Psychiatry has been given the role of investigating, understanding, and treating the effects of stress, including anxiety, dysphoria, and feelings of discomfort. In addition to conventional psychotherapy models, psychiatrists worked on pharmacological therapies and consequently sedatives, anxiolytics, and hypnotics were created. By the 19th century, bromide salts, chloral hydrate, and paraldehyde were used in medicine. Subsequently, barbiturates were first synthesized for medical use in 1903, followed by meprobamate in 1950.[1] By 1959, the benzodiazepine chlordiazepoxide was created, giving rise to at least 3000 different benzodiazepines, of which 13 are currently marketed.[2] New benzodiazepines are currently being developed as well.[3]
The therapeutic value of these agents as anxiolytics and hypnotics has been well established, and they continue to serve an important role in managing many debilitating anxiety symptoms in the context of both psychiatric disorders and medical illness. However, the toxic effects of these drugs have also been established, including various withdrawal syndromes, dependence, and tolerance.
Per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) published in May 2013, the appropriate diagnosis for a prolonged and problematic pattern of use of these substances would be “Sedative, Hypnotic, or Anxiolytic Use Disorder.” For acute intoxication and withdrawal, the DSM-5 diagnoses would be “Sedative, Hypnotic, or Anxiolytic Intoxication” and “Sedative, Hypnotic, or Anxiolytic Withdrawal,” respectively.[4] There are additional specifiers based on the severity of symptoms, remission status, and the presence of perceptual disturbances as well.
Mr. X is a 27-year-old white male with a past psychiatric history of anxiety, insomnia, and substance abuse and no past medical history who presents in the emergency department with a friend for confusion and diaphoresis.
He was recently seen at a community clinic 1 week ago for a sinus infection and was given a 10-day course of antibiotics, but did not receive his alprazolam refill. He states he has taken his antibiotics as prescribed for the past 10 days, but that his heart has been racing and his insomnia has worsened; his friend states that for the past 4 days he has been having difficulty following conversations and focusing on daily tasks. He has been off his alprazolam for 7 days because he ran out of his prescription. He denied any recent psychosocial stressors and did not endorse feelings of guilt, helplessness, or hopelessness. Furthermore, he denied any fever, nausea, vomiting, diarrhea, myalgia, abdominal cramps, and seizures. He denied any recent alcohol/illicit drug use.
Upon physical examination, he was found to be tachycardic (pulse, 110 beats/min) and hypertensive (blood pressure, 170/90 mm Hg). His medical workup, including CBC count, electrolyte panel, liver function tests, blood glucose level, and urine toxicology screen, and his lumbar puncture were within normal limits.
His mental status examination revealed a casually dressed male who appeared to be restless and irritable. His speech was normal in rate and content. His mood was subjectively anxious and objectively dysphoric, and his affect was congruent with mood. His thought form was linear and goal directed. There was no evidence of paranoid ideations/delusions. He denied any auditory or visual hallucinations. He was oriented to time, place, and person. He scored 30/30 on the Mini-Mental State Examination. He had good insight and judgment. He endorsed passive suicidal ideations. He denied any homicidal ideations.
Mr X was diagnosed with Anxiolytic Withdrawal due to recent abrupt discontinuation of benzodiazepines. He did not have symptoms suggestive of worsening infection, and there were no apparent stressors/neurovegetative symptoms to explain recurrence of depressive episode.
Gamma-aminobutyric acid (GABA) is the key inhibitory neurotransmitter involved in anxiety and in the anxiolytic action of psychotropic drugs used to treat anxiety disorders. GABA opens chloride (Cl) channels, causing an influx of Cl ions. The influx of Cl ions causes hyperpolarization of the neuron, subsequently inhibiting neuronal discharge. The action of hyperpolarization is reversed by the influx of calcium into the cell.[6]
The 3 major types of GABA receptors include GABA-A, GABA-B and GABA-C receptors. The GABA (A) receptor subunit, composed of multiple forms (eg, alpha, beta, gamma) has been proposed as the functional unit on which benzodiazepines and barbiturates operate. GABA-A receptors can be further classified as benzodiazepine-sensitive and benzodiazepine-insensitive based on structural differences between these receptor subtypes. The GABA-A receptor is a protein, which forms a chloride-selective ion channel and ligands. The metabolized benzodiazepine binds this site and stabilizes 3 different conformations. Classic benzodiazepines exert a positive effect by increasing the affinity of channel opening. [7]
Benzodiazepine-sensitive GABA receptors with alpha-1 subunits may be most important for regulating sleep and are the presumed targets of sedative-hypnotic agents. On the other hand, benzodiazepine-sensitive GABA-A receptors with alpha-2 subunits may be most important for regulating anxiety and are presumed targets of anxiolytic agents. Flumazenil, a benzodiazepine antagonist, interacts with GABA-A receptors and can be used clinically to rapidly reverse the effects of benzodiazepine overdoses.[6]
The long-term pharmacodynamic interaction of benzodiazepines with the GABA receptor is thought to be extremely complex. After long-term benzodiazepine use, the receptor effects caused by the agonist are attenuated. This down-regulation of receptor response is not due to decrease in receptor number or to decreased affinity of the receptor for GABA. The basis for down-regulation seems to be in the coupling between GABA-binding site and the activation of the chloride ion channel.[8]
These changes are potential mechanisms of tolerance, withdrawal, and dependence. The abrupt cessation of benzodiazepines, as in the case of a patient discontinuing a benzodiazepine after long-term use, is thought to result in the classically described acute withdrawal symptoms as the inhibitory effect of benzodiazepines is removed, thus leading to a relative excitatory state. [9]
United States
Sedative-hypnotics are among the most commonly prescribed psychoactive drugs by primary care physicians. Approximately 4.6% of all Americans have used legally prescribed anxiolytics, sedatives, or hypnotics in the past 30 days.[10] According to the 2014 National Survey on Drug Use and Health, 2.5% of the US population aged 12 or older (ie, 6.5 million people) used psychotherapeutic drugs for nonmedical purposes; of them, 1.9 million used tranquilizers and 330,000 used sedatives.[11]
A 2010 analysis of data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), found that of the 34,653 respondents aged 18-80 years who completed interviews during waves of the research from 2001-2002 and 2004-2005, 11.8% of respondents had received prescriptions for anxiety medication; 16% of this subgroup reported lifetime nonmedical use and 4.6% reported abuse of or dependence on these drugs.[12, 13] The age group with highest lifetime prevalence of sedative (3%) and tranquilizer (6%) nonmedical use was 26-34 years, while those aged 18-25 years were most likely to have used them in the prior year.[14]
The nonmedical use of anxiety prescriptions continues to garner clinical attention because abuse by patients has been increasing.
According to one study, the early onset of nonmedical use of prescription drugs was a significant predictor of prescription drug abuse and dependence. A higher percentage of individuals who began using prescription drugs nonmedically at or before age 13 years were found to have developed prescription drug abuse and dependence versus those individuals who began using at or after age 21 years.[15] Furthermore, nearly 10% of those with nonmedical use met criteria for abuse/dependence.
These are important considerations for clinicians, given that they can screen for potential abuse/dependence in patients who present with anxiety or panic symptoms and offer alternative treatments or referrals.
Race
Among adults, 12-month prevalence is greatest among Native Americans and Alaska Natives (0.8%), with rates of approximately 0.2% among African Americans, whites, and Hispanics and 0.1% among Asian Americans and Pacific Islanders.[4]
Sex
Rates of sedative, hypnotic, or anxiolytic use disorder are slightly greater among adult males (0.3%) than among adult females (0.2%).[4]
Age
Sedatives, anxiolytics, and hypnotics are commonly prescribed for people in the sixth and seventh decades of life; however, nonmedical use is highest in people aged 26-35 years and higher in men compared with women and non-Hispanic whites compared with African Americans or Hispanics.[15]
Some individuals respond to treatment and stay in remission, while others experience periods of relapse, in which they begin sedative-hypnotic-anxiolytic use/abuse after a period of remission, and again meet the criteria for substance dependence. Some individuals are never able to abstain from use and do not experience any periods of remission.
Only a handful of studies have investigated the long-term success of benzodiazepine discontinuation programs. Most studies indicate a high relapse state; however, outcome is more favorable in those individuals who manage to complete a discontinuation program.[31] A 4- to 6-year post discharge follow-up study of patients primarily admitted for primary sedative-hypnotic dependence showed that 84% of the patients had resumed using sedative-hypnotics, 52% were abusing drugs at follow-up, and 42% had been readmitted for drug abuse.[32]
A 10-year follow-up study analyzed the importance of the physician-patient relationship and examined whether a discontinuation letter from the provider was enough motivation to stop using the medication. After 10 years, researchers found that 58% of patients had discontinued benzodiazepine use and overall those who had not discontinued their use had decreased their dose of benzodiazepines. Those who had discontinued by 21 months of the intervention had a higher rate of being abstinent at a 10-year follow-up.[33]
There is some data regarding the success of varying outpatient tapering schedules. In one study, at 36 months, 39% of patients in a written step dose reduction program, 41% in a structured intervention with stepped-dose reduction and follow-up visit, and 26% in a control group discontinued benzodiazepine use. The groups showed no significant differences in anxiety, depression, or sleep dissatisfaction. The results of this study imply that patients are likely to be as successful discontinuing benzodiazepine use by self-tapering with written instructions from their physician as they are from being followed up more closely during the taper by their provider.[49]
Outcome is better in individuals with good social support, absence of psychiatric co-morbidity or remission of preexisting psychiatric symptoms, and absence of dependence on other drugs.[34]
Excellent patient education resources are available at eMedicineHealth's Mental Health Center. Also, see eMedicineHealth's patient education articles Benzodiazepine Abuse, Barbiturate Abuse, and Substance Abuse.
Sedative-hypnotic abuse/dependence can affect the entire family, it is necessary to inform them of the pertinent issues. In certain cases, family members can be enablers. Research shows that family-based treatments may be superior to other individual and group treatment approaches.[50] The NIH has published a guide surrounding the different types of family-based therapies and research supporting their use.[51]
It is important for the prescribing physician to know about the harmful effects and complications related to sedative-hypnotic use. Sedative-hypnotics were once believed to be helpful to patients suffering from a variety of psychological disorders, such as PTSD, but more recent studies have shown that they can actually be harmful.[52] Often, the patient will seek supply of these drugs from many practitioners. Physicians may also benefit from feedback on their prescribing practices.
While no foolproof techniques exist to prevent malpractice, there are ways to reduce exposure to litigation procedures. An estimated 7% of all malpractice claims against psychiatrists result from medication errors and drug-related reactions. The most common pitfalls are as follows.[5]
All physicians are judged by certain standards of care and guidelines. Their actions are compared to the standards expected of an average physician in their community under the circumstances.
When treating a patient with any medication, meeting certain expectations can minimize unnecessary litigation. Note the following:
Patients who abuse or become dependent on sedative-hypnotics may fall into 2 broad categories.
The first category includes patients who have prescriptions and medical indications for the use of these drugs for the symptomatic treatment of a psychiatric disorder. Such patients have a high risk of developing sedative-hypnotic dependence, particularly if they have a history of alcohol or prescription drug abuse, are being prescribed high doses of sedative-hypnotics, or are prescribed these drugs for longer than 1 month. Patients with a family history of alcoholism may be genetically predisposed to benzodiazepine dependence. Unless dose escalation is evident or deliberate use to produce high or dangerous states of intoxication, there is no reason to assume that chronic benzodiazepine users are abusers.[16] It is vital for clinicians to take thorough social histories of patients to better understand their use of other substances, including alcohol, to avoid potentially dangerous interactions.
The second category includes patients who use sedative-hypnotics in nonmedical settings of self-medicating or potentially alcohol or polydrug abuse or dependence. Sometimes, these individuals may use benzodiazepines to manage chronic anxiety or insomnia, to enhance the euphoric effects of opioids, and to lessen the withdrawal associated with cocaine.[17]
Both groups of patients experience similar effects of the sedative-hypnotics and their reported histories highlight these effects.
Direct toxic effects of sedative-hypnotics
Relatively low doses may lead to drowsiness, impaired judgment, and diminished motor skills.
A significant impact on driving ability, job performance, and personal relationships is possible. In particular, the literature indicates that the greatest accident risk is associated with the use agents with a long half-life, increasing dosage, and the first weeks of use of benzodiazepines.[18]
Benzodiazepines may cause dose-related anterograde amnesia; significantly impairing the ability to learn new information while the retrieval of previously learned information remains intact. This effect is exploited when patients undergo uncomfortable procedures, as comfort and postoperative amnesia are beneficial.
Other clinical features include slurred speech, ataxia, nystagmus, decreased reflexes, stupor, coma, and cardiorespiratory arrest. The latter are more commonly seen with use of barbiturates (e.g. chloral hydrate) due to steep dose-response properties.
In the United States, barbiturates are subject to more stringent federal control and are less commonly used, whereas benzodiazepines are more prone to abuse or dependence because of their perceived safety and more frequent prescribing.
Benzodiazepines are considered safer because of a higher therapeutic index ratio and flatter dose-response curves. Most cases of coma or respiratory depression usually occur in conjunction with other CNS depressants.
Diagnosis of a sedative, anxiolytic, or hypnotic use disorder
According to DSM-5, diagnosing a use disorder requires clinically significant impairment or distress over a 12-month period. There must also be at least 2 out of 11 specific additional criteria listed in the DSM present as well. These additional criteria include tolerance and withdrawal. The list of these criteria along with additional details can be found in the DSM-5.[4]
Withdrawal, symptom rebound, and symptom reemergence
The DSM-5 requires 2 or more of the following characteristics to be present for diagnosis of this syndrome and these must occur within hours or days of benzodiazepine cessation: autonomic hyperactivity (e.g. sweating, pulse rate >100); increased hand tremor; insomnia; nausea or vomiting; transient visual, tactile, or auditory hallucinations or illusions; psychomotor agitation; anxiety; and grand mal seizures.[4]
Symptom reemergence
While not a withdrawal syndrome, symptom reemergence describes the reappearance of symptoms of an underlying mood or anxiety disorder after discontinuation of the medication. Unlike symptom rebound, these symptoms do not subside over time.
Symptom rebound
Symptoms for which the sedative-hypnotic was used to treat (e.g. insomnia) may return with increased intensity soon after discontinuation of the medication. The symptoms may last from days to weeks but subside over time.
Protracted withdrawal syndrome
Some patients who have been maintained on therapeutic doses of benzodiazepines for extended periods may experience a relatively mild form of withdrawal, marked by symptoms of anxiety, irritability, and insomnia, which can last for weeks or months.
Low-dose withdrawal
Low-dose withdrawal (also called therapeutic dose withdrawal or benzodiazepine discontinuation syndrome) is a withdrawal state in the setting of therapeutic doses being prescribed. It is thought that withdrawal symptoms generally do not appear if the duration of the treatment is less than 4 months, but may appear earlier if higher doses are used. While some patients can abruptly discontinue their medications without withdrawal, symptoms associated with this syndrome are the same as high-dose withdrawal, minus seizures and delirium.
Depersonalization, heightened perceptions, and illusions have also been described. Symptoms may vary from mild to severe, and a protracted withdrawal syndrome may develop. Patients with a family or personal history of alcoholism or those who also use other sedatives may be at increased risk for this syndrome.
High-dose withdrawal
This is a withdrawal state in the setting of discontinuation of high-dose sedative-hypnotics. Symptoms include anxiety, insomnia, postural hypotension, nausea, vomiting, tremor, incoordination, restlessness, blurred vision, sweating, hyperpyrexia, anorexia, seizures, and delirium. Severe dependence confers increased risk for medical complications including death. Time course of withdrawal symptoms from the last dose taken depend on the biological half-life of the drug. Drugs with a short half-life (e.g. alprazolam) may induce a more rapid onset of withdrawal and a more severe withdrawal than drugs with longer half-life (e.g. diazepam). Short-acting sedative-hypnotics can trigger withdrawal in 1-2 days, with symptoms peaking between 1 and 3 days. Withdrawal from longer-acting sedative-hypnotics may peak in approximately 1 week.
The most vital aspects in assessing sedative-hypnotic intoxication or withdrawal are detailed mental status and neurologic examinations in addition to comprehensive physical examination.
Physical findings of intoxication include the following:
Mental status examination findings of intoxication include the following:
Physical signs of withdrawal syndromes include the following:
Mental status examination findings in withdrawal syndromes include the following:
Careful review of the patient's history and examination should typically suffice; however, further studies may be performed to rule out an underlying pathology with a similar presentation. This is particularly relevant if the patient presents with severe symptoms or when a reliable history cannot be obtained. Workup depends on presenting symptoms (intoxication/withdrawal), especially if no prior knowledge of ingestion of sedatives is known.[19] If a laboratory workup is necessary, it should include the following:
CT/MRI of the head can be performed to rule out mass-occupying lesions and intracranial bleeding if these are suspected.
ECG may be helpful to rule out arrhythmias, which can increase the probability of emboli to the brain and cause altered mental status.
Consider an EEG, as it may show paroxysmal bursts of high-voltage, slow-frequency activities that precede the development of seizures in the setting of sedative-hypnotic withdrawal. In the context of hallucinations, EEG may rule out neurologic conditions such as temporal lobe epilepsy.
Patients with sedative-hypnotic use disorders are frequently treated in the outpatient setting, as most are stable and require minimal monitoring.[47] Inpatient hospitalization is reserved for the most severely impaired patients requiring complicated withdrawals, patients who have been unsuccessful as outpatients, or patients with medical and/or psychiatric comorbidity.
A recent study confirms the efficacy of cognitive behavior therapy (CBT) in both hypnotic-abusing and non-abusing patients with chronic insomnia. The results of this study suggest that tapered withdrawal of third-generation hypnotics during CBT therapy for chronic insomnia could be associated with improvement rather than worsening of sleep continuity. [29, 30] Similarly, CBT has been shown to reduce benzodiazepine use in patients with GAD, with one study showing 75% of patients receiving CBT completely ceasing benzodiazepine use, as compared with 37% in the control group.[48]
Some may benefit from enrollment in support groups, such as Pills Anonymous, and attending drug-free outpatient counseling.
Definitive treatment can be a lengthy process, taking months or years. A return to drug use should not be considered a treatment failure but rather a time to intensify treatment.
After successful medical treatment of sedative/hypnotic withdrawal/intoxication on a medical floor, the patient may be transferred to the psychiatric unit, if he or she meets criteria for inpatient psychiatric treatment.
Effective treatment requires a thorough evaluation of the patient's underlying psychiatric problems and development of long-term treatment plans.
Urine drug screens should be performed periodically to monitor illicit drug use.
Family counseling should be completed to focus on the family's role in helping the patient develop a successful long-term treatment plan.
Referrals for long-term outpatient or residential treatment for sedative-hypnotic addiction should be made early in the treatment process to prevent relapse.
For treatment of overdose, please see Benzodiazepine Toxicity / Treatment/Approach Considerations. While flumazenil is the only antidote for benzodiazepine overdose, it should be used with extreme caution. Generally the risks of its use are thought to outweigh the benefits.[35] For a more extensive discussion of the risks and benefits, please see Benzodiazepine Toxicity / Treatment/Flumazenil
Treatment of withdrawal syndromes is identical for withdrawal from all sedative-hypnotics because all drugs in this category, including barbiturates, sleeping pills, benzodiazepines, and alcohol, exhibit cross-dependence. The basic principle is to withdraw the addicting agent slowly to avoid severe withdrawal reactions like delirium tremens and seizures.
The first step in treatment is to objectively determine the patient's approximate drug tolerance level because patients often inaccurately estimate the amount of drug they have been taking. Direct observation of early withdrawal symptoms is ideal and may be best accomplished in a supervised setting. There are several objective scoring measures to determine the severity of withdrawal symptoms. The most studied is the Clinical Institute Withdrawal Assessment (CIWA) Scale. However, there have been recent studies that have supported the use of newly developed simplified scales, such as the Anxiety Sweats Tremor Scale (AST).[36]
The use of a long-acting barbiturate decreases the severity of withdrawal symptoms, and phenobarbital can be chosen in preference to other sedatives because of its longer half-life. Phenobarbital is a pharmaceutical that binds to the GABA-A receptor like benzodiazepines. Its half-life is at least double and, in some cases, up to 6 times as long as long-acting benzodiazepines such as clonazepam.[23] However, unlike benzodiazepines, there is no reversal agent for barbiturates and its long half-life places patients at risk of barbiturate toxicity, especially in elderly patients and those with hepatic impairment.
An initial dose is given, usually 30-60 mg of phenobarbital or equivalent. The withdrawal drug is repeated at hourly or 2-hour intervals as needed for 2-7 days.[16] The patient should be monitored closely for acute changes in vital signs or worsening delirium, as well as for other withdrawal symptoms.
After the patient has received similar 24-hour doses for 2 consecutive days, the 24-hour stabilizing dose is given in divided doses every 3-6 hours. This index dose is then tapered, reducing subsequent daily doses by 30-60 mg/day.[16]
Many patients who have mild dependence on benzodiazepines can be managed by a slow taper of the drug in an outpatient setting. However, this is often unsuccessful if the patient cannot cope with mild withdrawal effects. An alternative is to replace short-acting benzodiazepines (e.g. alprazolam) with equivalent dosing of a longer-acting drug (e.g. clonazepam), which may provide for a milder withdrawal syndrome during the taper.[16]
The following is a commonly used benzodiazepine equivalence schedule. Diazepam 10 mg is approximately equivalent to the following drugs and doses:[37]
More information can be found here: Benzodiazepine Equivalency Table
The weekly tapering dose can be calculated by first converting the current prescription to an equivalent diazepam dosage. Although a gradual taper using long half-life benzodiazepines over a greater period of time, is seen to be superior over abrupt discontinuation of benzodiazepines, no particular tapering method proved significantly more efficacious than another. Therefore, patients may benefit from tapers that convert their current daily dose of one (or more) benzodiazepine(s) into a longer acting form and tapering that dose by 25% per 1-2 weeks, though a more gradual taper may be beneficial to long-term elderly users.[38]
Anticonvulsant agents that do not demonstrate cross-dependence with sedative-hypnotics (e.g. carbamazepine) have been used successfully in the treatment of mild sedative-hypnotic withdrawal. The main rationales for using anticonvulsants in substance-abuse patients are their lack of addiction potential, evidence supporting a role of kindling mechanisms in withdrawal syndromes, and efficacy in comorbid psychiatric disorders. The available data indicate that carbamazepine has demonstrated safety, tolerability and efficacy in treatment of moderate to severe symptoms of alcohol withdrawal, however, there is inconclusive evidence for prevention of alcohol withdrawal seizures and DTs in comparison with benzodiazepines and thus benzodiazepines remain the typical treatment of choice.[39]
Other studied options with some data supportive of mono or adjunctive treatment of benzodiazepines include gabapentin[40] , pregabalin[41] , and melatonin[26] .
If a patient who has been using sedative-hypnotics on a long-term basis presents with advanced withdrawal (e.g. elevated vital signs, delirium, seizures, etc.), it is important to medicate rapidly and in doses sufficient to suppress withdrawal symptoms.
Advanced withdrawal is most safely managed in an intensive care environment, especially if the patient has been using high doses of sedative-hypnotics, has a history of withdrawal seizures or delirium tremens, or has concurrent medical illness.
For treatment with oral agents when the daily dose of sedatives cannot be determined due to the patient’s incapacity, the level of tolerance can be determined by giving pentobarbital, 200 mg by mouth and waiting 1 hour. Look for signs of nystagmus, ataxia, drowsiness, dysarthria, decreased blood pressure, and decreased pulse. If 2 or more signs are present, stop the procedure and convert to phenobarbital; if not, give pentobarbital (100 mg by mouth) every hour until 2 or more signs are present or a total of 600 mg pentobarbital has been given. Convert to phenobarbital, 30 mg for every 100 mg of pentobarbital given. Then, decrease phenobarbital by 10% of the initial dose per day. This method has been found to be a reasonable option in a systematic literature review, though data is limited.[42]
For treatment with parenteral agents, phenobarbital is recommended for most patients due to its long half-life, which allows less frequent dosing once the total daily dose needed to control withdrawal symptoms is determined. Infuse phenobarbital intravenously until the patient shows signs of mild intoxication (nystagmus, ataxia, drowsiness, dysarthria, decreased blood pressure, and decreased pulse). Once that dose is determined, it is the daily dose required to block withdrawal and may be given on subsequent days in divided doses and tapered.
Short-acting medications are indicated for patients with severe hepatic failure and for hemodynamically unstable patients who require very rapid medication titration to control withdrawal symptoms. If a short-acting medication is to be used, choose among oxazepam, temazepam, or lorazepam as these do not have active metabolites after hepatic conjugation and thus their half-lives are less dependent upon hepatic functioning.[43]
Intravenous medication should be given until signs of intoxication or reduction of withdrawal signs occurs. For the short-acting intravenous medications, adjust frequency of administration to duration of action of the medication and reduce the total daily dose 10% per day.[44]
More recent studies have shown some benefit to the use of ketamine, an N-methyl-d-aspartate antagonist, as an effective adjunct agent for severe withdrawal. It has been found to reduce the benzodiazepine requirement while being relatively well tolerated in small doses in the management of withdrawal.[45]
Patients who have been using benzodiazepines consistently in the long-term oftentimes feel increased anxiety around being tapered off their medication because of the aforementioned withdrawal symptoms. It is important to understand why patients are taking these medications and to offer a number of alternative therapies. Recent research suggests that patients using benzodiazepines for anxiety may benefit from including pregabalin and those using them for sleep aids may benefit from melatonin or zolpidem during tapering measures.[26, 27]
Pregabalin is an alpha2-delta ligand that has shown analgesic, anxiolytic, and anticonvulsive properties. In patients with generalized anxiety disorder, pregabalin appears to show an anxiolytic effect similar to that of alprazolam, lorazepam, or venlafaxine. Pregabalin has also exhibits sleep-improving properties. Anecdotal reports suggest that gabapentin, another alpha2-delta ligand, may also be useful in benzodiazepine withdrawal. In an open-label study of 15 long-term benzodiazepine users, pregabalin (225–900 mg/day), used as adjunctive medication for the discontinuation of benzodiazepines, obtained a significant reduction of anxiety symptoms and all patients were able to successfully discontinue their benzodiazepine treatment.[25]
For those patients taking benzodiazepines as sleep aids, emerging research suggests that adjunctive melatonin therapy may facilitate the discontinuation therapy for long-term users compared with placebo. Melatonin dosages included 5 mg in addition to their tapering dosage of benzodiazepines. Furthermore, another study showed that zolpidem, 10 mg once daily at bed time, reduced the occurrence of withdrawal symptoms induced by the abrupt or gradual discontinuation of long-term triazolam treatment in outpatients with insomnia.[26, 27]
For pediatric populations, a limited number of studies and case reports suggest that dexmedetomidine, an alpha2-receptor agonist with a mechanism of action similar to that of clonidine but with greater alpha2-receptor specificity, blunts withdrawal symptoms without causing respiratory depression. Potential adverse effects associated with dexmedetomidine use in pediatric patients are generally associated with use of bolus doses and mainly involve central nervous system effects (eg, hypotension, bradycardia), with no hemodynamic manifestations. When bolus doses are used, strategies described in published reports entail a loading dose of 0.5-1.0 μg/kg administered over 5-10 minutes, followed by a continuous infusion at 0.1-1.4 μg/kg/h for a period of 1-16 days.[28]
Guidelines also exist for pregnant women. These typically emphasize collaboration with obstetrics, informed consent for both mother and fetus, and recommend specific tapers (for example, taper inpatient pregnant women by 20–33% of the total daily dose every 24 hours until the medication has been safely discontinued.)[46]
Neurologist consultation is indicated if seizures are unresponsive to usual treatment of the withdrawal symptoms or when neurologic symptoms not explained by the usual symptoms of intoxication or withdrawal are present.
Psychiatrist consultation is indicated in the context of suicidal risk, aggressive behavior, or comorbid psychiatric disorders (e.g., mood or psychotic disorders).
Poison centers should be contacted to obtain information in overdose situations.
A variety of drugs are used both in the acute and the long-term setting for the treatment of sedative, hypnotic, and anxiolytic use disorders. Drug selection depends upon whether toxicity or withdrawal symptoms are being targeted.
Clinical Context: Depresses all levels of CNS (eg, limbic, reticular formation), possibly by increasing activity of GABA. Individualize the dosage and increase cautiously to avoid adverse effects.
Clinical Context: Sedative-hypnotic with short onset of effects and relatively long half-life.
By increasing the action of GABA, which is the major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.
Important to monitor patient's blood pressure after administering dose. Adjust dose as necessary.
Clinical Context: Suppresses muscle contractions by facilitating neurotransmission of GABA and other inhibitory transmitters.
Clinical Context: Has a wide therapeutic window and is “self-tapering” because of its long half-life. Longer acting than diazepam and lorazepam and thus is more commonly used, especially in outpatient tapers.
Clinical Context: Temazepam is a short- to intermediate-acting benzodiazepine with longer latency to onset and half-life. It depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.
Clinical Context: Binds to benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system. This causes an increase in the inhibitory activity of GABA on neuronal excitability, which in turn makes the neuronal membranes less excitable and more stable.
In dependent patients, these are used in a manner similar to phenobarbital to wean patients from short-acting benzodiazepines. The general principle is that sedatives with longer half-lives have less severe withdrawal symptoms. Various patient-specific dosing strategies are used. If symptoms are severe enough to require inpatient treatment, IV lorazepam or diazepam is used.
Clinical Context: This benzodiazepine antagonist has a high affinity for the benzodiazepine receptor, making it a competitive antagonist. Flumazenil is short-acting, with a half-life of 0.7-1.3 h. Because most benzodiazepines have longer half-lives, multiple doses of flumazenil may be required to avoid relapse back into a sedative state. However, it is not typically used due to the fact that the risks of inducing life-threatening withdrawal in chronic users outweighs the potential benefits.
These agents are used in reversing the CNS depressant effects of benzodiazepine overdose. Its ability to reverse the benzodiazepine-induced respiratory depression is difficult to predict.
Clinical Context: Chosen for withdrawal because of long half-life and wide therapeutic index. General principle is that sedatives with longer half-lives have less severe withdrawal symptoms. Since there is no reversal agent and these agents can accumulate in the system due to their long half-lives, this class is less favored in general.
Clinical Context: Pentobarbital is a short-acting barbiturate that interferes with transmission of impulses from the thalamus to the cortex. It has sedative, hypnotic, and anticonvulsant properties. It is a second-line drug for treatment of drug-induced seizures.
These agents are used in some cases to facilitate smooth withdrawals in patients with benzodiazepine and barbiturate dependence.
Clinical Context: Carbamazepine is a sodium-channel blocker that typically provides substantial or complete relief of pain. It reduces sustained high-frequency repetitive neural firing and is a potent enzyme inducer that can induce own metabolism. Initially used as an antiseizure medication and mood stabilizer, carbamazepine is also used for explosive outbursts. Carbamazepine is metabolized in the liver to its active metabolite (ie, epoxide derivative) with a half-life of 5-8 hours.
Some agents in this class have been used successfully in the treatment of mild sedative-hypnotic withdrawal.