Dependence, Withdrawal and Rebound of CNS

doi:10.
1093/braincomms/fcz025 BRAIN COMMUNICATIONS 2019: Page 1 of 23 | 1
BRAIN
AIN COMMUNICATIONS
Dependence, withdrawal and rebound of CNS

drugs: an update and regulatory
considerations for new drugs development
Alicja Lerner1 and Michael Klein2
The purpose of this article is to describe dependence and withdrawal phenomena related to CNS drugs discontinuation and to clar-
ify issues related to the evaluation of clinical drug withdrawal and rebound as they relate to safety in new drug development. The
article presents current understanding and definitions of drug dependence and withdrawal which are also relevant and important
features of addiction, though not the same. Addiction, called substance use disorder in DSM-5, affects an individual’s brain and be-
haviour, represents uncontrollable drug abuse and inability to stop taking a drug regardless of the harm it causes. Characteristic
withdrawal syndromes following abrupt discontinuation of CNS-active drugs from numerous drug classes are described. These in-
clude drugs both scheduled and non-scheduled in the Controlled Substances Act, which categorizes drugs in five schedules based
on their relative abuse potentials and dependence liabilities and for regulatory purposes. Schedules 1 and 2 contain drugs identified
as those with the highest abuse potential and strictest regulations. Less recognized aspects of drug withdrawal, such as rebound
and protracted withdrawal syndromes for several drug classes are also addressed. Part I presents relevant definitions and describes
clinical withdrawal and dependence phenomena. Part II reviews known withdrawal syndromes for the different drug classes, Part
III describes rebound and Part IV describes protracted withdrawal syndromes. To our knowledge, this is the first compilation of
withdrawal syndromes for CNS drugs. Part V provides details of evaluation of dependence and withdrawal in the clinical trials for
CNS drugs, which includes general design recommendations, and several tools, such as withdrawal questionnaires and multiple
scales that are helpful in the systematic evaluation of withdrawal. The limitations of different aspects of this method of dependence
and withdrawal evaluation are also discussed.
1 Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993-0002, USA
2 Controlled Substance Scientific Solutions LLC, 4601 North Park Avenue #506, Chevy Chase, MD 20815-4572, USA
Correspondence to: Alicja Lerner, MD, PhD, FDA
Controlled Substance Staff, Center for Drug Evaluation and Research, Food and Drug Administration
10903 New Hampshire Avenue, Building 51
Silver Spring, MD 20993-0002, USA
E-mail: [email protected]
Correspondence may also be addressed to: Michael Klein, PhD
Controlled Substance Scientific Solutions LLC
4601 North Park Avenue #506
Chevy Chase, MD 20815-4572
USA
E-mail: [email protected]
Keywords: dependence; withdrawal syndromes; rebound; human dependence evaluation
Received April 29, 2019. Revised September 12, 2019. Accepted September 16, 2019. Advance Access publication October 16, 2019
C The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse,
distribution, and reproduction in any medium, provided the original work is properly cited.
2 | BRAIN COMMUNICATIONS 2019: Page 2 of 23 A. Lerner and M. Klein
Abbreviations: ARSW ¼ Adjective Rating Scale for Withdrawal; ASAM ¼ American Society of Addiction Medicine; BZ ¼ benzo-
diazepines; CB1 ¼ cannabinoid 1 receptors; COWS ¼ Clinical Opiate Withdrawal Scale; DSM-5 ¼ diagnostic and statistical man-
ual of mental disorders, fifth edition; FDA ¼ Food and Drug Administration; INF ¼ information not found; MAOIs ¼ monoamine
oxidase inhibitors; NMS ¼ neuroleptic malignant syndrome; NAS ¼ neonatal abstinence syndrome; SSRIs ¼ selective serotonin re-
uptake inhibitors; SNRIs ¼ serotonin–norepinephrine reuptake inhibitors; THC ¼ D9-tetrahydrocannabinol; VAS ¼ Visual
Analogue Scale
Graphical Abstract
Part I: Introduction, their significance underappreciated, particularly for drugs

not known for abuse potential and which are not sched-
definitions and general uled substances in the Controlled Substances Act
(Newman et al., 2009; Rabinak and Nirenberg, 2010;
considerations of drug Reidenberg, 2011; Hudak et al., 2012; Chouinard and
dependence, withdrawal Chouinard, 2015; Fava et al., 2015).
Thus, this article has two main goals, one is to provide
and rebound brief condensed summaries of withdrawal syndromes for
the majority of the CNS-active drug groups which are of
Introduction interest to prescribers, patients and also clinical scientists,
In the United States, the significance of drug dependence, this addresses a gap of knowledge usually not readily
especially as it relates to addiction, came to the foreground available in the drug labels.
and captured public attention only in recent decades, fol- The second goal is to emphasize the importance of
lowing epidemics of drug abuse, dependence and addiction, evaluating dependence and withdrawal for all CNS-active
sweeping the country, resulting in staggering numbers of drugs and to provide standardized advice how to assess
deaths. Most cases are related not only to opioid drugs, symptoms of drug withdrawal. The information obtained
but also to benzodiazepines (BZ), stimulants and street will be used to provide safety data for warnings on drug
drugs, including heroin, highly potent fentanyl and its ana- labels and to inform patients and physicians about pos-
logues, cathinone-like hallucinogens and dissociative sub- sible dependence, withdrawal and rebound related to the
stances, and stimulants similar in action to cocaine and drug—and their consequences.
methamphetamine (Dowell et al., 2017; Scholl et al., 2018;
Colon-Berezin et al., 2019; Kariisa et al., 2019). Definitions of dependence and
Serious and potentially life-threatening adverse events
related to drug withdrawal and dependence may result also
withdrawal
from other drug classes generally not associated with abuse The phrase ‘drug dependence and withdrawal’ most often
and not scheduled under the Controlled Substances Act. and traditionally relates to substance abuse. However, at
Withdrawal of antidepressants and other CNS drugs such other times it can relate to a broader concept of ‘depend-
as BZ and stimulants may lead to dangerous, even life- ence and withdrawal’, which potentially may encompass
threatening, withdrawal symptoms and lead to significant all drug classes, because it may be viewed as a function
public health concerns, such as suicidality (Risse et al., of an organism’s adaptation to the presence of a drug in
1990; Valuck et al., 2009; APA, 2013; Fava et al., 2015). the body. In this study, we will discuss both approaches.
A widespread misunderstanding regarding dependence In the DSM-5 (Diagnostic and Statistical Manual of
and withdrawal is that both need to be related to drug Mental Disorders, Fifth Edition; APA, 2013) definitions
abuse and addiction. Also, in general, the occurrence of of drug dependence and withdrawal related to substance
dependence and withdrawal may be underestimated, and use disorder are described in the ‘Substance-Related and
CNS drug dependence and new drug development BRAIN COMMUNICATIONS 2019: Page 3 of 23 | 3
Addictive Disorders’ section, and are further defined for dependence; but again, this would not be classified as an
drugs and substances known to be related to substance addiction.
use disorders. These substances include opioids, sedatives, The phenomena of dependence are related to withdraw-
hypnotics, anxiolytics, stimulants, cannabis, caffeine, alco- al, tolerance and rebound. Ashton (1991) described the
hol and tobacco. Of these substances, cannabis is listed in relation of withdrawal, rebound and tolerance using the
Schedule 1 of the Controlled Substances Act, many example of BZ. The excerpt below is somewhat lengthy
opioids and stimulants are listed in Schedule 2; sedatives, for the citation, but it describes withdrawal phenomena,
hypnotics and anxiolytics are listed in Schedule 3 or 4, their sequence and physiological background so well that
whereas caffeine, alcohol and tobacco are not listed in the the authors decided to provide it here in full.
Controlled Substances Act (United States Congress, 1970). Any chronically used drug gradually engenders a series of homeo-
However, for drugs, in particular CNS active, which are static responses which tend to restore normal function despite the
being developed and evaluated by FDA, we will be using presence of the drug. With chronic benzodiazepine use, compensa-
another definition, more appropriate for this function, tory changes occur in GABA receptors. Such changes consist of
namely, part (i) of the dependence definition cited by the decreased sensitivity of these receptors to GABA, probably as a re-
American Society of Addiction Medicine (ASAM). The result of alterations in affinity state and decreased density (Cowen
cent ASAM definitions of dependence, addiction, tolerance and Nutt, 1982; Nutt and Malizia, 2001).
and withdrawal gained support by the American Academy
In addition, there are changes in the secondary systems controlled
of Pain Medicine and the American Pain Society in 2001,
by GABA, so that the output of excitatory neurotransmitters tends
and have since then been updated (Ries et al., 2014).
to be restored, and/or the sensitivity of their receptors increases. The
• Physical dependence—used in three different ways: (i) whole complex of primary and secondary changes eventually results
physical dependence is a state of adaptation that is in benzodiazepine tolerance.
manifested by a drug class-specific withdrawal syn-
The development of pharmacodynamic tolerance sets the scene for
drome that can be produced by abrupt cessation,
the withdrawal syndrome. Cessation of the drug exposes all the
rapid dose reduction, reducing blood level of the drug adaptations which have accrued to counteract its presence, releasing
and/or administration of an antagonist; (ii) psycho- a rebound of unopposed activity involving many neurotransmitters
logical dependence is a subjective sense of need for a and their receptors and many brain systems. Clinically this state is
specific psychoactive substance, either for its positive manifested as the withdrawal syndrome, consisting of effects that
effects or to avoid negative effects associated with its are largely the opposite of these originally induced by the drug.
abstinence; and (iii) one category of psychoactive sub-
stance use disorder in previous editions of the Evaluation of dependence and withdrawal is an integral
Diagnostic and Statistical Manual of Mental part of FDA’s evaluation of new drugs.
Disorders, but not in the DSM-5, published in 2013. The development of dependence is a general feature of
• Addiction is characterized by inability to consistently drug effects on the human body which frequently cannot
abstain, impairment in behavioural control, craving, be predicted a priori. Thus, it is important to evaluate
diminished recognition of significant problems with thoroughly new drugs for development of dependence,
one’s behaviours and interpersonal relationships, and withdrawal and rebound symptoms, as well for develop-
a dysfunctional emotional response. Like other chronic ment of abuse potential (FDA Abuse Guidance 2017;
diseases, addiction often involves cycles of relapse and FDA and Center for Drug Evaluation and Research,
remission. Without treatment or engagement in recov- 2017).
ery activities, addiction is progressive and can result in The evaluation of human dependence and withdrawal
disability or premature death. is important for regulatory reasons, as it relates to
• Tolerance—a state of adaptation in which exposure to 21U.S.C. 811 and 812 (United States Code, Title 21—
a drug over time results in diminution of one or more FOOD AND DRUGS; U.S. Government, 2006): a drug
of the drug’s physiologic effects. that is a controlled substance, needs to be monitored for
• Withdrawal syndrome—the onset of a predictable con- abuse and misuse and new data that relate to abuse and
stellation of signs and symptoms following the abrupt dependence liability resulting from abuse needs to be
discontinuation of, or rapid reduction in, the dose of assessed.
a psychoactive substance. The assessment of dependence and withdrawal is also
necessary as a potential warning for physicians and
These definitions are important for distinguishing between patients and should be provided in the drug label to in-
dependence and addiction or substance use disorder. form if the drug can be abruptly withdrawn at the end
To further clarify the concept of dependence it can be of treatment or must be slowly tapered to avoid poten-
said that an individual can be addicted to the drug of tially dangerous even life-threatening adverse events after
abuse, or merely develop dependence to the drug of abrupt withdrawal. It is also important to inform subjects
abuse without being addicted. For drugs not associated abusing the drug about health consequences of the devel-
with abuse potential, an individual may still develop opment of dependence and of drug withdrawal.
Drug dependence and withdrawal widely recognized that formation of physical dependence
We present here withdrawal-related phenomena which resulting in a clinically significant withdrawal syndrome can
can be identified for many different drug groups; this list occur within 6 weeks of BZ administration, especially if suf-
is based largely on a description of clinical aspects of ficiently high doses (two to three times the therapeutic dose)
withdrawal emerging after discontinuation of selective are used. MacKinnon and Parker (1982) reviewed the litera-
serotonin reuptake inhibitors (SSRIs; Chouinard and ture on this topic and found that withdrawal may occur
Chouinard, 2015). These withdrawal phenomena include: even after only 4–8 weeks of drug exposure; however, in
these cases frequently excessively high doses were used.
• New symptoms (acute withdrawal symptoms): Newly Kales et al. (1987) observed that after only 7 days of
emerging signs and symptoms which occur almost imme- administration of alprazolam (1 mg) insomnia patients de-
diately after abrupt drug discontinuation or sometimes velop tolerance and drug lost 40% of efficacy, addition-
even after the dose decrease. These symptoms are related ally abrupt withdrawal caused rebound insomnia.
to the disruption of neuroregulatory changes (neuroadap- Roy-Byrne et al. (1989) compared the withdrawal
tation) established during drug administration. effects of alprazolam and diazepam in patients with panic
• Rebound: Recurrence of symptoms of the treated dis- disorder after 6 weeks of drug administration. After an
order in patients, more severe than before the treatment. initial taper, abrupt discontinuation of drug treatment
• Protracted withdrawal syndrome: Usually appears long resulted in relapse and rebound in the patients taking al-
past the timeframe of acute withdrawal symptoms, prazolam and diazepam, with higher prevalence of these
may last for weeks and months, and sometimes may symptoms for alprazolam.
present as a newly emerging disorder. Dependence even after therapeutic exposure to opioids
• Relapse. Return of signs and symptoms of the disease such as oxycodone develops even more rapidly, within 2–
after a remission due to natural causes or termination 3 weeks as described by Wakim (2012), Pasero and
of treatment; it occurs as a phenomenon in the natural McCaffery (2010) and Dowell et al. (2016) in Oxycontin
history of the disorder. Relapse is not an aspect of de- label September 2018 and Roxybond label April 2017.
pendence; however, it is mentioned here because it These studies would suggest that dependence formation
occurs during the timeframe of acute withdrawal and after administration of opioids can occur within 2–
needs to be differentiated from the withdrawal. 3 weeks using therapeutic doses and for BZ can occur
• Symptoms of delayed drug toxicity: May be over- within 6 weeks using therapeutic doses of BZ and in 4
imposed on acute withdrawal symptoms and some- weeks with supratherapeutic doses.
times are difficult to differentiate from them.
Sex and age differences—a possible

Factors influencing formation of
factor in severity of withdrawal
drug dependence
Animal withdrawal studies, sex and age impact
Several studies were performed to evaluate the influence
Non-clinical withdrawal studies in rodents showed that
of various factors on the development of dependence. A
there are sex and age differences in the severity of symp-
general consensus is that: (i) timing and rate of expo-
toms and duration of withdrawal as described in Box 1.
sure(s); (ii) dose; and (iii) drug potency, critically impact
the formation of dependence, where with a longer time- Sex and age differences in humans during drugs
frame of use, higher dose and higher drug potency, the withdrawal
likelihood of dependence formation increases (MacKinnon
There are limited human data available regarding differ-
and Parker, 1982; Owen and Tyrer, 1983; Roy-Byrne
ence in severity of withdrawal symptoms by sex; some
et al., 1989; Rickels et al., 1990; Busto and Sellers, 1991;
studies discuss this topic for different pharmacological
Noyes et al., 1991; Chouinard, 2004; Kan et al., 2004).
groups (Agrawal et al., 2008; Copersino et al., 2010;
The neurotransmitter system affected by the drug is
Chen et al., 2014; Chartier et al., 2015; Herrmann et al.,
also an important variable. Opiate, GABA-ergic and
2015; Cuttler et al., 2016; Rungnirundorn et al., 2017).
dopaminergic systems tend to be more frequently linked
to the development of dependence. However, the impact Opioids. Back et al. (2011), studied demographic charac-
of other factors, such as gender and age, is less known. teristics and substance use parameters among opioid-de-
pendent men and women participating in a multisite
The length of exposure necessary for development effectiveness trial.
of dependence Withdrawal symptoms in this population were assessed
Probably the first studies examining the relationship be- using the Opiate Withdrawal Symptoms and Craving
tween time of drug exposure, dose and formation of de- (COWS), Adjective Rating Scale for Withdrawal (ARSW)
pendence and withdrawal were performed in psychiatric and Visual Analogue Scale (VAS). The results showed that
patients by Hollister et al. (1961, 1963) using the BZ, gender difference examined with COWS was small (effect
chlordiazepoxide and diazepam. Since then, it has been size ¼ 0.12), also no statistically significant gender-related
Box 1 Animal withdrawal studies, sex and age impact

Opioids
Cicero et al. (2002) found that there were sex-related differences in the severity of an opioid withdrawal syndrome after cessation of chronic mor-
phine administration. After stopping the chronic morphine injections or morphine pellet implantation, male rats experienced more severe spontan-
eous withdrawal syndrome than female rats, consisting of wet-dog shakes, diarrhoea and prominent body weight loss; also, the duration of the
withdrawal syndrome was longer in male rats.
In a more recent study, Bobzean et al. (2019) also observed that male morphine-dependent rats expressed more severe symptoms (wet-dog
shakes, writhing, global withdrawal score) during the early phases of spontaneous withdrawal compared with females.
Benzodiazepines
Pesce et al. (1994) reported sex differences in withdrawal symptoms of intact and castrated mice that were first treated with subcutaneously
implanted pellet of diazepam and then underwent precipitated withdrawal with flumazenil injection. Both sexes experienced seizures and jerks;
however, seizures were more pronounced in females. Castration significantly increased the incidence of seizures in male mice.
Sloan et al. (2000) observed the sex differences in the number in seizures, respiratory rate and vocalization in rats which first had implanted di-
azepam and then underwent withdrawal precipitated with either with PK11195, a peripheral BZ antagonist, and/or flumazenil. Flumazenil induced
higher withdrawal scores in females, also female rats vocalized significantly more than male rats; however, flumazenil tended to produce more tach-
ypnoea in male than in female rats.
Cannabis
Marusich et al. (2014) studied impact of gonadal hormones on D9-tetrahydrocannabinol (THC) dependence in gonadectomized rats. Rimonabant,
selective cannabinoid 1 receptor blocker, precipitated withdrawal in rats with increased forepaw tremors, licking, and increased startle amplitude.
However, testosterone treatment of gonadectomized males decreased withdrawal-induced licking, whereas oestradiol and progesterone treatment
of gonadectomized females increased withdrawal-induced chewing, and progesterone increased withdrawal-induced sniffing.
Harte-Hargrove and Dow-Edwards (2012) who studied the sex differences in adolescent THC-dependent rats after the spontaneous THC with-
drawal showed increased anxiety-like behaviour in females and decreased anxiety-like behaviour in males early in withdrawal, also female rats
showed greater locomotor depression than males.
Nicotine
Torres et al. (2013) reported that during nicotine withdrawal, adult female rats displayed higher levels of anxiety-like behaviour than adult males.
However, adolescents displayed less nicotine withdrawal than adults, but adolescent males displayed some increase in anxiety-like behaviour.
Hamilton et al. (2010) observed more severe withdrawal behaviours in adolescent male Long-Evans than females. However, these sex differen-
ces were not seen in the adolescent Sprague Dawley male and female rats, both sexes had significant withdrawal behaviours.
differences in withdrawal symptoms were revealed with score. Women had significantly higher composite WDS
the ARSW or VAS. Subjective craving as measured with scores than men as well as higher scores than men on six
VAS was significantly higher in women than men. individual symptoms in two domains: mood symptoms
However, further research studies with humans, males that included irritability, restlessness, increased anger and
and females, are needed to investigate sex and gender vari- violent outbursts; and gastrointestinal symptoms, that
ables that influence the various conditions affected by included nausea and stomach pain.
opioids, including treating pain, occurrence of adverse Cuttler et al. (2016) based on the online survey that
events and development of addiction (Koons et al., 2018). assessed the cannabis users’ practices and experiences
Cannabis. Agrawal et al. (2008) examined symptoms of found that during the withdrawal period men more often
cannabis withdrawal in subjects who reported its use during than women reported insomnia and vivid dreams, where-
the past 12 months to the National Epidemiologic Survey on as women more often reported nausea and anxiety. Also,
Alcohol and Related Conditions (NESARC). It was noted significantly more women (44.9%) than men (36.7%) did
that nausea was more frequently reported by women (3.2% not experience withdrawal symptoms.
versus 1.7%) and goose bumps and pupil dilation more fre- Stimulants. Chartier et al. (2015) examined sex-specific
quently reported by men (2.2% versus 4.6%) at P ¼ 0.02. factors associated with severity of stimulant withdrawal
Copersino et al. (2010), in a study that evaluated soci- in a population of abusing or dependent subjects under-
odemographic characteristics of the cannabis withdrawal going treatment. The results of the study that used
experience, reported that women were more likely than Stimulant Selective Severity Assessment (SSSA), showed
men to report physical withdrawal symptoms. Also, dur- that women reported greater severity of stimulant with-
ing cannabis withdrawal women reported more symptoms drawal, namely 13.78 (SD 11.9) than did men 10.44 (SD
of upset stomach but significantly fewer instances of crav- 11.1). This difference was seen in anxiety-related with-
ing or increased sex drive compared with men. drawal symptoms (anxiety, tension, attention and irrit-
Herrmann et al. (2015) reported on sex differences dur- ability) which were more frequent in women.
ing cannabis withdrawal which were assessed with the Rungnirundorn et al. (2017) evaluated withdrawal
Marijuana Withdrawal Checklist (MWC), then converted symptoms in both genders of methamphetamine users.
into a composite Withdrawal Discomfort Scale (WDS) Females were more likely than males to be
methamphetamine dependent (79% versus 60%), and to which is obviously incorrect, although it is not clear
experience withdrawal (65.3% versus 48.9%). Also, some where this statement originated as we did not find the
withdrawal symptoms were more frequent in women ver- source. For example, heroin half-life is 2-6 min, but dur-
sus men, including hypersomnia (77.2% versus 64.8%), ation of the withdrawal syndrome is approximately 4–
fatigue (77.5% versus 70.3%). 10 days (see Fig. 1), although this delay may be explained
Ketamine. Chen et al. (2014) analysed sex differences in by the fact that the main active molecule in the brain
subjective withdrawal symptoms associated with ketamine after heroin administration is not heroin itself but rather
use. Results of the study showed that female ketamine morphine and 6-acetylmorphine, which have longer half-
users, compared with male users, reported meaningful dif- lives and thus intoxication and withdrawal is longer last-
ference in withdrawal symptoms, such as anxiety (23.4% ing (Inturrisi et al., 1983; Rook et al., 2006). For
versus 17.4%), dysphoria (24.1% versus 15.9%) and amphetamines, half-life is 9–11 h, whereas withdrawal
cravings (23% versus 17.9%). symptoms only start 2–4 days after drug discontinuation
(New South Wales Government, 2008) and last at least
Nicotine. Foulkner et al. (2018) examined in young adult
2–4 weeks. Generally, acute withdrawal symptoms for
smokers impact of varied yields of nicotine on sex differen-
drugs with very short lifetimes (e.g. heroin) last about a
ces in craving, withdrawal and affect. Women reported
week; for drugs with a medium half-life of 10–20 h
greater psychological withdrawal, greater sedation and
(e.g. short-acting BZ), the acute withdrawal syndrome
trend towards greater craving than men during abstinence.
may last 2–4 weeks; whereas for drugs with longer half-
lives (e.g. long-half-life BZ) the withdrawal phase may
Age as a factor in dependence last 2–8 weeks (Fig. 2). However, this generalization
formation and severity of applies only to acute withdrawal syndrome; symptoms of
withdrawal syndrome protracted withdrawal may last for weeks and months.
There are some data available describing impact of age

on dependence formation, mainly in relation to opioids
Current theories on the
and BZ. It was noted that in children undergoing treat- neurobiological basis of dependence
ment with opioids, physical dependence may develop in and withdrawal
as little as 2–3 days of continuous opioid therapy (Fisher
et al., 2013). Also, it seems that signs of opioid with- Opponent process theory of drug withdrawal
drawal are more severe in older children than in younger Because few drug groups discussed in this manuscript
children and infants; thus, adolescents and children more namely opioids, stimulants and BZ are also involved in ad-
than 7 years old are particularly at risk for increased se- dictive disorders alternative concepts of dependence and
verity of withdrawal (Anand and Ingraham, 1996). withdrawal are presented (Koob and Le Moal, 2008a, b).
Regarding BZ withdrawal in children, in addition to Addiction is depicted as a compulsive disorder with exces-
classic BZ withdrawal symptoms, children may show vis- sive drug intake and loss of control over intake, with
ual hallucinations, agitation, facial grimacing, aerophagia, decreases in reward neurotransmission and activation of
myoclonus, ataxia, choreoathetoid movements and gener- brain stress systems. Addiction is a disorder that involves ele-
alized seizures (Anand and Ingraham, 1996). Dependence ments of both impulsivity and compulsivity in which impul-
and resulting withdrawal syndrome may develop in only sivity predominates at the early stages of addiction
7–17 days, although doses of midazolam used in the cases (preoccupation and anticipation) whereas compulsivity domi-
described were high (Sury et al., 1989). nates at the final stages of withdrawal and negative affect.
Also, older adults (aged >50 years) seem to develop The key brain structures involved in these processes are
somewhat different withdrawal symptoms than do ventral striatum with neurotransmitters dopamine and opi-
younger people after BZ discontinuation. These include oid peptides and extended amygdala with corticotropin-
emergence of confusion and disorientation, sometimes releasing factor, norepinephrine and dynorphin. In fact, it
with hallucinations in older people instead of anxiety, in- is proposed that all main drugs of abuse act through the
somnia and perceptual changes noted in younger people central nucleus of the amygdala producing increases in re-
(Kruse, 1990; Simoni-Wastila and Yang, 2006). Also, it ward thresholds, anxiety-like responses and extracellular
was observed that catatonia after BZ withdrawal occurs levels of corticotropin-releasing factor. Specifically, during
mainly in older adults (Rosebush and Mazurek, 1996; development of dependence and withdrawal brain antire-
Lebin and Cerimele, 2017). ward systems are recruited and include corticotropin-
releasing factor, norepinephrine and dynorphin which pro-
Five Half-life times rule—issues and duce aversive states such as dysphoria and stress. The
components of acute drug withdrawal include decrease of
misunderstandings activity of the mesocorticolimbic dopaminergic system and
Some investigators consider that withdrawal symptoms decreased activity in the nucleus accumbens/amygdala
last only for a maximum of five half-lives of the drug, mediated by opioid peptides, GABA and glutamate.
Summary points (1) New withdrawal symptoms include the symptoms that
first appeared during the drug discontinuation or dose
• Dependence and withdrawal are results of neuroadap-
decrease and are not related to symptoms of the
tation that occur during drug treatment.
patient’s original illness.
• Dependence and withdrawal are not equated with drug
(2) Different classes of CNS drugs have some common
addiction although may coexist.
withdrawal symptoms, as well as some specific to the
• The shortest known time to acquire dependence occurs
drug class withdrawal symptoms.
with opioid drugs where 2–3 weeks or longer exposure
(3) New withdrawal symptoms which are common to
at the therapeutic dose may produce dependence and
many CNS drugs include: nausea, anxiety, headaches,
upon drug discontinuation or exposure to antagonist
decreased concentration, irritability, agitation, tremor,
(naloxone) also an acute withdrawal syndrome.
sleep disturbances, dysphoria and depression.
(4) Some new withdrawal symptoms may be characteristic
Part II: Specific acute of a specific CNS drug class:
• Lacrimation, rhinorrhoea and sneezing for opioids
withdrawal syndromes • Electric-shock sensations, confusion and myoclonus
for SSRIs.
acute withdrawal (5) The new withdrawal symptoms are usually transient
syndrome—general features and reversible.
(6) Major complications of abrupt withdrawal may occur,
Ries et al. (2014) report the American Society of such as seizures and psychoses in cases of BZ with-
Addiction Medicine (ASAM) definition of withdrawal as drawal (Preskorn and Denner, 1977; Petursson, 1994),
‘The onset of a predictable constellation of signs and seizures in cases of sertraline (Zoloft label) and zolpi-
symptoms following the abrupt discontinuation of, or dem withdrawal (Aragona, 2000), and suicidality
rapid reduction in, the dose of a psychoactive substance’. involving antidepressants (Yerevanian et al., 2004;
Chouinard and Chouinard (2015) describe in a very com- Valuck et al., 2009) and MAO inhibitors such as phen-
prehensive manner general features of the emergence of elzine (Dilsaver, 1994).
new, acute withdrawal symptoms after drug discontinuation. (7) The onset of withdrawal symptoms depends on the
duration of action; usually, short-acting drugs have an
early peak of onset.
(8) Drugs with higher potency and short/intermediate half-
life have greater risks for formation of drug dependence
and withdrawal symptoms.
There are well-known withdrawal syndromes in differ-
ent classes of scheduled and unscheduled drugs. These
Figure 1 Course of opioid withdrawal. The figure shows

different time course for opioids heroine (red curve) and
methadone (blue curve). Although heroin half-life is 2–6 min, the
withdrawal symptoms start usually at 6–24 h after the last dose,
reach a peak at 24–48 h, and resolve after 4–10 days, although this
delay as already mentioned, maybe explained by the fact that the
main active molecule in the brain after heroin administration is not
heroin itself but rather morphine and 6-acetylmorphine, which have
much longer half-lives and thus longer-lasting intoxication and Figure 2 Course of BZ withdrawal. The figure shows different
withdrawal; for methadone, with a half-life of 15–55 h, the time course for short (red curve) and long half-life BZ (blue curve)
withdrawal symptoms start usually at 36–48 h after the last dose, which is related to the drugs half-lives. It shows also a formation of
the withdrawal may be prolonged, and last 3–6 weeks. Adapted protracted withdrawal (yellow curve) for short half-life BZ.
from Drug and Alcohol Withdrawal Clinical Practice Guidelines— Adapted from Drug and Alcohol Withdrawal Clinical Practice
NSW (New South Wales Government, 2008). Guidelines—NSW (New South Wales Government, 2008).
are described in detail below, along with symptoms and pressure, respiratory rate and heart rate (Oxycontin label
time course of withdrawal syndrome. Sep 2018, Roxybond label April 2017).
Withdrawal syndromes for scheduled drug classes apply Opioid withdrawal symptoms have been also observed
to: in children undergoing treatment with opioids. In these
cases, physical dependence developed as early as 2–3 days
• Opioids
following continuous opioid therapy; the most commonly
• Benzodiazepines
seen symptoms of withdrawal in children included:
• Z-Drugs (Zolpidem, Zaleplon and Eszopiclone)
• Barbiturates (1) Neurological adverse events such as anxiety, agitation,
• Stimulants (amphetamine, cocaine and methamphetamine) grimacing, insomnia, increased muscle tone, abnormal
• Testosterone and androgenic anabolic steroids tremors and choreoathetoid movements.
• Ketamine (2) Gastrointestinal symptoms included vomiting, diar-
• Cannabis rhoea and poor appetite.
(3) Autonomic signs included tachypnoea, tachycardia,
Withdrawal syndromes for unscheduled drug classes fever, sweating and hypertension (Ista et al., 2008;
apply to: Anand et al., 2010; Fisher et al., 2013).
• Antidepressants: SSRIs and serotonin-norepinephrine Neonatal abstinence syndrome (NAS) is unusual in that
reuptake inhibitors (SNRIs) the withdrawal symptoms are related to the maternal opi-
• Tricyclic antidepressants oid intake but then manifest in the newborn. The clinical
• Antipsychotics presentation of NAS includes signs of neurological excit-
• Anti-Parkinsonian drugs ability such as tremors, hyperirritability, increased wake-
• Monoamine oxidase inhibitors fulness, excessive high-pitched crying, increased muscle
• Gabapentin tone, hyperactive deep tendon reflexes, exaggerated Moro
• Nicotine/tobacco reflex, seizures, frequent yawning and sneezing, and also
• Corticosteroids symptoms of gastrointestinal dysfunction such as poor
• Statins feeding, unco-ordinated and constant sucking, hyperpha-
• Aspirin gia, vomiting, diarrhoea and dehydration. Onset varies
with the opioid pharmacology, in case of maternal use of
Acute withdrawal syndromes— heroin NAS may start 24 h of birth, whereas in case of
scheduled drugs—examples withdrawal from methadone NAS usually starts around
24–72 h of age (Hudak et al., 2012; Kocherlakota, 2014).
Opioid withdrawal syndrome Although generally not life-threating, in some cases opi-
The first descriptions of opioid withdrawal are those by oid withdrawal may lead to serious adverse events such
Light and Torrence (1929) and Himmelsbach (1939). The as Takotsubo cardiomyopathy ‘broken heart syndrome’
symptoms include yawning, rhinorrhoea, piloerection, in cases of methadone and extended-release long-acting
perspiration, lacrimation, mydriasis, hand tremors, hot oxycodone withdrawal (Rivera et al., 2006; Lemesle
and cold flashes, restlessness, muscle twitches, abdominal et al., 2010; Saiful et al., 2011; Spadotto et al., 2013), or
cramps, anxiety and chills, myalgia, irritability, backache, seizures due to neonatal abstinence syndrome (Hudak
joint pain, weakness, insomnia, nausea, anorexia, vomit- et al., 2012; Kocherlakota, 2014).
ing, diarrhoea, or increased blood pressure, respiratory The time course of the severity of acute withdrawal
rate or heart rate (Light and Torrence, 1929; symptoms for opioid drugs depends usually on the half-
Himmelsbach, 1939; Handelsman et al., 1987), morphine life of the drug, although it can be quite variable.
label (morphine sulphate extended-release tablets, mor- Figure 1 shows onset, peak, duration and severity of
phine sulfate Contin, label 2018; Table 1). Symptoms of acute withdrawal symptoms for two frequently used and
withdrawal may start as early as 6–24 h after the last abused opioids, heroin and methadone (New South
dose (heroin), peak at 24–48 h, and resolve after 5– Wales Government, 2008).
10 days. It is important to note that opioid withdrawal also
For long-acting opioid (methadone) withdrawal starts includes a protracted phase of withdrawal which occurs
after 36–48 h after the last dose, and may last 3–6 weeks after the acute withdrawal phase and is further discussed
(New South Wales Government, 2008). in the ‘Protracted Withdrawal Syndrome’ section.
The withdrawal symptoms of oxycodone products in- As mentioned in the ‘Definitions of dependence and
clude restlessness, lacrimation, rhinorrhoea, yawning, per- withdrawal’ section, there is a difference between with-
spiration, chills, myalgia and mydriasis, also other drawal syndrome and addiction.
symptoms may develop such as irritability, anxiety, back- Opioid addiction is a complex disorder and its develop-
ache, joint pain, weakness, abdominal cramps, insomnia, ment can vary. An individual’s risk in developing addic-
nausea, anorexia, vomiting, diarrhoea, increased blood tion likely relates to a combination of health, social,
Table 1 Summary table for the most common withdrawal syndromes
Adverse events Opioids BZ Stimulants SSRIs-SNRIs Cannabis Nicotine Anti-psychotics Androgenic

anabolic ste-
roids and
testosterone
Acute withdrawal syndrome
Anxiety þ þ þ þ þ þ þ þ
Depression/depressed mood þ þ þ þ þ þ
Irritability þ þ þ þ þ þ
Agitation þ þ þ þ
Insomnia þ þ þ þ þ þ þ þ
Somnolence/lethargy þ þ þ þ
Psychotic behaviours þ þ
Hallucinations þ þ þ
CNS drug dependence and new drug development
Suicidality (rare) þ þ þ þ
Tremors þ þ þ þ
Restlessness þ þ þ þ þ þ þ
Seizures þ Neonates þ
Nausea/vomiting þ þ þ þ
Diarrhoea þ þ þ
Constipation þ
Appetite # " # # " # #
Weight # # "
Heart rate " " # " #
Blood pressure " #Postural
Sweating " " " " "
Drug group specific AEs Piloerection/mydria- Depersonalization/ Vivid, unpleasant Brain zaps/ dereal- Disturbing dreams/ Rhinorrhea/rare Decreased libido/
sis/yawning/ derealization/ dreams/paranoid ization/deperson- abdominal pain NMS hypogonado-
rhinorrhea delirium ideation alization/ tropic
myoclonus hypogonadism
Acute withdrawal syndrome. þ þ þ þ þ þ þ þ
• Onset 6 h to 2 days 2–7 days 1–4 days 36–96 h 1–4 days 24–72 h 36–96 h INF
• Duration 10 days to 6 weeks 2–8 weeks 1–4 weeks 6 weeks 2–3 weeks 2–4 weeks 6 weeks
Rebound þ þ þ þ
• Peak onset 1–5 daysa hours-attention-def- 36–96 h 36–96 h
• Duration Insomnia 3 nights icit/hyperactivity 6 weeks 6 weeks
Anxiety 2 weeks disorder
INF
Protracted withdrawal þ þ þ þ þ þ
• Onset after drug discontinuation 6–9 weeks 4–6 weeks 2–4 weeks 24 h to 6 weeks 24 h to 6 weeks weeks to months
• Duration 6–9 months 6–12 months Weeks to months Months or longer Months or longer
a
Rebound insomnia is specific to short and intermediate half-life BZ compounds.
þ
, symptom/syndrome present; ", symptom increased; #, symptom decreased; BZ ¼ benzodiazepines; INF ¼ information not found; NMS ¼ neuroleptic malignant syndrome; SSRIs ¼ selective serotonin reuptake inhibitors; SNRIs ¼ selective
serotonin-norepinephrine reuptake inhibitors.
BRAIN COMMUNICATIONS 2019: Page 9 of 23
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economic, lifestyle and genetic factors. A history of sub- Landowski, 2007; Victorri-Vigneau et al., 2007; Victorri-
stance abuse, psychiatric disorders, mistreatment, poverty, Vigneau et al., 2014; Chattopadhyay et al., 2016).
and access to prescription or illegal opioids may also The withdrawal syndrome after abrupt withdrawal of
contribute to a person’s risk of opioid addiction (Webster zolpidem was already noted during the clinical studies of
et al., 2011). Ambien (zolpidem tartrate). Adverse events reported with-
in 48 h of drug discontinuation included fatigue, nausea,
Benzodiazepine withdrawal flushing, lightheadedness, uncontrolled crying, emesis,
stomach cramps, panic attack, nervousness, abdominal
syndrome discomfort, hyperventilation, shallow breathing, angry
BZ withdrawal symptoms may vary in intensity. Mild feelings, cramping muscles and restlessness (Watsky,
withdrawal may include anxiety, apprehension, fearful- 1996; Sethi and Khandelwal, 2005) and labels for zolpi-
ness, insomnia, irritability, agitation, restlessness, dizzi- dem (e.g. Ambien, Edluar 2019). Withdrawal seizures
ness, headache, anorexia, weight loss, difficulty in after zolpidem discontinuation were reported mainly in
concentration, muscle stiffness and pain, hyperosmia, me- cases of use of supratherapeutic doses (Aragona, 2000;
tallic taste, perceptual changes, sweating and intolerance Tripodianakis et al., 2003; Sethi and Khandelwal, 2005;
to light and sound. More severe symptoms include nau- Cubala and Landowski, 2007).
sea, vomiting, vertigo, cramps, weakness, tremor, tachy- Also, withdrawal symptoms after discontinuation of
cardia, postural hypotension, hyperthermia, panic attacks, zopiclone were reported, and included cravings, rebound
depression, psychotic reactions, depersonalization, de- insomnia, anxiety or panic attacks, weakness, palpita-
realization, delirium, delusions and hallucinations tions, tachycardia, tremor and withdrawal seizures. These
(MacKinnon and Parker, 1982; Petursson, 1994; New symptoms were mainly seen in subjects using suprathera-
South Wales Government, 2008). The most serious ad- peutic doses; rebound insomnia and rebound anxiety
verse events which may occur are psychosis, delirium, were also noted (Cimolai, 2007).
suicidality, seizures and in older people catatonia
(Preskorn and Denner, 1977; Owen and Tyrer, 1983; Barbiturate withdrawal syndrome
Risse et al., 1990; Lader, 1994; Petursson, 1994;
Abrupt discontinuation of a barbiturate after prolonged
Rosebush and Mazurek, 1996; Lebin and Cerimele,
use or abuse can result in a withdrawal syndrome which
2017; Reeves and Kamal, 2019; Table 1).
is sometimes life-threatening. Withdrawal symptoms in-
The timing of withdrawal symptoms depends on several
clude weakness, tremor, muscle twitches, agitation, anx-
factors; the main one is BZ half-life. Long-acting BZs in-
iety, anorexia, nausea, vomiting, weight loss,
clude diazepam, chlordiazepoxide, flurazepam and clora-
disorientation in time and place, agitation, tremulousness,
zepate; shorter-acting BZs include oxazepam, lorazepam
insomnia, delusions, visual and auditory hallucinations,
and triazolam. For the long-acting BZs, there is a lag
postural hypotension and high fever. The most serious
period of 3–7 days for onset of withdrawal symptoms
adverse events of withdrawal are delirium, generalized
following the drug discontinuation; whereas the short-act-
convulsions and cardiovascular collapse that may lead to
ing BZs symptoms of withdrawal may occur within 24 h.
death; however, severe withdrawal occurs mainly after
The correlation between drug half-life and onset of symp-
dependence on short- or intermediate-acting barbiturates
toms and length of the withdrawal is presented in Fig. 2,
such as pentobarbital, secobarbital, amobarbital or butal-
below (New South Wales Government, 2008). Figure 2
bital (Fraser et al., 1953; Essig, 1968; Gault, 1976;
also shows formation of protracted withdrawal which
Gussow and Carlson, 2013).
starts at the end of the acute withdrawal phase.
Also, neonatal withdrawal syndrome associated with
Use of BZ during the later stages of pregnancy can result
barbiturates has been identified.
in withdrawal symptoms in the neonate such as apnoea,
Infants born to mothers physically dependent on barbi-
bradycardia, hypertonia, irritability, hypothermia, hyper- turates may develop dependence and subsequently experi-
activity, tachypnoea, restlessness, tremors, hyperreflexia, in- ence withdrawal. The withdrawal may manifest within
consolable crying, cyanosis, diarrhoea, vomiting and feeding the first few days of life and symptoms include excessive
difficulties (Iqbal et al., 2002; Hudak et al., 2012). crying, hyperphagia, vomiting, diarrhoea, tremors, irrit-
ability, hyperacusis, vasomotor instability, sweating, rest-
Z-drugs withdrawal syndrome lessness, sleeplessness, increased tone and sometimes
(zolpidem and zopiclone) seizures (Desmond et al., 1972; Hudak et al., 2012;
Gresham and LoVecchio, 2015) and label Butisol (2019).
Dependence following the use of zolpidem has been
known since the 1990s as occurring mainly in people
abusing it. There are also a considerable number of zolpi- Stimulant withdrawal syndrome
dem dependence case reports in the scientific literature Withdrawal from stimulants such as amphetamine
(Aragona, 2000; Tripodianakis et al., 2003; Cubala and (including dexamphetamine and methamphetamine),
sweating, palpitations, tiredness, low appetite, low mood,

chills, autonomic arousal, lacrimation, restlessness, anx-
iety, nightmares, paranoia, delusions and hallucinations
(Lim, 2003; Critchlow, 2006; Chen et al., 2014).
Addiction websites (American Addiction Centers and
Addiction Center) additionally list the following adverse
events occurring in ketamine abusing subjects during the
withdrawal period: agitation, confusion, psychosis, includ-
ing delusion and hallucination; loss of motor skills, rage,
nausea, decreased respiratory and cardiac functions, in-
somnia, cognitive impairment, loss of appetite, tremors,
restlessness, depression, nightmares and chills.
Timelines of ketamine withdrawal include: (i) acute
Figure 3 Phasal model of cocaine withdrawal. The figure
shows three phases of cocaine withdrawal: crash, withdrawal and
withdrawal symptoms that typically begin within 24 h of
extinction, which have somewhat different symptoms profile. discontinuing ketamine use and last approximately 3
Adapted from Baker et al. (2004). days; symptoms include shaking, fatigue, insomnia, rage,
depression, hallucinations, delusions, tremors, nausea and
rapid breathing; (ii) withdrawal symptoms that may per-
sist for 2 weeks, but begin to decrease; and (iii) after ap-
MDMA (ecstasy) and cocaine usually occurs in three proximately 2 weeks, most withdrawal symptoms usually
phases (crash, withdrawal and extinction phase), Fig. 3. stabilize.
The crash phase, starts as stimulants wear off, can last
for several days and includes fatigue, flat affect, increased Testosterone and anabolic-
sleep and reduced cravings; severe depressive symptoms
may occur. The withdrawal phase typically starts 2–
androgenic steroids withdrawal
4 days after the last amphetamine use and 1–2 days after syndrome
the last cocaine use. Withdrawal phase symptoms may in- The withdrawal syndrome after a chronic intake of
clude strong cravings, fluctuating mood and energy levels, supratherapeutic doses of testosterone and androgenic
psychomotor retardation or agitation, irritability, restless- anabolic steroids can last for weeks or months and is
ness, anxiety, fatigue, lack of energy, anhedonia, vivid characterized by depressed mood, major depression, suici-
and unpleasant dreams, insomnia or hypersomnia, general dality, fatigue, craving, headache, muscle and joint pain,
aches and pains, headaches, muscle tension, increased ap- anorexia, anxiety, restlessness, irritability, insomnia or
petite, poor concentration and attention, disturbances of hypersomnia, decreased libido, hypogonadotropic hypo-
thought (paranoid ideation, strange beliefs) and hallucina- gonadism and suppression of the hypothalamic–pituitary–
tions; bradycardia may be present and is a reliable meas- testicular (HPT) axis (Thiblin et al., 1999; Medras and
ure of stimulant withdrawal (Kosten and O’Connor, Tworowska, 2001; Brower, 2002, 2009; Kanayama
2003; New South Wales Government, 2008; APA, 2013; et al., 2009) and Testosterone label, 2017 (Table 1).
Table 1). The withdrawal symptoms gradually decrease
over 2–4 weeks for amphetamine and 1–2 weeks for co-
Cannabis withdrawal syndrome
caine, although some symptoms persist during the extinc-
tion phase/protracted withdrawal. Withdrawal symptoms of cannabis include irritability,
Withdrawal from stimulant drugs is generally not med- anger, aggression, decreased appetite, weight loss, ner-
ically dangerous; however, depressive symptoms with sui- vousness, anxiety, restlessness, sleep difficulties including
cidal ideation or behaviour may occur and are generally insomnia and strange or disturbing dreams, abdominal
the most serious problems seen during the stimulant with- pain, shakiness, tremors, fever and headache. Less com-
drawal (APA, 2013). mon symptoms include chills, depressed mood and sweat-
ing (Budney et al., 2004; Budney and Hughes, 2006;
New South Wales Government, 2008; Gorelick et al.,
Ketamine withdrawal syndrome 2012; APA, 2013; Bonnet and Preuss, 2017; Schlienz
Ketamine is known for the formation of severe psycho- et al., 2017; Table 1).
logical dependence and significant, rapidly developing tol- Withdrawal symptoms usually start within the first 1–
erance (Kamaya and Krishna, 1987; Hurt and Ritchie, 4 days of abstinence, peak within the first week, and then
1994; Jansen and Darracot-Cankovic, 2001; Pal et al., resolve within 2–3 weeks of drug discontinuation
2002) without a prominent physical withdrawal syn- (Schlienz et al., 2017). Strange dreams and sleep difficul-
drome. However, the presence of physical withdrawal ties can persist longer (Budney and Hughes, 2006;
symptoms after ketamine discontinuation has also been Herrmann et al., 2015). Also, there is temporal variation
described, and includes craving, dysphoria, shaking, in the occurrence of specific symptoms, with the early
onset of insomnia and shakiness, followed by irritability is misleading since withdrawal may occur without discon-
and anxiety (day 4–5) and anger and aggression peaking tinuation, for example, in between two doses of rapid-
after 2 weeks of abstinence (Fig. 4) setting. The timing of onset and short-acting drugs (e.g. clock watching syn-
the severity of withdrawal symptoms to some degree drome) and with a decrease in medication’. Fava et al.
reflects the changes at the cannabinoid 1 (CB1) receptors (2015) adds, ‘The term “discontinuation syndrome” mini-
level in the brain where regular cannabis intake causes a mizes the vulnerabilities induced by SSRI and should be
desensitization and down-regulation of CB1 receptors, replaced by “withdrawal syndrome”’. However, discus-
and during the first 2 days of withdrawal this begins to sion on the topic of this nomenclature continues in the
reverse and the receptors begin to return to normal func- scientific literature (Schatzberg et al., 1997; Shelton,
tioning within 4 weeks of abstinence (Bonnet and Preuss, 2006; Nielsen et al., 2012; Chouinard and Chouinard,
2017). 2015; Fava et al., 2015).
In addition, neonatal withdrawal syndrome associated
Acute withdrawal syndromes— with SSRIs has been identified. It includes respiratory dis-
non-scheduled drugs—examples tress, cyanosis, seizures, feeding difficulty, vomiting,
hypoglycaemia, hypotonia or hypertonia, hyperreflexia,
Antidepressant SSRIs and SNRIs withdrawal tremor, jitteriness, irritability, pulmonary hypertension;
syndrome and with paroxetine use, necrotizing enterocolitis (Stiskal
Some more frequently used SSRIs include: fluoxetine, flu- et al., 2001; Sanz et al., 2005; Koren and Boucher, 2009;
voxamine, paroxetine, citalopram and sertraline. Some Hudak et al., 2012) and SSRI labels e.g. Paxil, 2014;
more frequently used SNRIs include: venlafaxine, desven- Prozac, 2017; Zoloft, 2017.
lafaxine and duloxetine.
The SSRIs and SNRIs withdrawal syndrome is charac-
terized by the following symptoms, general: headaches, Tricyclic antidepressant withdrawal syndrome
flu-like symptoms, tachycardia; gastrointestinal: nausea, Some more frequently used tricyclic antidepressants in-
vomiting, diarrhoea, anorexia; sleep-related: vivid dreams, clude: imipramine, clomipramine, amitriptyline, amoxa-
nightmares, insomnia or hypersomnia; neuropsychiatric:
pine, desipramine, doxepin and nortriptyline. Tricyclic
anxiety, depression, suicidality, hypomania, agitation, dys-
antidepressant withdrawal symptoms can be grouped into
phoria, aggression, hallucinations, de-realization and de-
four discrete syndromes: (i) gastrointestinal and general
personalization, decreased concentration, dizziness, ataxia,
somatic distress with occasional anxiety and agitation,
electric-shock sensations (‘brain-zaps’), confusion and
also nausea, vomiting, diarrhoea, abdominal pain and
myoclonus (Leiter et al., 1995; Rosenbaum et al., 1998;
anorexia; (ii) sleep disturbances, such as initial and mid-
Haddad, 2001; Yerevanian et al., 2004; Chouinard and
dle insomnia, vivid dreams and nightmares; (iii) parkin-
Chouinard, 2015; Fava et al., 2015) and labels e.g. Paxil,
sonism including bradykinesia, cogwheel rigidity, tremor
2014; Prozac, 2017; Zoloft, 2017, Table 1. SSRIs and
or akathisia; and (iv) paradoxical mania. Sometimes with-
SNRIs withdrawal symptoms have their peak of onset at
drawal syndrome presents as a ‘flu-like’ syndrome; which
36–96 h or later, depending on the drug’s half-life, and
may last up to 6 weeks, also depending on drug half-life in addition to gastrointestinal symptoms, also includes
(Chouinard and Chouinard, 2015). The individual SSRIs diaphoresis, dizziness, chills, malaise, fatigue, myalgia and
have somewhat different profiles of adverse events, and it headache; also suicidality and delirium may occur
seems that severity might be related to half-life (Dilsaver, 1990; Ceccherini-Nelli et al., 1993; Garner
(Rosenbaum et al., 1998; Fava et al., 2015). Also, it was et al., 1993; Dilsaver, 1994; Haddad, 2001; Yerevanian
observed that withdrawal syndrome was more common et al., 2004) and label Anafranil, 2014.
in young patients than in the elderly (Himei and In paediatric populations, the most frequent symptoms
Okamura, 2006; Fava et al., 2015). Frequently, acute are irritability, decreased appetite, drowsiness, fatigue, in-
withdrawal syndrome may be followed by disease re- somnia; also nausea, vomiting and abdominal cramps,
bound (see Rebound section) and protracted withdrawal which, if severe, may lead to dehydration (Garner et al.,
syndrome (see Protracted Withdrawal Syndrome section). 1993).
Of note, there is a tendency in the scientific literature There are also neonatal withdrawal symptoms that are
to call SSRIs and SNRIs withdrawal syndrome a ‘discon- attributed to maternal use of tricyclic antidepressants;
tinuation syndrome’, which in our opinion is both scien- these adverse events include irritability, respiratory diffi-
tifically incorrect and misleading, as it may suggest an culty, hypothermia, poor feeding, tremors, jitteriness,
absence of the withdrawal syndrome. A comment by myoclonus and hyperactive Moro reflex. Serious with-
Chouinard and Chouinard (2015) explains this issue well: drawal reactions may be present, such as tachycardia,
‘The terminology discontinuation refers to the medical cyanosis and convulsions (Cowe et al., 1982; Bloem
prescribing act or a patient’s self-discontinuation of medi- et al., 1999; Haddad, 2001; Hudak et al., 2012; ter
cation. Furthermore, the term discontinuation syndrome Horst et al., 2012) and label Anafranil (2014).
hypotonia, respiratory distress and feeding disorder (e.g.

label Risperdal 2019; Haldol 2019, Clozaril 2017).
Levodopa-withdrawal malignant syndrome

(withdrawal-emergent hyperpyrexia and confusion)
This is an uncommon, but potentially fatal complication
(Sechi et al., 1984) which follows reduction or cessation
of anti-parkinsonian medications, including levodopa,
dopamine agonists, and even amantadine (Friedman
et al., 1985; Rosse and Ciolino, 1985; Rainer et al.,
1991; Mizuno et al., 2003; Serrano-Duenas, 2003;
Brantley et al., 2009; Newman et al., 2009) and labels
e.g. Apokyn 2004, Parlodel 2012, Sinemet 2017, Requip
2017. Typically, symptoms develop between 18 h and 7
days following anti-parkinsonian drug discontinuation.
Figure 4 Course of cannabis withdrawal. The figure shows
different phases of occurrence of cannabis withdrawal symptoms, Clinical features include high fever, marked rigidity, con-
with the early phase (red curve) of insomnia, shakiness, decreased sciousness disturbances ranging from drowsiness to coma,
appetite symptoms, middle phase (yellow curve) with irritability, autonomic dysfunction such as tachycardia, perspiration,
anxiety, restlessness symptoms and late somewhat prolonged phase non-paralytic ileus, blood pressure fluctuation, rhabdo-
(blue curve) of anger and aggression. Adapted from Drug and myolysis and elevation of serum creatinine phosphoki-
Alcohol Withdrawal Clinical Practice Guidelines – NSW (New nase. Symptoms are similar to those of NMS.
South Wales Government, 2008). Amantadine withdrawal may precipitate NMS also in
patients with other than Parkinson’s disease, namely with
influenza A encephalopathy (Ito et al., 2001).
Antipsychotic drug withdrawal syndrome Dopamine agonist withdrawal syndrome in
Antipsychotic drugs belong to multiple pharmacological Parkinson’s patients
groups: phenothiazines, thioxanthenes, butyrophenones
The syndrome was described by Rabinak and Niremberg
and atypical antipsychotics. For these drugs, the common (2010) in Parkinson’s disease patients who were with-
withdrawal symptoms are nausea, vomiting, diarrhoea, drawn from long-term treatment with dopamine agonists
anorexia, influenza-like syndrome, rhinorrhoea, diaphor- due to the development of impulse control disorders. The
esis, myalgia, paraesthesia, anxiety, agitation, restlessness, syndrome presents as a constellation of neuropsychiatric
insomnia, vertigo and tremor (Dilsaver, 1994; Borison, and autonomic symptoms: depression, anxiety, agorapho-
1996; Shiovitz et al., 1996) and labels e.g. Clozaril bia, fatigue, dysphoria, irritability, agitation, pain, sleep
February 2017, Table 1. Symptoms may appear 36–96 h disturbances, diaphoresis, orthostatic hypotension and
or later after drug discontinuation, dose reduction or drug cravings.
switch, depending on the drug’s duration of action and
last up to 6 weeks (Chouinard et al., 2017). Of note is Nicotine/tobacco withdrawal syndrome
that during the withdrawal period, not uncommon is also The nicotine withdrawal syndrome includes subsets of
psychosis rebound which results in re-emergence or wor- somatic components, cognitive, and affective components;
sening of psychosis (see Rebound section) or supersensi- the somatic signs include bradycardia, constipation,
tivity psychosis and occurrence of withdrawal-emergent increased appetite and weight gain; affective symptoms
tardive dyskinesia (Crane, 1968; Chouinard and Jones, include depressed mood and anhedonia, anxiety, irritabil-
1980; Borison et al., 1988; Schultz et al., 1995; ity, frustration, dysphoria, emotional lability, anger, other
Margolese et al., 2005; Karas et al., 2016; Chouinard symptoms are restlessness, insomnia, fatigue, somnolence,
et al., 2017). difficulty concentrating, sweating, confusion and craving.
A rare, but potentially life-threatening reaction with Tobacco/nicotine withdrawal usually begins within 24–
10% mortality rate (Strawn et al., 2007), to antipsychotic 72 h of stopping or decreasing tobacco use, peaks at 2–
withdrawal is a neuroleptic malignant syndrome (NMS), 3 days after abstinence, and lasts 2–4 weeks (Hughes,
characterized by hyperthermia, muscular rigidity, rhabdo- 2007; New South Wales Government, 2008; APA, 2013;
myolysis, autonomic instability, mental status changes, Jackson et al., 2015) and label Nicotrol 2010, Table 1.
diaphoresis, incontinence and elevated creatine phospho-
kinase (Corrigan and Coulter, 1988; Kasckow et al., Treatment and prevention of acute withdrawal
1990; Spivak et al., 1990; Amore and Zazzeri, 1995). syndrome
Anti-psychotics taken during the third trimester of preg- For the drugs with known acute withdrawal syndromes,
nancy may cause neonatal withdrawal symptoms which the main treatments and prevention measures are: (i)
may include agitation, tremor, somnolence, hypertonia, taper at the end of treatment; (ii) after abrupt drug
discontinuation immediate substitute with the drug with discontinuation, such as severe psychosis after neurolep-
similar mechanism of action or reinstitute the discontin- tics (Chouinard et al., 2017), severe worsening of mul-
ued drug, if possible, and taper much slower; (iii) treat tiple sclerosis after immunomodulatory drugs (Gonzalez-
symptomatically the dangerous or unpleasant symptoms Suarez et al., 2017; Larochelle et al., 2017) or suicidality
such as seizures, psychosis, depression, headaches, vomit- after antidepressants (Valuck et al., 2009). However, un-
ing, diarrhoea (Ashton, 1994; Kosten and O’Connor, like protracted withdrawal syndromes rebound symptoms
2003; O’Brien C, 2005; New South Wales Government, are transient and reversible and return after days or
2008; Chouinard and Chouinard, 2015; Chouinard et al., weeks to the baseline.
2017). Lupolover et al. (1982) reviewed several CNS-active
The above presented list of acute withdrawal syn- and non-CNS-active drugs and provided the following
dromes is by no means complete; it only represents better conclusion. ‘The survey of the medical literature with re-
known syndromes. However, it is important to emphasize gard to the “rebound phenomenon” after withdrawal of
that the list of new withdrawal syndromes is growing drugs shows that it can appear after all classes of drugs,
along with new drug approvals and the identification of irrespective of their chemical formulation or pharmaco-
new withdrawal syndromes for older drugs that are fre- logical action. Cardiovascular drugs, diuretics, hormones,
quently recognized only during the post-marketing anticoagulants, antacids and neuropsychiatric drugs have
period. been said to produce “rebound phenomena” on
The reason for listing the above non-scheduled drugs, withdrawal’.
which are used by innumerable numbers of patients, is to Emergence of rebound is variable for different drugs
point out that these drugs not only can produce depend- and may be seen in only 36–96 h for SSRIs and oral anti-
ence, withdrawal and rebound; but in some cases, these psychotics (Chouinard and Chouinard, 2015; Chouinard
adverse events may be life-threatening, and the labels do et al., 2017) and in 1–5 days for some BZ such as in
not necessarily reflect this fact and provide necessary patients with anxiety experiencing rebound after abrupt
warnings for patients and physicians. discontinuation of bromazepam and diazepam (Fontaine
We provide the additional listing of acute withdrawal et al., 1984) and Fig. 6 and in the cases of patients with
syndromes in the Supplementary material 2 for less fre- insomnia after abrupt withdrawal of triazolam (Kales
quently used drugs and/or few not CNS-active drugs al- et al., 1987) or lorazepam (Scharf et al., 1982).
though frequently used including monoamine oxidase The mechanisms that underlie the occurrence of the re-
inhibitors, gabapentin, corticosteroids, statins and aspirin. bound effect are not yet fully elucidated; also, for the dif-
In Table 1 are listed the most frequent and relevant ferent CNS drugs the brain mechanism implicated in
acute withdrawal syndromes, rebound and protracted rebound may differ.
withdrawal syndromes. Generally, rebound is explained as a consequence of
down-regulation and desensitization of the receptors tar-
Summary points geted by the therapeutic drug, where increased severity of
disease symptoms is related to the lag in time for recep-
• Majority of CNS-active drugs, scheduled and not
tors to be synthesized after the decrease in receptor sites
scheduled, produce acute withdrawal syndromes. during treatment (Fontaine et al., 1984; Bhanji et al.,
• Onset and duration of withdrawal depends on drugs’
2006). An alternative explanation is that there is a lag
duration of action and half-life. in production and replacement of endogenous neurotrans-
• The characteristic of withdrawal syndrome mainly
mitters after their production was suppressed during
depends on neurotransmitter system affected, and gen- treatment with the drug (Kales et al., 1983b).
erally presents opposite symptoms to that seen during The treatment options for the rebound are the same as
drug administration. for acute withdrawal syndrome, but there is one more
option, namely, the rebound symptoms also often im-
prove rapidly after reintroduction of the discontinued
Part III. Rebound drug, if it is not medically contraindicated (Chouinard
phenomena—definition and and Chouinard, 2015; Chouinard et al., 2017), then the
drug should be tapered very slowly.
examples
Another aspect of withdrawal, rebound effect, also called
Benzodiazepine rebound
rebound phenomenon, occurs in a similar timeframe to One of the most common examples is anxiety and insom-
that of acute withdrawal. Rebound phenomenon is a nia rebound following abrupt discontinuation of treat-
rapid return of the patient’s original symptoms at a ment with BZ. Symptoms usually appear within 1–5 days
greater intensity than before the treatment. Rebound may of drug discontinuation, depending on the half-life of the
cause in a small subset of susceptible individuals serious individual drug, and may last at least 3 days for insomnia
and fatal adverse events after abrupt drug rebound (Kales et al., 1983a, 1987; Bixler et al., 1985),
Following is an example of rebound anxiety after with-

drawal of BZ in patients with generalized anxiety dis-
order treated successfully with diazepam or bromazepam
(Fontaine et al., 1984) and Fig. 6. The patients were
treated for 4 weeks with BZ, then one group was abrupt-
ly withdrawn, and the second group gradually with-
drawn. The scores of patients withdrawn abruptly
increased 10% or more on both the Hamilton Rating
Scale for Anxiety and the Self Rating Symptom Scale. In
patients with rebound anxiety, previous anxiety symp-
toms returned and were more severe than before treat-
ment, beginning in some cases within 24 h of drug
withdrawal.
Also, Z-drugs such as zopiclone were reported to cause
rebound insomnia (Soldatos et al., 1999; Tsutsui and
Zolipidem Study Group, 2001; Cimolai, 2007).
Stimulant rebound
Stimulants such as methylphenidate and amphetamine
may cause rebound in children with attention-deficit/
hyperactivity disorder, which can include serious and
Figure 5 Rebound insomnia in patients treated with consistent deterioration of behaviour manifested in sad-
triazolam after abrupt drug withdrawal. The figure shows ness, crying, emotional lability, irritability, social with-
that after abrupt drug discontinuation the symptoms of insomnia
drawal, restlessness, distractibility, belligerence,
(measured as total wake time) not only promptly return but there
excitability, talkativeness, euphoria and insomnia, emerg-
is a rebound of insomnia, that is worsening of the symptoms far
above disease baseline from pre-treatment period (red arrow), in ing after the last stimulant dose has worn off (Rapoport
fact, this worsening is considerably greater than the maximal degree et al., 1978; Porrino et al., 1983; Smucker and Hedayat,
of improvement of sleep during the drug treatment. Adapted from 2001; Carlson and Kelly, 2003; Connor, 2015). In fact,
Kales et al. (1983a). up to one-third of children taking methylphenidate for at-
tention-deficit/hyperactivity disorder experience a rebound
as interdose recurrence of symptoms in the late afternoon
when the medication wears off and symptoms of atten-
and at least 2 weeks for anxiety rebound (Fontaine et al., tion-deficit/hyperactivity disorder, such as irritability and
1984), but frequently the rebound was not evaluated for non-compliance, return (Riccio et al., 2001); however, the
all its full duration. Patients experienced rebound insom- total duration is not known as the next dose of drug
nia after treatment with several short- and intermediate- is given; in more severe cases the medication is
acting BZ used for insomnia, including alprazolam, lor- discontinued.
azepam, nitrazepam, triazolam, midazolam, flunitrazepam
and lormetazepam (Kales et al., 1978, 1983a, 1987;
Bixler et al., 1985; Lader and Lawson, 1987; Roehrs
Selective serotonin reuptake
et al., 1992). Figure 5 shows rebound insomnia after inhibitor’s rebound
abrupt withdrawal of treatment with triazolam (Kales Rebound involves the return of symptoms of the treated
et al., 1983b). However, rebound insomnia was not disorder, but at greater intensity. These include: anxiety,
reported following use of long-acting BZ such as quaze- panic, agitation, insomnia, depression, obsessions and
pam and flurazepam (Kales et al., 1982; Bixler et al., compulsions (Bhanji et al., 2006; Chouinard and
1985). Chouinard, 2015). Generally, peak of onset is 36–96 h
Rebound anxiety or panic attacks resulted from abrupt which depends mainly on drug duration of action, where-
withdrawal of BZ such as alprazolam, lorazepam, diaze- as the duration can be up to 6 weeks, which depends on
pam, clorazepate and bromazepam (Scharf et al., 1982; drug elimination half-life (Chouinard and Chouinard,
Fontaine et al., 1984; Pecknold et al., 1988; Rickels 2015).
et al., 1988; Roy-Byrne et al., 1989; Chouinard, 2004).
Anxiety patients more frequently experience rebound with
short- and intermediate-actin BZ than long-acting
Antipsychotic rebound
(Chouinard, 2004). Rebound psychosis, was noted not only for many classic
Rebound insomnia was also reported for a non-BZ antipsychotics, such as haloperidol; but also, atypical
hypnotic drug, zolpidem (Voshaar et al., 2004). antipsychotics such as quetiapine and clozapine. Rebound
dependence which are exposed during drug discontinu-

ation; thus, rebound is more severe for drugs which
produce tolerance and dependence within a short time
and to a higher degree.
• Rebound coincides in time with acute withdrawal syn-
drome but is differentiated from it by the fact that rep-
resents the symptom of the underlying disorder but of
the greater severity than before the treatment, whereas
acute withdrawal represents a new symptom.
• Rebound is of relatively short duration and self-terminat-
ing, although at times may be severe and life-threatening.
Part IV. Protracted

withdrawal syndrome—
definition and examples
Figure 6 Rebound anxiety in patients treated with Protracted withdrawal also called post-acute withdrawal
diazepam or bromazepam who were abruptly withdrawn. syndrome (PAWS), persistent post-withdrawal syndrome,
The figure shows anxiety scores (HAM-A) for three arms in the and prolonged withdrawal syndrome, describes a set of
study: patients who were treated with BZ but then either persistent impairments that occur after withdrawal from
discontinued drug abruptly (blue line) or discontinued drug
some drug classes, such as BZ, opioids, antipsychotics
gradually (green line), the study included also a placebo arm (black
line). After abrupt drug discontinuation the symptoms of anxiety
and antidepressants. Symptoms of protracted withdrawal
not only return to pre-treatment state, but there is also a rebound frequently appear later, well past the expected timeframe
of anxiety (red arrow), that is a worsening of the symptoms above for acute withdrawal, last longer, and sometimes are irre-
disease baseline. However, the gradual drug discontinuation does versible. Because many names are used to describe pro-
not produce the rebound and is similar to placebo arm. Adapted tracted withdrawal symptoms, which makes identification
from Fontaine et al. (1984). confusing at times, we present a list of all known to date
names of this syndrome, compiled by the Substance
Abuse and Mental Health Services Administration
(SAMHSA, 2010).
psychosis may include positive symptoms from pre-treat-
ment level, however, at greater severity: illusions, halluci- • Chronic withdrawal
nations, delusions, catatonia, Schneider passivity • Extended withdrawal
experiences (Borison et al., 1988; Kahne, 1989; • Late withdrawal
Margolese et al., 2002; Chouinard et al., 2017). The • Long-term withdrawal
peak of onset is 36–96 h after drug discontinuation or • Persistent post-use symptoms
dose reduction and may last up to 6 weeks depending on • Post-acute withdrawal syndrome
drug elimination (Chouinard et al., 2017). • Post-use syndrome
• Protracted abstinence
• Sobriety-based symptoms
Immunomodulatory drug rebound • Subacute withdrawal
Recently, a new rebound syndrome was identified for
immunomodulatory drugs indicated for treatment of mul- The most characteristic feature of this disorder is its dur-
tiple sclerosis, namely Gilenya (fingolimod) and natalizu- ation, sometimes persisting for weeks and months after ces-
mab. The abrupt withdrawal of these drugs produces sation of the drug; additionally, new disorders may emerge.
severe, sometimes life-threatening or fatal rebound in Protracted withdrawal syndrome is not only character-
multiple sclerosis patients, accompanied by drastic istic of drugs of abuse but also was described for non-
increases in new lesions or enhancing lesions seen on scheduled drug classes, such as SSRIs and antipsychotics.
MRI (Sorensen et al., 2014; Faissner et al., 2015; In this study, we present some known examples of post-
Hatcher et al., 2016; Czlonkowska et al., 2017; Gunduz acute withdrawal syndromes.
et al., 2017; Larochelle et al., 2017).
Scheduled drugs
Summary points Opioid protracted withdrawal syndrome
• Rebound reflects drug’s ability to affect organism’s Protracted withdrawal symptoms related to opioid with-
neuroadaptation expressed as tolerance and drawal include: opioid cravings, memory problems,
inability to think clearly, fatigue, anxiety, depression, dys- 2017). The peak of onset is 24 h to 6 weeks after drug
phoria, irritability, sleep disturbances, insomnia, palpita- discontinuation or dose reduction or switch and pro-
tions, restlessness, periodic diarrhoea and hypomania tracted withdrawal may last several months (Chouinard
(Kolb, 1928; Satel et al., 1993; SAMHSA, 2010). Some et al., 2017).
symptoms, such as fatigue, insomnia and restlessness can
last for weeks or months following withdrawal from Summary points
opioids, in some cases, 6–9 months.
• Protracted withdrawal is a relatively less known aspect
Some opioid drugs may produce physiological pro-
of dependence and withdrawal; however, its duration
tracted withdrawal symptoms. During abrupt morphine
and severity affect the ability of subjects to terminate
withdrawal, Martin and Jasinski (1969) observed after
therapeutic drugs and drugs of abuse and addiction.
the acute withdrawal phase occurrence of a protracted or
• Protracted withdrawal may represent very slowly re-
secondary phase which usually began to emerge between
versible or permanent pathological changes in the
the sixth and ninth weeks after drug withdrawal and per-
neurocircuitry.
sisted through the weeks 26–30. This phase was charac-
terized by decreased blood pressure, heart rate and body
temperature, as well as miosis and hyposensitivity of the
respiratory centre to CO2.
Part V: Evaluation of drug
Benzodiazepine protracted withdrawal syndrome
dependence in clinical
Protracted withdrawal symptoms include: anxiety, depres- studies—regulatory
sion, psychotic reactions, memory impairment, motor
symptoms (muscle jerking, blepharospasm), paraesthesia, considerations
formication, tinnitus and irritable bowel syndrome, and
there is a characteristic fluctuation of symptoms that may
Human dependence study—design
wax and wane (Smith and Wesson, 1983; Ashton, 1991; and considerations
SAMHSA, 2010). Generally, the symptoms of protracted Evaluation of dependence, withdrawal and rebound for
withdrawal start 4–6 weeks after drug discontinuation new drugs being developed is of great importance, as it
and may last 6–12 months, but some symptoms, such as provides information related to potential drug scheduling
anxiety, may persist for up to 2 years (Ashton, 1991). and safe use. The evaluation provides critically important
safety information for patients and physicians, especially
Stimulants protracted withdrawal
in cases when the drug must be abruptly withdrawn due
Protracted withdrawal sometimes called the extinction
to serious, life-threatening adverse events.
phase is characterized by symptoms such as fluctuations
It is probably important to note here that for regula-
in mood and energy levels, irritability, restlessness, anx-
tory purposes an animal dependence study is not an al-
iety, agitation, fatigue, lacking energy and anhedonia, ternative to a human dependence evaluation. It is only a
cravings and disturbed sleep and this phase may last for first step, one which is important for gathering informa-
weeks to months (New South Wales Government, 2008). tion about potentially serious adverse events of withdraw-
al, such as convulsions.
Non-scheduled drugs The recommended design of a clinical dependence study
SSRIs and SNRIs protracted withdrawal syndrome contains consideration of the following components:
population, design, statistical considerations, dose, phar-
Protracted withdrawal symptoms include: tardive insom-
macodynamic and pharmacokinetic assessments, evalu-
nia, major depression, bipolar disorder, panic disorder,
ation of rebound, adverse events collection and analysis.
agitation, anxiety disorders and panic attacks, emotional
All listed technical details and considerations are available
lability, mood swings, irritability, aggression, impaired
as the Supplementary material 1.
concentration, impaired memory and pathological gam-
bling. These disorders can last for several months to
years when the previous drug treatment is not restarted
(Bhanji et al., 2006; Belaise et al., 2012, 2014;
Discussion
Chouinard and Chouinard, 2015). Major issues in the evaluation of dependence and with-
drawal involve the definitions and nomenclature currently
Antipsychotic protracted withdrawal syndrome used. Both can possibly contribute to misunderstanding
Main protracted withdrawal symptoms for antipsychotics and confusion. This particularly affects different authors’
include tardive dyskinesia and supersensitivity psychosis naming conventions for acute withdrawal syndrome, and
(Crane, 1968; Chouinard and Jones, 1980; Margolese even more so, for protracted withdrawal syndrome.
et al., 2005; Chouinard and Chouinard, 2008; Oda In general, the authors consider the nomenclature of
et al., 2015; Chouinard et al., 2017; Nakata et al., withdrawal syndrome and the time course of withdrawal
phenomena, presented by Chouinard and Chouinard

(2015) to be clear and comprehensive. This nomenclature
Supplementary material
and the presentation of the different aspects of withdraw- Supplementary material is available at Brain
al phenomena could be adapted to describe withdrawal Communications online.
from other drugs and drug classes.
It is important to note that some drugs and drug
classes were not mentioned in this short review. This Acknowledgements
does not necessarily mean that these drugs do not pro- The authors thank Joanne M. Berger, FDA Lead Librarian,
duce a withdrawal syndrome, it may simply mean that and Vivianna P. Cowl, FDA Project Manager, for proofread-
withdrawal has never been evaluated and described. ing the manuscript, FDA, CDER-Designz visual information
specialists Geninne John-Crosland and Joshua Budich for
adapting and creating the figures and FDA ORISE Fellow
Conclusions Sasha Farley, BS, for editorial work.
As discussed above, the evaluation of dependence and

withdrawal is critically important for CNS-active drugs, Disclaimer
which are likely to be scheduled. However, the withdraw- This article reflects the views of the authors and should not
al evaluation is also important for non-scheduled CNS- be construed to represent FDA’s views or policies. Contact
active drugs, mainly for safety reasons. Reidenberg FDA to obtain the most recent and updated recommenda-
(2011) summarizing issues related to drug dependence tions regarding evaluation of drug dependence, withdrawal
and withdrawal, stated: ‘Drug discontinuation effects can and rebound. The information provided here is not intended
occur and are usually neglected in pharmacology and to replace the pertinent FDA Guidance for Industry, which is
medicine until adverse clinical events force them to be updated continuously.
noticed’. It is vital that dependence, withdrawal and re-
bound be recognized and understood by healthcare prac-
titioners, because these effects may constitute major Competing interests
safety issues. The data on acute withdrawal symptoms
Dr. A.L. is employed by the FDA and has no competing inter-
and rebound obtained from the study and evaluation of ests to disclose. Dr. M.K. provides consulting services to com-
dependence will provide physicians and patients with in- panies on drugs that affect the central nervous system. Dr.
formation on drug tapering and constitute a warning M.K. is Principal of Controlled Substance Scientific Solutions,
about possible effects related to abrupt drug discontinu- LLC and Member of the Scientific Advisory Board, Analgesic
ation (Kosten and O’Connor, 2003). Solutions LLC. He has been a consultant for INC Research,
Except for a few drug groups comprising highly addict- IQVIA, Cote Orphan LLC, and Pinney Associates.
ive drugs, such as opioids, BZ and stimulants; and non-
scheduled drugs such as SSRIs, there is relatively little
knowledge of different aspects of the withdrawal phe- References
nomena for most currently used drugs. But even for these Agrawal A, Pergadia ML, Lynskey MT. Is there evidence for
drug classes mentioned above, product labels often do symptoms of cannabis withdrawal in the national epidemiologic sur-
not always reflect all current information available in the vey of alcohol and related conditions? Am J Addict 2008; 17:
199–208.
scientific literature and fail to provide adequate warnings
Amore M, Zazzeri N. Neuroleptic malignant syndrome after neurolep-
for patients and physicians. tic discontinuation. Prog Neuropsychopharmacol Biol Psychiatry
The evaluation of dependence and withdrawal for 1995; 19: 1323–34.
drugs in paediatric population is very important and Anand KJ, Ingraham J. Pediatric. Tolerance, dependence, and strat-
egies for compassionate withdrawal of analgesics and anxiolytics in
should be also addressed in the future. The current avail-
the pediatric ICU. Crit Care Nurse 1996; 16: 87–93.
able data are more than sparse and only available for Anand KJ, Willson DF, Berger J, Harrison R, Meert KL, Zimmerman
some opioid and BZ drugs and some stimulants. Also, J. Tolerance and withdrawal from prolonged opioid use in critically
the sex differences in the withdrawal symptomatology ill children. Pediatrics 2010; 125: e1208–25.
should be further explored as the data for many sched- APA. Diagnostic and statistical manual of mental disorders, 5th
Edition: DSM-5. 5th edn. Arlington, VA: American Psychiatric
uled and unscheduled drug is not available. Publishing; 2013.
This is the authors’ hope that future drug development Aragona M. Abuse, dependence, and epileptic seizures after zolpidem
will incorporate many of the methods described in this withdrawal: review and case report. Clin Neuropharmacol 2000;
review as the knowledge of the withdrawal symptoms is 23: 281–3.
Ashton H. Protracted withdrawal syndromes from benzodiazepines. J
critical for patients’ safety. Also, equally important is
Subst Abuse Treat 1991; 8: 19–28.
incorporating knowledge on withdrawal and dependence Ashton H. The treatment of benzodiazepine dependence. Addiction
in the drug labels. 1994; 89: 1535–41.
Back SE, Payne RL, Wahlquist AH, Carter RE, Stroud Z, Haynes L, Chen WY, Huang MC, Lin SK. Gender differences in subjective dis-
et al. Comparative profiles of men and women with opioid depend- continuation symptoms associated with ketamine use. Subst Abuse
ence: results from a national multisite effectiveness trial. Am J Drug Treat Prev Policy 2014; 9: 39.
Alcohol Abuse 2011; 37: 313–23. Chouinard G. Issues in the clinical use of benzodiazepines: potency,
Baker A, Lee NK, Jenner L, editors. Models of intervention and care withdrawal, and rebound. J Clin Psychiatry 2004; 65 (Suppl 5): 7–12.
for psychostimulant users. In: Psychostimulant withdrawal and de- Chouinard G, Chouinard VA. Atypical antipsychotics: CATIE study,
toxification. 2nd edn, Chap. 7, National Drug Strategy Monograph drug-induced movement disorder and resulting iatrogenic psychi-
Series No. 51. Canberra: Australian Government Department of atric-like symptoms, supersensitivity rebound psychosis and with-
Health and Ageing, p. 102–19. drawal discontinuation syndromes. Psychother Psychosom 2008; 77:
Belaise C, Gatti A, Chouinard VA, Chouinard G. Patient online report 69–77.
of selective serotonin reuptake inhibitor-induced persistent postwith- Chouinard G, Chouinard VA. New classification of selective serotonin
drawal anxiety and mood disorders. Psychother Psychosom 2012; reuptake inhibitor withdrawal. Psychother Psychosom 2015; 84:
81: 386–8. 63–71.
Belaise C, Gatti A, Chouinard VA, Chouinard G. Persistent postwith- Chouinard G, Jones BD. Neuroleptic-induced supersensitivity psych-
drawal disorders induced by paroxetine, a selective serotonin re- osis: clinical and pharmacologic characteristics. Am J Psychiatry
uptake inhibitor, and treated with specific cognitive behavioral 1980; 137: 16–21.
therapy. Psychother Psychosom 2014; 83: 247–8. Chouinard G, Samaha AN, Chouinard VA, Peretti CS, Kanahara N,
Bhanji NH, Chouinard G, Kolivakis T, Margolese HC. Persistent tar- Takase M, et al. Antipsychotic-induced dopamine supersensitivity
dive rebound panic disorder, rebound anxiety and insomnia follow- psychosis: pharmacology, criteria, and therapy. Psychother
ing paroxetine withdrawal: a review of rebound-withdrawal Psychosom 2017; 86: 189–219.
phenomena. Can J Clin Pharmacol 2006; 13: e69–74. Cicero TJ, Nock B, Meyer ER. Gender-linked differences in the expres-
Bixler EO, Kales JD, Kales A, Jacoby JA, Soldatos CR. Rebound in- sion of physical dependence in the rat. Pharmacol Biochem Behav
somnia and elimination half-life: assessment of individual subject re- 2002; 72: 691–7.
sponse. J Clin Pharmacol 1985; 25: 115–24. Cimolai N. Zopiclone: is it a pharmacologic agent for abuse? Can
Bloem BR, Lammers GJ, Roofthooft DW, De Beaufort AJ, Brouwer Fam Physician 2007; 53: 2124–9.
OF. Clomipramine withdrawal in newborns. Arch Dis Child Fetal Colon-Berezin C, Nolan ML, Blachman-Forshay J, Paone D. Overdose
Neonatal Ed 1999; 81: F77. deaths involving fentanyl and fentanyl analogs—New York City,
Bobzean SAM, Kokane SS, Butler BD, Perrotti LI. Sex differences in 2000–2017. MMWR Morb Mortal Wkly Rep 2019; 68: 37–40.
the expression of morphine withdrawal symptoms and associated Connor DF. Stimulant and nonstimulant medications for childhood
activity in the tail of the ventral tegmental area. Neurosci Lett 2019; ADHD. In: Barkley RA, editor. Attention-deficit hyperactivity dis-
705: 124–30. order, a handbook for diagnosis and treatment. 4th edn. The
Bonnet U, Preuss UW. The cannabis withdrawal syndrome: current Guilford Press; 2015. p. 666–85.
insights. Subst Abuse Rehabil 2017; 8: 9–37. Copersino ML, Boyd SJ, Tashkin DP, Huestis MA, Heishman SJ,
Borison RL. Changing antipsychotic medication: guidelines on the Dermand JC, et al. Sociodemographic characteristics of cannabis
transition to treatment with risperidone. The Consensus Study smokers and the experience of cannabis withdrawal. Am J Drug
Group on Risperidone Dosing. Clin Ther 1996; 18: 592–607; dis- Alcohol Abuse 2010; 36: 311–9.
cussion 591. Corrigan FM, Coulter F. Neuroleptic malignant syndrome, amitriptyl-
Borison RL, Diamond BI, Sinha D, Gupta RP, Ajiboye PA. Clozapine ine, and thioridazine. Biol Psychiatry 1988; 23: 320–1.
withdrawal rebound psychosis. Psychopharmacol Bull 1988; 24: Cowe L, Lloyd DJ, Dawling S. Neonatal convulsions caused by with-
260–3. drawal from maternal clomipramine. Br Med J (Clin Res Ed) 1982;
Brantley E, Cohn J, Babu K. Case files of the program in 284: 1837–8.
medical toxicology at brown university: amantadine withdrawal Cowen PJ, Nutt DJ. Abstinence symptoms after withdrawal of tran-
and the neuroleptic malignant syndrome. J Med Toxicol 2009; 5: quillising drugs: is there a common neurochemical mechanism?
92–8. Lancet 1982; 2: 360–2.
Brower KJ. Anabolic steroid abuse and dependence. Curr Psychiatry Crane GE. Tardive dyskinesia in schizophrenic patients treated with
Rep 2002; 4: 377–87. psychotropic drugs. Agressologie 1968; 9: 209–18.
Brower KJ. Anabolic steroid abuse and dependence in clinical practice. Critchlow DG. A case of ketamine dependence with discontinuation
Phys Sportsmed 2009; 37: 131–40. symptoms. Addiction 2006; 101: 1212–3.
Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr Cubala WJ, Landowski J. Seizure following sudden zolpidem with-
Opin Psychiatry 2006; 19: 233–8. drawal. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:
Budney AJ, Hughes JR, Moore BA, Vandrey R. Review of the validity 539–40.
and significance of cannabis withdrawal syndrome. Am J Psychiatry Cuttler C, Mischley LK, Sexton M. Sex differences in cannabis use and
2004; 161: 1967–77. effects: a cross-sectional survey of cannabis users. Cannabis
Busto UE, Sellers EM. Anxiolytics and sedative/hypnotics dependence. Cannabinoid Res 2016; 1: 166–75.
Br J Addict 1991; 86: 1647–52. Czlonkowska A, Smolinski L, Litwin T. Severe disease exacerbations
Carlson GA, Kelly KL. Stimulant rebound: how common is it and in patients with multiple sclerosis after discontinuing fingolimod.
what does it mean? J Child Adolesc Psychopharmacol 2003; 13: Neurol Neurochir Pol 2017; 51: 156–62.
137–42. Desmond MM, Schwanecke RP, Wilson GS, Yasunaga S, Burgdorff I.
Ceccherini-Nelli A, Bardellini L, Cur A, Guazzelli M, Maggini C, Maternal barbiturate utilization and neonatal withdrawal symptom-
Dilsaver SC. Antidepressant withdrawal: prospective findings. Am J atology. J Pediatr 1972; 80: 190–7.
Psychiatry 1993; 150: 165. Dilsaver SC. Heterocyclic antidepressant, monoamine
Chartier KG, Sanchez K, Killeen TK, Burrow A, Carmody T, Greer oxidase inhibitor and neuroleptic withdrawal phenomena. Prog
TL. Men and women from the STRIDE clinical trial: an assessment Neuropsychopharmacol Biol Psychiatry 1990; 14: 137–61.
of stimulant abstinence symptom severity at residential treatment Dilsaver SC. Withdrawal phenomena associated with antidepressant
entry. Am J Addict 2015; 24: 336–40. and antipsychotic agents. Drug Saf 1994; 10: 103–14.
Chattopadhyay AC, Shukla L, Kandasamy A, Benegal V. High-dose Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing
zolpidem dependence—psychostimulant effects? A case report and opioids for chronic pain–United States, 2016. JAMA 2016; 315:
literature review. Ind Psychiatry J 2016; 25: 222–4. 1624–45.
Dowell D, Noonan RK, Houry D. Underlying factors in drug overdose Himmelsbach CK. Studies of certain addiction characteristics of (a)
deaths. JAMA 2017; 318: 2295–6. dihydromorphine (“Paramorphan”); (b) dihydrodesoxymorphineD
Essig CF. XIV. Addiction to barbiturate and nonbarbiturate sedative (“Desomorphine”); (c) dihydrodesoxycodeine (“Desocodeine”) and
drugs. Res Publ Assoc Res Nerv Ment Dis 1968; 46: 188–98. (d) methyldihydromorphinone (“Metopon”). Pharmacol Exp Ther
Faissner S, Hoepner R, Lukas C, Chan A, Gold R, Ellrichmann G. 1939; 67: 239–2.
Tumefactive multiple sclerosis lesions in two patients after Hollister LE, Bennett JL, Kimbell I Jr, Savage C, Overall JE.
cessation of fingolimod treatment. Ther Adv Neurol Disord 2015; 8: Diazepam in newly admitted schizophrenics. Dis Nerv Syst 1963;
233–8. 24: 746–50.
Foulkner P, Petersen N, Ghahremani DG, Cox CM, Tyndale RF, Hollister LE, Motzenbecker FP, Degan RO. Withdrawal reactions
Hellemann GS, et al. Sex differences in tobacco withdrawal and from chlordiazepoxide (“Librium”). Psychopharmacologia 1961; 2:
responses to smoking reduced-nicotine cigarettes in young smokers. 63–8.
Psychopharmacology (Berl). 2018; 235: 193–202. Hudak ML, Tan RC; Committee on Drugs, Committee on Fetus and
Fava GA, Gatti A, Belaise C, Guidi J, Offidani E. Withdrawal symp- Newborn, American Academy of Pediatrics. Neonatal drug with-
toms after selective serotonin reuptake inhibitor discontinuation: a drawal. Pediatrics 2012; 129: e540–60.
systematic review. Psychother Psychosom 2015; 84: 72–81. Hughes JR. Effects of abstinence from tobacco: valid symptoms and
Fisher D, Grap MJ, Younger JB, Ameringer S, Elswick RK. Opioid time course. Nicotine Tob Res 2007; 9: 315–27.
withdrawal signs and symptoms in children: frequency and determi- Hurt PH, Ritchie EC. A case of ketamine dependence. Am J Psychiatry
nants. Heart Lung 2013; 42: 407–13. 1994; 151: 779.
Fontaine R, Chouinard G, Annable L. Rebound anxiety in anxious Inturrisi CE, Schultz M, Shin S, Umans JG, Angel L, Simon EJ.
patients after abrupt withdrawal of benzodiazepine treatment. Am J Evidence from opiate binding studies that heroin acts through its
Psychiatry 1984; 141: 848–52. metabolites. Life Sci 1983; 33 (Suppl 1): 773–6.
Fraser HF, Shaver MR, Maxwell ES, Isbell H. Death due to withdraw- Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiaze-
al of barbiturates. Ann Intern Med 1953; 38: 1319–25. pines on the fetus, the neonate, and the nursing infant. Psychiatr
Friedman JH, Feinberg SS, Feldman RG. A neuroleptic malignantlike Serv 2002; 53: 39–49.
syndrome due to levodopa therapy withdrawal. JAMA 1985; 254: Ista E, van Dijk M, Gamel C, Tibboel D, de Hoog M. Withdrawal
2792–5. symptoms in critically ill children after long-term administration of
Garner EM, Kelly MW, Thompson DF. Tricyclic antidepressant with- sedatives and/or analgesics: a first evaluation. Crit Care Med 2008;
drawal syndrome. Ann Pharmacother 1993; 27: 1068–72. 36: 2427–32.
Gault FP. A review of recent literature on barbiturate addiction and Ito T, Shibata K, Watanabe A, Akabane J. Neuroleptic malignant syn-
withdrawal. Bol Estud Med Biol 1976; 29: 75–83. drome following withdrawal of amantadine in a patient with influ-
Gonzalez-Suarez I, Rodriguez de Antonio L, Orviz A, Moreno-Garcia enza A encephalopathy. Eur J Pediatr 2001; 160: 401.
S, Valle-Arcos MD, Matias-Guiu JA, et al. Catastrophic outcome of Jackson KJ, Muldoon PP, De Biasi M, Damaj MI. New mechanisms
patients with a rebound after Natalizumab treatment discontinu- and perspectives in nicotine withdrawal. Neuropharmacology 2015;
ation. Brain Behav 2017; 7: e00671. 96: 223–34.
Gorelick DA, Levin KH, Copersino ML, Heishman SJ, Liu F, Boggs Jansen KL, Darracot-Cankovic R. The nonmedical use of ketamine,
DL, et al. Diagnostic criteria for cannabis withdrawal syndrome. part two: a review of problem use and dependence. J Psychoactive
Drug Alcohol Depend 2012; 123: 141–7. Drugs 2001; 33: 151–8.
Gresham C, LoVecchio F. Barbiturates. In: JE Tintinalli, editor. Kahne GJ. Rebound psychoses following the discontinuation of a high
Tintinalli’s emergency medicine: a comprehensive study guide. 8th potency neuroleptic. Can J Psychiatry 1989; 34: 227–9.
edn. Chap. 182, Mc Graw-Hill Education; 2015, 1–11. Kales A, Bixler EO, Soldatos CR, Vela-Bueno A, Jacoby J, Kales JD.
Gunduz T, Kurtuncu M, Eraksoy M. Severe rebound after withdrawal Quazepam and flurazepam: long-term use and extended withdrawal.
of fingolimod treatment in patients with multiple sclerosis. Mult Clin Pharmacol Ther 1982; 32: 781–8.
Scler Relat Disord 2017; 11: 1–3. Kales A, Bixler EO, Vela-Bueno A, Soldatos CR, Manfredi RL.
Gussow L, Carlson A. Sedative hypnotics. In: Marx JA, Hockberger Alprazolam: effects on sleep and withdrawal phenomena. J Clin
R, Walls RM, Biros MH, editors. Rosen’s emergency medicine: Pharmacol 1987; 27: 508–15.
Concepts and clinical practice. 8th edn. Chap. 165, Philadelphia, Kales A, Scharf MB, Kales JD. Rebound insomnia: a new clinical syn-
PA: Elsevier Saunders; 2013. p. 2076–83. drome. Science 1978; 201: 1039–41.
Haddad PM. Antidepressant discontinuation syndromes. Drug Saf Kales A, Soldatos CR, Bixler EO, Goff PJ, Vela-Bueno A. Midazolam:
2001; 24: 183–97. dose-response studies of effectiveness and rebound insomnia.
Hamilton KR, Perry ME, Berger SS, Grunberg NE. Behavioral effects Pharmacology 1983a; 26: 138–49.
of nicotine withdrawal differ by genetic strain in male and female Kales A, Soldatos CR, Bixler EO, Kales JD. Rebound insomnia and re-
adolescent rats. Nicotine Tob Res 2010; 12: 1236–45. bound anxiety: a review. Pharmacology 1983b; 26: 121–37.
Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kamaya H, Krishna PR. Ketamine addiction. Anesthesiology 1987;
Kanof PD. Two new rating scales for opiate withdrawal. Am J Drug 67: 861–2.
Alcohol Abuse 1987; 13: 293–308. Kan CC, Hilberink SR, Breteler MH. Determination of the main
Harte-Hargrove LC, Dow-Edwards DL. Withdrawal from THC during risk factors for benzodiazepine dependence using a multivariate
adolescence: sex differences in locomotor activity and anxiety. and multidimensional approach. Compr Psychiatry 2004; 45:
Behav Brain Res 2012; 231: 48–59. 88–94.
Hatcher SE, Waubant E, Nourbakhsh B, Crabtree-Hartman E, Graves Kanayama G, Brower KJ, Wood RI, Hudson JI, Pope HG Jr.
JS. Rebound syndrome in patients with multiple sclerosis after cessa- Anabolic-androgenic steroid dependence: an emerging disorder.
tion of fingolimod treatment. JAMA Neurol 2016; 73: 790–4. Addiction 2009; 104: 1966–78.
Herrmann ES, Weerts EM, Vandrey R. Sex differences in cannabis Karas H, Guduk M, Saatcioglu O. Withdrawal-emergent dyskinesia
withdrawal symptoms among treatment-seeking cannabis users. Exp and supersensitivity psychosis due to olanzapine use. Arch
Clin Psychopharmacol 2015; 23: 415–21. Neuropsychiatr 2016; 53: 178–80.
Himei A, Okamura T. Discontinuation syndrome associated with Kariisa M, Scholl L, Wilson N, Seth P, Hoots B. Drug overdose deaths
paroxetine in depressed patients: a retrospective analysis of factors involving cocaine and psychostimulants with abuse potential—
involved in the occurrence of the syndrome. CNS Drugs 2006; 20: United States, 2003–2017. MMWR Morb Mortal Wkly Rep 2019;
665–72. 68: 388–95.
Kasckow J, Dolor R, Lipper S. Delayed onset of neuroleptic malignant Mizuno Y, Takubo H, Mizuta E, Kuno S. Malignant syndrome in
syndrome after discontinuation of thioridazine. J Clin Parkinson’s disease: concept and review of the literature.
Psychopharmacol 1990; 10: 146. Parkinsonism Relat Disord 2003; 9 (Suppl 1): S3–9.
Kocherlakota P. Neonatal abstinence syndrome. Pediatrics 2014; 134: Nakata Y, Kanahara N, Iyo M. Dopamine supersensitivity psychosis
e547–61. in schizophrenia: concepts and implications in clinical practice. J
Kolb L. Clinical contribution to drug addiction: the struggle for cure Psychopharmacol 2017; 31: 1511–8.
and the conscious reasons for relapse. Edinb Med J 1928; 35: New South Wales Government. Drug and alcohol withdrawal clinical
740–1. practice guidelines—NSW. In: Ministry of Health NG, AU, editor.
Koob GF, Le Moal M. Addiction and the brain antireward system. Sydney, NSW: NSW Department of Health; 2008.
Annu Rev Psychol 2008a; 59: 29–53. Newman EJ, Grosset DG, Kennedy PG. The parkinsonism-hyperpyr-
Koob GF, Le Moal M. Neurobiological mechanisms for opponent mo- exia syndrome. Neurocrit Care 2009; 10: 136–40.
tivational processes in addiction. Phil Trans R Soc B 2008b; 363: Nielsen M, Hansen EH, Gotzsche PC. What is the difference between
3113–23. dependence and withdrawal reactions? A comparison of benzodiaze-
Koons AL, Rayl Greenberg M, Cannon RD, Beauchamp GA. Women pines and selective serotonin re-uptake inhibitors. Addiction 2012;
and the experience of pain and opioid use disorder: a literature- 107: 900–8.
based commentary. Clin Ther 2018; 40: 190–6. Noyes R Jr, Garvey MJ, Cook B, Suelzer M. Controlled discontinu-
Koren G, Boucher N. Adverse effects in neonates exposed to SSRIs ation of benzodiazepine treatment for patients with panic disorder.
and SNRI in late gestation–Motherisk Update 2008. Can J Clin Am J Psychiatry 1991; 148: 517–23.
Pharmacol 2009; 16: e66–7. Nutt DJ, Malizia AL. New insights into the role of the GABA(A)-
Kosten TR, O’Connor PG. Management of drug and alcohol with- benzodiazepine receptor in psychiatric disorder. Br J Psychiatry
drawal. N Engl J Med 2003; 348: 1786–95. 2001; 179: 390–6.
Kruse WH. Problems and pitfalls in the use of benzodiazepines in the O’Brien CP. Benzodiazepine use, abuse, and dependence. J Clin
elderly. Drug Saf 1990; 5: 328–44. Psychiatry 2005; 66 (Suppl 2): 28–33.
Lader M. Anxiety or depression during withdrawal of hypnotic treatments. Oda Y, Kanahara N, Iyo M. Alterations of dopamine D2 receptors
J Psychosom Res 1994; 38 (Suppl 1): 113–23; discussion 118–23. and related receptor-interacting proteins in schizophrenia: the piv-
Lader M, Lawson C. Sleep studies and rebound insomnia: methodo- otal position of dopamine supersensitivity psychosis in treatment-re-
logical problems, laboratory findings, and clinical implications. Clin sistant schizophrenia. Int J Mol Sci 2015; 16: 30144–63.
Neuropharmacol 1987; 10: 291–312. Owen RT, Tyrer P. Benzodiazepine dependence. A review of the evi-
Larochelle C, Metz I, Lécuyer M-A, Terouz S, Roger M, Arbour N, dence. Drugs 1983; 25: 385–98.
Pal HR, Berry N, Kumar R, Ray R. Ketamine dependence. Anaesth
et al. Immunological and pathological characterization of fatal re-
Intensive Care 2002; 30: 382–4.
bound MS activity following natalizumab withdrawal. Mult Scler
Pasero C, McCaffery M. Misconception that hamper assessment and
2017; 23: 72–81.
treatment of patients who report pain. In: Pain assessment and
Lebin LG, Cerimele JM. Recurrent benzodiazepine withdrawal catato-
pharmacologic management Chap. 2. St. Louis, MO: Elsevier
nia in an older adult. Am J Psychiatry 2017; 174: 1001–2.
Health Sciences; 2010, 20–48.
Leiter FL, Nierenberg AA, Sanders KM, Stern TA. Discontinuation
Pecknold JC, Swinson RP, Kuch K, Lewis CP. Alprazolam in panic dis-
reactions following sertraline. Biol Psychiatry 1995; 38: 694–5.
order and agoraphobia: results from a multicenter trial. III.
Lemesle F, Lemesle F, Nicola W, Pierre Jonville-Bera A. First case
Discontinuation effects. Arch Gen Psychiatry 1988; 45: 429–36.
of stress cardiomyopathy as a result of methadone withdrawal
Pesce ME, Acevedo X, Pinardi G, Miranda HF. Gender differences in
secondary to drug-drug interaction. Am J Emerg Med 2010; 28:
diazepam withdrawal syndrome in mice. Pharmacol Toxicol 1994;
387.e5–6.
75: 353–5.
Light AB, Torrence EG. Opium addiction. Arch Intern Med (Chic)
Petursson H. The benzodiazepine withdrawal syndrome. Addiction
1929; 44: 1–16.
1994; 89: 1455–9.
Lim DK. Ketamine associated psychedelic effects and dependence.
Porrino LJ, Rapoport JL, Behar D, Ismond DR, Bunney WE Jr. A nat-
Singapore Med J 2003; 44: 31–4. uralistic assessment of the motor activity of hyperactive boys. II.
Lupolover R, Dazzi H, Ward J. Rebound phenomena: results of a 10
Stimulant drug effects. Arch Gen Psychiatry 1983; 40: 688–93.
years’ (1970–1980) literature review. Int Pharmacopsychiatry 1982; Preskorn SH, Denner LJ. Benzodiazepines and withdrawal psychosis.
17: 194–237. Report of three cases. JAMA 1977; 237: 36–8.
MacKinnon GL, Parker WA. Benzodiazepine withdrawal syndrome: a Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome
literature review and evaluation. Am J Drug Alcohol Abuse 1982; 9: in Parkinson disease. Arch Neurol 2010; 67: 58–63.
19–33. Rainer C, Scheinost NA, Lefeber EJ. Neuroleptic malignant syndrome.
Margolese HC, Chouinard G, Beauclair L, Belanger MC. Therapeutic When levodopa withdrawal is the cause. Postgrad Med 1991; 89:
tolerance and rebound psychosis during quetiapine maintenance 175–8, 180.
monotherapy in patients with schizophrenia and schizoaffective dis- Rapoport JL, Buchsbaum MS, Zahn TP, Weingartner H, Ludlow C,
order. J Clin Psychopharmacol 2002; 22: 347–52. Mikkelsen EJ. Dextroamphetamine: cognitive and behavioral effects
Margolese HC, Chouinard G, Kolivakis TT, Beauclair L, Miller R. in normal prepubertal boys. Science 1978; 199: 560–3.
Tardive dyskinesia in the era of typical and atypical antipsychotics. Reeves RR, Kamal A. Complicated withdrawal phenomena during
Part 1: pathophysiology and mechanisms of induction. Can J benzodiazepine cessation in older adults. J Am Osteopath Assoc
Psychiatry 2005; 50: 541–7. 2019; 119: 327–31.
Martin WR, Jasinski DR. Physiological parameters of morphine de- Reidenberg MM. Drug discontinuation effects are part of the pharma-
pendence in man–tolerance, early abstinence, protracted abstinence. cology of a drug. J Pharmacol Exp Ther 2011; 339: 324–8.
J Psychiatr Res 1969; 7: 9–17. Riccio CA, Waldrop JJ, Reynolds CR, Lowe P. Effects of stimulants
Marusich JA, Lefever TW, Antonazzo KR, Craft RM, Wiley JL. on the continuous performance test (CPT): implications for CPT use
Evaluation of sex differences in cannabinoid dependence. Drug and interpretation. J Neuropsychiatry Clin Neurosci 2001; 13:
Alcohol Depend 2014; 137: 20–8. 326–35.
Medras M, Tworowska U. [Treatment strategies of withdrawal from Rickels K, Schweizer E, Case GW, Garcia-Espana F. Benzodiazepine
long-term use of anabolic-androgenic steroids]. Pol Merkur Lekarski dependence, withdrawal severity, and clinical outcome: effects of
2001; 11: 535–8. personality. Psychopharmacol Bull 1988; 24: 415–20.
Rickels K, Schweizer E, Case WG, Greenblatt DJ. Long-term thera- Sethi PK, Khandelwal DC. Zolpidem at supratherapeutic doses can
peutic use of benzodiazepines. I. Effects of abrupt discontinuation. cause drug abuse, dependence and withdrawal seizure. J Assoc
Arch Gen Psychiatry 1990; 47: 899–907. Physicians India 2005; 53: 139–40.
Ries RK, Fiellin DA, Miller SC, Saitz R. The ASAM principles of ad- Shelton RC. The nature of the discontinuation syndrome associated
diction medicine. Chevy Chase, MD: American Academy of with antidepressant drugs. J Clin Psychiatry 2006; 67 (Suppl 4): 3–7.
Addiction Medicine Wolters Kluver; 2014. Shiovitz TM, Welke TL, Tigel PD, Anand R, Hartman RD, Sramek JJ,
Risse SC, Whitters A, Burke J, Chen S, Scurfield RM, Raskind MA. et al. Cholinergic rebound and rapid onset psychosis following
Severe withdrawal symptoms after discontinuation of alprazolam in abrupt clozapine withdrawal. Schizophr Bull 1996; 22: 591–5.
eight patients with combat-induced posttraumatic stress disorder. J Simoni-Wastila L, Yang HK. Psychoactive drug abuse in older adults.
Clin Psychiatry 1990; 51: 206–9. Am J Geriatr Pharmacother 2006; 4: 380–94.
Rivera JM, Locketz AJ, Fritz KD, Horlocker TT, Lewallen DG, Prasad Sloan JW, Wala EP, Jing X, Holtman JR Jr. The pharmacodynamics
A, et al. “Broken heart syndrome” after separation (from of PK 11195 in diazepam-dependent male and female rats.
OxyContin). Mayo Clin Proc 2006; 81: 825–8. Pharmacol Biochem Behav 2000; 66: 751–64.
Roehrs T, Merlotti L, Zorick F, Roth T. Rebound insomnia in normals Smith DE, Wesson DR. Benzodiazepine dependency syndromes. J
and patients with insomnia after abrupt and tapered discontinu- Psychoactive Drugs 1983; 15: 85–95.
ation. Psychopharmacology (Berl) 1992; 108: 67–71. Smucker WD, Hedayat M. Evaluation and treatment of ADHD. Am
Rook E, Huitema A, Brink W, Ree J, Beijnen J. Pharmacokinetics and Fam Physician 2001; 64: 817–29.
pharmacokinetic variability of heroin and its metabolites: review of Soldatos CR, Dikeos DG, Whitehead A. Tolerance and rebound in-
the literature. Curr Clin Pharmacol 2006; 1: 109–18. somnia with rapidly eliminated hypnotics: a meta-analysis of sleep
Rosebush PI, Mazurek MF. Catatonia after benzodiazepine withdraw- laboratory studies. Int Clin Psychopharmacol 1999; 14: 287–303.
al. J Clin Psychopharmacol 1996; 16: 315–9. Sorensen PS, Koch-Henriksen N, Petersen T, Ravnborg M, Oturai A,
Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective Sellebjerg F. Recurrence or rebound of clinical relapses after discon-
serotonin reuptake inhibitor discontinuation syndrome: a random- tinuation of natalizumab therapy in highly active MS patients. J
ized clinical trial. Biol Psychiatry 1998; 44: 77–87. Neurol 2014; 261: 1170–7.
Rosse R, Ciolino C. Dopamine agonists and neuroleptic malignant Spadotto V, Zorzi A, Elmaghawry M, Meggiolaro M, Pittoni GM.
syndrome. Am J Psychiatry 1985; 142: 270–1. Heart failure due to ‘stress cardiomyopathy’: a severe manifestation
Roy-Byrne PP, Dager SR, Cowley DS, Vitaliano P, Dunner DL. of the opioid withdrawal syndrome. Eur Heart J Acute Cardiovasc
Care 2013; 2: 84–7.
Relapse and rebound following discontinuation of benzodiazepine
Spivak B, Weizman A, Wolovick L, Hermesh H, Tyano S, Munitz H.
treatment of panic attacks: alprazolam versus diazepam. Am J
Neuroleptic malignant syndrome during abrupt reduction of neuro-
Psychiatry 1989; 146: 860–5.
leptic treatment. Acta Psychiatr Scand 1990; 81: 168–9.
Rungnirundorn T, Verachai V, Gelernter J, Malison RT, Kalayasiri R.
Stiskal JA, Kulin N, Koren G, Ho T, Ito S. Neonatal paroxetine with-
Sex differences in methamphetamine use and dependence in a thai
drawal syndrome. Arch Dis Child Fetal Neonatal Ed 2001; 84:
treatment center. J Addict Med 2017; 11: 19–27.
F134–5.
Saiful FB, Lafferty J, Jun CH, Teli S, Duvvuri S, Khattri S, et al.
Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome.
Takotsubo cardiomyopathy due to iatrogenic methadone withdraw-
Am J Psychiatry 2007; 164: 870–6.
al. Rev Cardiovasc Med 2011; 12: 164–7.
Sury MR, Billingham I, Russell GN, Hopkins CS, Thornington R,
SAMHSA—Substance Abuse and Mental Health Services
Vivori E. Acute benzodiazepine withdrawal syndrome after midazo-
Administration. Protracted Withdrawal. Substance Abuse Treatment
lam infusions in children. Crit Care Med 1989; 17: 301–2.
Advisory 2010; 9: 1–8.
ter Horst PG, van der Linde S, Smit JP, den Boon J, van Lingen RA,
Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R. Selective sero-
Jansman FG, et al. Clomipramine concentration and withdrawal
tonin reuptake inhibitors in pregnant women and neonatal with- symptoms in 10 neonates. Br J Clin Pharmacol 2012; 73:
drawal syndrome: a database analysis. Lancet 2005; 365: 482–7. 295–302.
Satel SL, Kosten TR, Schuckit MA, Fischman MW. Should protracted Thiblin I, Runeson B, Rajs J. Anabolic androgenic steroids and suicide.
withdrawal from drugs be included in DSM-IV? Am J Psychiatry Ann Clin Psychiatry 1999; 11: 223–31.
1993; 150: 695–704. Torres OV, Gentil LG, Natividad LA, Carcoba LM, O’Dell LE.
Scharf MB, Kales A, Bixler EO, Jacoby JA, Schweitzer PK. Biochemical, and molecular indices of stress are enhanced in female
Lorazepam-efficacy, side effects, and rebound phenomena. Clin versus male rats experiencing nicotine withdrawal. Front Psychiatry
Pharmacol Ther 1982; 31: 175–9. 2013; 4: 38.
Schatzberg AF, Haddad P, Kaplan EM, Lejoyeux M, Rosenbaum JF, Tripodianakis J, Potagas C, Papageorgiou P, Lazaridou M, Matikas
Young AH, et al. Serotonin reuptake inhibitor discontinuation syn- N. Zolpidem-related epileptic seizures: a case report. Eur Psychiatry
drome: a hypothetical definition. Discontinuation Consensus panel. 2003; 18: 140–1.
J Clin Psychiatry 1997; 58 (Suppl 7): 5–10. Tsutsui S, Zolipidem Study Group. A double-blind comparative study
Schlienz NJ, Budney AJ, Lee DC, Vandrey R. Cannabis withdrawal: a of zolpidem versus zopiclone in the treatment of chronic primary in-
review of neurobiological mechanisms and sex differences. Curr somnia. J Int Med Res 2001; 29: 163–77.
Addict Rep 2017; 4: 75–81. U.S. Department of Health and Human Services, Food and Drug
Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and opioid- Administration, Center for Drug Evaluation and Research (CDER).
involved overdose deaths—United States, 2013–2017. MMWR Guidance for industry - assessment of abuse potential of drugs.
Morb Mortal Wkly Rep 2018; 67: 1419–27. Silver Spring, MD 20993-0002; 2017. https://www.fda.gov/regula
Schultz SK, Miller DD, Arndt S, Ziebell S, Gupta S, Andreasen NC. tory-information/search-fda-guidance-documents/assessment-abuse-
Withdrawal-emergent dyskinesia in patients with schizophrenia dur- potential-drugs.
ing antipsychotic discontinuation. Biol Psychiatry 1995; 38: 713–9. U.S. Government PO. Title 21 - FOOD AND DRUGS, United States
Sechi GP, Tanda F, Mutani R. Fatal hyperpyrexia after withdrawal of Code, Supplement 5 2006.
levodopa. Neurology 1984; 34: 249–51. United States Congress. Title II of the Comprehensive Drug Abuse
Serrano-Duenas M. Neuroleptic malignant syndrome-like, or–dopa- Prevention and Control Act of 1970. US Government. 1970.
minergic malignant syndrome–due to levodopa therapy withdrawal. Valuck RJ, Orton HD, Libby AM. Antidepressant discontinuation and
Clinical features in 11 patients. Parkinsonism Relat Disord 2003; 9: risk of suicide attempt: a retrospective, nested case-control study. J
175–8. Clin Psychiatry 2009; 70: 1069–77.
Victorri-Vigneau C, Dailly E, Veyrac G, Jolliet P. Evidence of zolpidem Wakim JH. Alleviating symptoms of withdrawal from an opioid. Pain
abuse and dependence: results of the French Centre for Evaluation Ther 2012; 1: 4.
and Information on Pharmacodependence (CEIP) network survey. Watsky E. Management of zolpidem withdrawal. J Clin
Br J Clin Pharmacol 2007; 64: 198–209. Psychopharmacol 1996; 16: 459.
Victorri-Vigneau C, Gerardin M, Rousselet M, Guerlais M, Grall- Webster LR, Cochella S, Dasgupta N, Fakata KL, Fine PG, Fishman
Bronnec M, Jolliet P. An update on zolpidem abuse and dependence. SM. An analysis of the root causes for opioid-related overdose
J Addict Dis 2014; 33: 15–23. deaths in the United States. Pain Med 2011; 12 (Suppl 2): S26–35.
Voshaar RC, van Balkom AJ, Zitman FG. Zolpidem is not superior to Yerevanian BI, Koek RJ, Feusner JD, Hwang S, Mintz J.
temazepam with respect to rebound insomnia: a controlled study. Antidepressants and suicidal behaviour in unipolar depression. Acta
Eur Neuropsychopharmacol 2004; 14: 301–6. Psychiatr Scand 2004; 110: 452–8.

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1093/braincomms/fcz025 BRAIN COMMUNICATIONS 2019: Page 1 of 23 | 1

Dependence, withdrawal and rebound of CNS

Keywords: dependence; withdrawal syndromes; rebound; human dependence evaluation

Part I: Introduction, their significance underappreciated, particularly for drugs

Sex and age differences—a possible

Box 1 Animal withdrawal studies, sex and age impact

There are some data available describing impact of age

Figure 1 Course of opioid withdrawal. The figure shows

Adverse events Opioids BZ Stimulants SSRIs-SNRIs Cannabis Nicotine Anti-psychotics Androgenic

sweating, palpitations, tiredness, low appetite, low mood,

hypotonia, respiratory distress and feeding disorder (e.g.

Levodopa-withdrawal malignant syndrome

Following is an example of rebound anxiety after with-

dependence which are exposed during drug discontinu-

Part IV. Protracted

phenomena, presented by Chouinard and Chouinard

As discussed above, the evaluation of dependence and

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