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system; roughly one-quarter to one-third of synapses use GABA. GABA mediates the influx of chloride ions through ligand-gated chloride channels called GABAA
receptors. When chloride enters the nerve cell, the cell membrane
potential hyperpolarizes thereby inhibiting depolarization, or reduction
in the firing rate of the post-synaptic nerve cell. Benzodiazepines potentiate the action of GABA, by binding a site between the α and γ subunits of the 5-subunit receptor thereby increasing the frequency of the GABA-gated chloride channel opening in the presence of GABA.
When potentiation is sustained by long-term use, neuroadaptations
occur which result in decreased GABAergic response. What is certain is
that surface GABAA receptor protein levels are altered in response to benzodiazepine exposure, as is receptor turnover rate.
The exact reason for the reduced responsiveness has not been elucidated
but down-regulation of the number of receptors has only been observed
at some receptor locations including in the pars reticulata of the substantia nigra; down-regulation of the number of receptors or internalization does not appear to be the main mechanism at other locations.
Evidence exists for other hypotheses including changes in the receptor
conformation, changes in turnover, recycling, or production rates,
degree of phosphorylation and receptor gene expression, subunit
composition, decreased coupling mechanisms between the GABA and
benzodiazepine site, decrease in GABA production, and compensatory
increased glutamatergic activity.
A unified model hypothesis involves a combination of internalization of
the receptor, followed by preferential degradation of certain receptor
sub-units, which provides the nuclear activation for changes in receptor
gene transcription.
It has been postulated that when benzodiazepines are cleared from
the brain, these neuroadaptations are "unmasked", leading to unopposed
excitability of the neuron. Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. Increased glutamate excitatory activity during withdrawal may lead to sensitization or kindling of the CNS, possibly leading to worsening cognition and symptomatology and making each subsequent withdrawal period worse. Those who have a prior history of withdrawing from benzodiazepines are found to be less likely to succeed the next time around.
Diagnosis
In
severe cases, the withdrawal reaction or protracted withdrawal may
exacerbate or resemble serious psychiatric and medical conditions, such
as mania, schizophrenia, agitated depression, panic disorder, generalised anxiety disorder, and complex partial seizures and, especially at high doses, seizure disorders.
Failure to recognize discontinuation symptoms can lead to false
evidence for the need to take benzodiazepines, which in turn leads to
withdrawal failure and reinstatement of benzodiazepines, often to higher
doses. Pre-existing disorder or other causes typically do not improve,
whereas symptoms of protracted withdrawal gradually improve over the
ensuing months.
Symptoms may lack a psychological cause and can fluctuate in
intensity with periods of good and bad days until eventual recovery.
Prevention
According to the British National Formulary, it is better to withdraw too slowly rather than too quickly from benzodiazepines.
The rate of dosage reduction is best carried out so as to minimize the
symptoms' intensity and severity. Anecdotally, a slow rate of reduction
may reduce the risk of developing a severe protracted syndrome.
Long half-life benzodiazepines like diazepam or chlordiazepoxide
are preferred to minimize rebound effects and are available in low dose
forms. Some people may not fully stabilize between dose reductions,
even when the rate of reduction is slowed. Such people sometimes simply
need to persist as they may not feel better until they have been fully
withdrawn from them for a period of time.
Management of benzodiazepine dependence involves considering the
person's age, comorbidity and the pharmacological pathways of
benzodiazepines.
Psychological interventions may provide a small but significant
additional benefit over gradual dose reduction alone at post-cessation
and at follow-up.
The psychological interventions studied were relaxation training,
cognitive-behavioral treatment of insomnia, and self-monitoring of
consumption and symptoms, goal-setting, management of withdrawal and
coping with anxiety.
There is no standard approach to managing benzodiazepine withdrawal.
With sufficient motivation and the proper approach, almost anyone can
successfully withdraw from benzodiazepines. However, a prolonged and
severe syndrome can lead to collapsed marriages, business failures,
bankruptcy, hospitalization, and the most serious adverse effect,
suicide. As such, long-term users should not be forced to discontinue against their will.
Over-rapid withdrawal, lack of explanation, and failure to
reassure individuals that they are experiencing temporary withdrawal
symptoms led some people to experience increased panic and fears they
are going mad, with some people developing a condition similar to
post-traumatic stress disorder as a result. A slow withdrawal regimen,
coupled with reassurance from family, friends, and peers improves the
outcome. According to a 2015 Cochrane review, cognitive behavior therapy plus taper was effective in achieving discontinuation in the short-term but the effect was not certain after six months.
Medications
While some substitutive pharmacotherapies may have promise, current evidence is insufficient to support their use.
Some studies found that the abrupt substitution of substitutive
pharmacotherapy was actually less effective than gradual dose reduction
alone, and only three studies found benefits of adding melatonin, paroxetine, trazodone, or valproate in conjunction with a gradual dose reduction.
Antipsychotics are generally ineffective for benzodiazepine withdrawal-related psychosis.
Antipsychotics should be avoided during benzodiazepine withdrawal as
they tend to aggravate withdrawal symptoms, including convulsions. Some antipsychotic agents may be riskier than others during withdrawal, especially clozapine, olanzapine or low potency phenothiazines (e.g., chlorpromazine), as they lower the seizure threshold and can worsen withdrawal effects; if used, extreme caution is required.
Barbiturates are cross tolerant to benzodiazepines and should generally be avoided; however phenobarbital can be used, as it is relatively safe, see below.
Benzodiazepines or cross tolerant drugs should be avoided after discontinuation, even occasionally. These include the nonbenzodiazepinesZ-drugs,
which have a similar mechanism of action. This is because tolerance to
benzodiazepines has been demonstrated to be still present at four months
to two years after withdrawal depending on personal biochemistry.
Re-exposures to benzodiazepines typically resulted in a reactivation of
the tolerance and benzodiazepine withdrawal syndrome.
Bupropion,
which is used primarily as an antidepressant and smoking cessation aid,
is contraindicated in persons experiencing abrupt withdrawal from
benzodiazepines or other sedative-hypnotics (e.g. alcohol), due to an
increased risk of seizures.
Buspirone augmentation was not found to increase the discontinuation success rate.
Caffeine may worsen withdrawal symptoms because of its stimulatory properties. At least one animal study has shown some modulation of the benzodiazepine site by caffeine, which produces a lowering of seizure threshold.
Carbamazepine, an anticonvulsant,
appears to have some beneficial effects in the treatment and management
of benzodiazepine withdrawal; however, research is limited and thus the
ability of experts to make recommendations on its use for
benzodiazepine withdrawal is not possible at present.
Ethanol, the primary alcohol in alcoholic beverages, even mild to moderate use, has been found to be a significant predictor of withdrawal failure, probably because of its cross tolerance with benzodiazepines.
Flumazenil
has been found to stimulate the reversal of tolerance and the
normalization of receptor function. However, further research is needed
in the form of randomised trials to demonstrate its role in the
treatment of benzodiazepine withdrawal. Flumazenil stimulates the up-regulation and reverses the uncoupling of benzodiazepine receptors to the GABAA receptor, thereby reversing tolerance and reducing withdrawal symptoms and relapse rates.
Because of limited research and experience compared to the possible
risks involved, the flumazenil detoxification method is controversial
and can only be done as an inpatient procedure under medical
supervision.
Flumazenil was found to be more effective than placebo in
reducing feelings of hostility and aggression in patients who had been
free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.
A study into the effects of the benzodiazepine receptor
antagonist, flumazenil, on benzodiazepine withdrawal symptoms persisting
after withdrawal was carried out by Lader and Morton. Study subjects
had been benzodiazepine-free for between one month and five years, but
all reported persisting withdrawal effects to varying degrees.
Persistent symptoms included clouded thinking, tiredness, muscular
symptoms such as neck tension, depersonalisation, cramps and shaking and the characteristic perceptual
symptoms of benzodiazepine withdrawal, namely, pins and needles
feeling, burning skin, pain and subjective sensations of bodily
distortion. Therapy with 0.2–2 mg of flumazenil intravenously was found to decrease these symptoms in a placebo-controlled
study. This is of interest as benzodiazepine receptor antagonists are
neutral and have no clinical effects. The author of the study suggested
the most likely explanation is past benzodiazepine use and subsequent
tolerance had locked the conformation of the GABA-BZD receptor complex
into an inverse agonist conformation, and the antagonist
flumazenil resets benzodiazepine receptors to their original
sensitivity. Flumazenil was found in this study to be a successful
treatment for protracted benzodiazepine withdrawal syndrome, but further
research is required. A study by Professor Borg in Sweden produced similar results in patients suffering from protracted withdrawal. In 2007, Hoffmann–La Roche
the makers of flumazenil, acknowledged the existence of protracted
benzodiazepine withdrawal syndromes, but did not recommended flumazenil
to treat the condition.
Fluoroquinolone antibiotics
have been noted to increase the incidence of a CNS toxicity from 1% in
the general population, to 4% in benzodiazepine-dependent population or
in those undergoing withdrawal from them. This is probably the result of
their GABA antagonistic effects as they have been found to
competitively displace benzodiazepines from benzodiazepine receptor
sites. This antagonism can precipitate acute withdrawal symptoms, that
can persist for weeks or months before subsiding. The symptoms include
depression, anxiety, psychosis, paranoia, severe insomnia, paresthesia, tinnitus, hypersensitivity to light and sound, tremors,
status epilepticus, suicidal thoughts and suicide attempt.
Fluoroquinolone antibiotics should be contraindicated in patients who
are dependent on or in benzodiazepine withdrawal. NSAIDs
have some mild GABA antagonistic properties and animal research
indicate that some may even displace benzodiazepines from their binding
site. However, NSAIDs taken in combination with fluoroquinolones cause a
very significant increase in GABA antagonism, GABA toxicity, seizures,
and other severe adverse effects.
Imidazenil has received some research for management of benzodiazepine withdrawal, but is not currently used in withdrawal.
Imipramine was found to statistically increase the discontinuation success rate.
Melatonin augmentation was found to statistically increase the discontinuation success rate for people with insomnia.
Phenobarbital, (a barbiturate), is used at "detox" or other inpatient facilities to prevent seizures during rapid withdrawal or cold turkey. The phenobarbital is followed by a one- to two-week taper, although a slow taper from phenobarbital is preferred. In a comparison study, a rapid taper using benzodiazepines was found to be superior to a phenobarbital rapid taper.
Pregabalin may help reduce the severity of benzodiazepine withdrawal symptoms, and reduce the risk of relapse.
Propranolol was not found to increase the discontinuation success rate.
SSRI antidepressants have been found to have little value in the treatment of benzodiazepine withdrawal.
Trazodone was not found to increase the discontinuation success rate.
Inpatient treatment
Inpatientdrug detox or rehabilitation
facilities may be inappropriate for those who have become tolerant or
dependent while taking the drug as prescribed, as opposed to
recreational use. Such inpatient referrals may be traumatic for
non-abusers.
Prognosis
A 2006 meta-analysis
found evidence for the efficacy of stepped care: minimal intervention
(e.g. send an advisory letter, or meet large number of patients to
advise discontinuation), followed by systematic tapered discontinuation
alone without augmentation if the first try was unsuccessful.
Cognitive behavioral therapy improved discontinuation success rates for
panic disorder, melatonin for insomnia, and flumazenil or sodium
valproate for general long-term benzodiazepine use.
A ten-year follow-up found that more than half of those who had
successfully withdrawn from long-term use were still abstinent two years
later, and that if they were able to maintain this state at two years,
they were likely to maintain this state at the ten-year followup.
One study found that after one year of abstinence from long-term use of
benzodiazepines, cognitive, neurological and intellectual impairments
had returned to normal.
Those who had a prior psychiatric diagnosis had a similar success rate from a gradual taper at a two-year follow-up. Withdrawal from benzodiazepines did not lead to an increased use of antidepressants.
The consensus is to reduce dosage gradually over several weeks, e.g. 4 or more weeks for diazepam doses over 30 mg/day,
with the rate determined by the person's ability to tolerate symptoms.
The recommended reduction rates range from 50% of the initial dose every week or so,
to 10-25% of the daily dose every 2 weeks.
For example, the reduction rate used in the Heather Ashton protocol
calls for eliminating 10% of the remaining dose every two to four weeks,
depending on the severity and response to reductions with the final
dose at 0.5 mg dose of diazepam or 2.5 mg dose of chlordiazepoxide.
For most people, discontinuation over 4-6 weeks or 4-8 weeks is suitable.
Prolonged period of reduction over many months should be avoided to
prevent the withdrawal process from becoming a "morbid focus" for the
person.
Duration
After
the last dose has been taken, the acute phase of the withdrawal
generally lasts for about two months although withdrawal symptoms, even
from low-dose use, can persist for six to twelve months gradually
improving over that period, however, clinically significant withdrawal symptoms may persist for years, although gradually declining.
A clinical trial of patients taking the benzodiazepine alprazolam
for as short as eight weeks triggered protracted symptoms of memory
deficits which were still present up to eight weeks after cessation of
alprazolam.
Protracted withdrawal syndrome
Protracted
withdrawal syndrome refers to symptoms persisting for months or even
years. A significant minority of people withdrawing from
benzodiazepines, perhaps 10% to 15%, experience a protracted withdrawal syndrome which can sometimes be severe. Symptoms may include tinnitus, psychosis, cognitive deficits, gastrointestinal complaints,
insomnia, paraesthesia (tingling and numbness), pain (usually in limbs
and extremities), muscle pain, weakness, tension, painful tremor,
shaking attacks, jerks, dizziness and blepharospasm
and may occur even without a pre-existing history of these symptoms.
Tinnitus occurring during dose reduction or discontinuation of
benzodiazepines is alleviated by recommencement of benzodiazepines.
Dizziness is often reported as being the withdrawal symptom that lasts
the longest.
A study testing neuropsychological factors found
psychophysiological markers differing from normals, and concluded that
protracted withdrawal syndrome was a genuine iatrogenic condition caused
by the long-term use.
The causes of persisting symptoms are a combination of pharmacological
factors such as persisting drug induced receptor changes, psychological
factors both caused by the drug and separate from the drug and possibly
in some cases, particularly high dose users, structural brain damage or
structural neuronal damage.
Symptoms continue to improve over time, often to the point where people
eventually resume their normal lives, even after years of incapacity.
A slow withdrawal rate significantly reduces the risk of a
protracted or severe withdrawal state. Protracted withdrawal symptoms
can be punctuated by periods of good days and bad days. When symptoms
increase periodically during protracted withdrawal, physiological
changes may be present, including dilated pupils as well as an increase in blood pressure and heart rate.
The change in symptoms has been proposed to be due to changes in
receptor sensitivity for GABA during the process of tolerance reversal.[6] A meta-analysis
found cognitive impairments in many areas due to benzodiazepine use
show improvements after six months of withdrawal, but significant
impairments in most areas may be permanent or may require more than six
months to reverse.
Protracted symptoms continue to fade over a period of many months
or several years. There is no known cure for protracted benzodiazepine
withdrawal syndrome except time,
however, the medication flumazenil was found to be more effective than
placebo in reducing feelings of hostility and aggression in patients who
had been free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.
Epidemiology
The
severity and length of the withdrawal syndrome is likely determined by
various factors, including rate of tapering, length of use and dosage
size, and possible genetic factors. Those who have a prior history of withdrawing from benzodiazepines may have a sensitized or kindled central nervous system leading to worsening cognition and symptomatology, and making each subsequent withdrawal period worse.
Special populations
Pediatrics
A neonatal withdrawal syndrome, sometimes severe, can occur when the mother had taken benzodiazepines, especially during the third trimester. Symptoms include hypotonia, apnoeic spells, cyanosis, impaired metabolic responses to cold stress, and seizures. The neonatal benzodiazepine withdrawal syndrome has been reported to persist from hours to months after birth.
A withdrawal syndrome is seen in about 20% of pediatric intensive care unit children after infusions with benzodiazepines or opioids.
The likelihood of having the syndrome correlates with total infusion
duration and dose, although duration is thought to be more important. Treatment for withdrawal usually involves weaning over a 3- to 21-day period if the infusion lasted for more than a week.
Symptoms include tremors, agitation, sleeplessness, inconsolable
crying, diarrhea and sweating. In total, over fifty withdrawal symptoms
are listed in this review article.
Environmental measures aimed at easing the symptoms of neonates with
severe abstinence syndrome had little impact, but providing a quiet
sleep environment helped in mild cases.
Pregnancy
Discontinuing benzodiazepines or antidepressants abruptly due to concerns of teratogenic
effects of the medications has a high risk of causing serious
complications, so is not recommended. For example, abrupt withdrawal of
benzodiazepines or antidepressants has a high risk of causing extreme
withdrawal symptoms, including suicidal ideation and a severe rebound
effect of the return of the underlying disorder if present. This can
lead to hospitalisation and potentially, suicide. One study reported
one-third of mothers who suddenly discontinued or very rapidly tapered
their medications became acutely suicidal due to 'unbearable symptoms'.
One woman had a medical abortion,
as she felt she could no longer cope, and another woman used alcohol in
a bid to combat the withdrawal symptoms from benzodiazepines. Spontaneous abortions
may also result from abrupt withdrawal of psychotropic medications,
including benzodiazepines. The study reported physicians generally are
not aware of the severe consequences of abrupt withdrawal of psychotropic medications such as benzodiazepines or antidepressants.
Elderly
A study
of the elderly who were benzodiazepine dependent found withdrawal could
be carried out with few complications and could lead to improvements in
sleep and cognitive abilities. At 52 weeks after successful withdrawal,
a 22% improvement in cognitive status was found, as well as improved
social functioning. Those who remained on benzodiazepines experienced a
5% decline in cognitive abilities, which seemed to be faster than that
seen in normal aging, suggesting the longer the intake of
benzodiazepines, the worse the cognitive effects become. Some worsening
of symptoms were seen in the first few months of benzodiazepine
abstinence, but at a 24-week followup, elderly subjects were clearly
improved compared to those who remained on benzodiazepines. Improvements
in sleep were seen at the 24- and 52-week followups. The authors
concluded benzodiazepines were not effective in the long term for sleep
problems except in suppressing withdrawal-related rebound insomnia.
Improvements were seen between 24 and 52 weeks after withdrawal in many
factors, including improved sleep and several cognitive and performance
abilities. Some cognitive abilities, which are sensitive to
benzodiazepines, as well as age, such as episodic memory
did not improve. The authors, however, cited a study in younger
patients who at a 3.5-year followup showed no memory impairments and
speculated that certain memory functions take longer to recover from
chronic benzodiazepine use and further improvements in elderly people's
cognitive function may occur beyond 52 weeks after withdrawal. The
reason it took 24 weeks for improvements to be seen after cessation of
benzodiazepine use was due to the time it takes the brain to adapt to
the benzodiazepine-free environment.
At 24 weeks, significant improvements were found, including
accuracy of information processing improved, but a decline was seen in
those who remained on benzodiazepines. Further improvements were noted
at the 52-week followup, indicating ongoing improvements with
benzodiazepine abstinence. Younger people on benzodiazepines also
experience cognitive deterioration in visual spatial memory, but are not
as vulnerable as the elderly to the cognitive effects.
Improved reaction times were noted at 52 weeks in elderly patients free
from benzodiazepines. This is an important function in the elderly,
especially if they drive a car due to the increased risk of road traffic
accidents in benzodiazepine users.
At the 24-week followup, 80% of people had successfully withdrawn from
benzodiazepines. Part of the success was attributed to the placebo method used for part of the trial which broke the psychological dependence
on benzodiazepines when the elderly patients realised they had
completed their gradual reduction several weeks previously, and had only
been taking placebo tablets. This helped reassure them they could sleep
without their pills.
The authors also warned of the similarities in pharmacology and mechanism of action of the newer nonbenzodiazepineZ drugs.
The elimination half-life
of diazepam and chlordiazepoxide, as well as other long half-life
benzodiazepines, is twice as long in the elderly compared to younger
individuals. Many doctors do not adjust benzodiazepine dosage according
to age in elderly patients.
