Sedative, Hypnotic, Anxiolytic Use Disorders Treatment & Management
- Author: Lorin M Scher, MD; Chief Editor: Iqbal Ahmed, MBBS, FRCPsych(UK) more...
Treatment of sedative-hypnotic overdose
Initially, treat a patient who has taken an overdose of sedative-hypnotics like any other patient with drug intoxication. Provide an adequate airway and ventilation. Stabilize and maintain the hemodynamic status. Once initial measures have been carried out, consider inducing emesis, performing lavage, and administering activated charcoal to a patient who has orally ingested the drug, depending on the time of ingestion and level of consciousness. Emesis, lavage, and/or activated charcoal prevent absorption of the drug into the system and absorption of the drug or active metabolites through enterohepatic recirculation. Laxatives may be used to induce catharsis.
Benzodiazepines are the most commonly prescribed and abused sedative-hypnotics, but they produce less respiratory depression than barbiturates. Long-acting metabolites often cause intoxication that lasts for several days. Benzodiazepine overdose is most dangerous in combination with other sedative-hypnotics.
The benzodiazepine antagonist flumazenil is available for the treatment of benzodiazepine intoxication. Flumazenil acts by competitively inhibiting the benzodiazepine binding site on the GABA-A receptor, thereby reversing the effects of benzodiazepines on the central nervous system. It must be used with some caution; in some cases, it has not completely reversed respiratory depression, and it can cause seizures in patients with benzodiazepine dependence. Furthermore, flumazenil increases the risk of seizures, particularly in mixed overdosage with tricyclic antidepressants.
Flumazenil is contraindicated in patients with increased intracranial pressure (ICP) or closed-head injury (CHI), those with a history of epilepsy.
For adults Flumazenil should be administered in an initial IV dose of 0.2 mg given over 30 seconds, followed by a second 0.2 mg IV dose if there is no response after 45 seconds. This procedure can be repeated at 1-minute intervals up to a cumulative dose of 5 mg. The peak effect of the drug is within 6-10 minutes. In patients who are physically dependent on benzodiazepines, slowly administer repeated doses of flumazenil. (See Flumazenil.)
For pediatric patients, the initial dose is 0.01 mg/kg given IV over 15 seconds (not to exceed 0.2 mg). This initial dose may be followed at 1-minute or more intervals with up to 4 repeat doses of 0.005-0.01 mg/kg (not to exceed 0.2 mg) per dose. The maximum dose should not exceed 1 mg total or 0.05 mg/kg; the lower dose is preferable.
Flumazenil is a short-acting drug; therefore, sedation after an initial awakening may recur. Observe patients with benzodiazepine toxicity for at least 2 hours after recovery from flumazenil for late respiratory depression or resedation. Resedation may be treated in adults by using 0.2-mg doses (not to exceed total dose of 1 mg) until the desired effect is achieved. For patients with exposures to long-acting benzodiazepines or those with hepatic insufficiency with prolonged exposure to benzodiazepines, a continuous flumazenil infusion (0.25-1 mg/h) may be useful.
If the patient overdosed on barbiturates, administer intravenous sodium bicarbonate to alkalinize the urine, which increases the rate of barbiturate excretion. The dose of bicarbonate varies depending on the patient's metabolic state. Urine pH should be monitored and maintained at 7.5. Dialysis may be required, depending on the severity of the patient's condition.
Address all potential complications, such as aspiration, pulmonary edema, and respiratory failure due to sedative-hypnotic drug overdose. If a suicide attempt is suspected, then place the patient on suicide precautions and order a psychiatric evaluation.
General principles for treatment of sedative-hypnotic withdrawal syndromes
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 convulsions.
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 is ideal and may be best accomplished in a supervised setting.
The use of a long-acting barbiturate decreases the severity of withdrawal symptoms, and phenobarbital is chosen in preference to other sedatives because it has a 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.
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. 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.
Treatment of mild-to-moderate sedative-hypnotic withdrawal
Many patients who have mild dependence on benzodiazepines can be managed by a slow taper of the drug in an outpatient setting. The first step is to objectively determine an approximate level of drug to which the patient is tolerant; patients tend to overestimate or underestimate the amount of drug they have been taking.
A patient can be slowly weaned off the medication; however, this is often unsuccessful if the patient cannot cope with mild withdrawal effects. An alternative is to replace short-acting benzodiazepines (eg, alprazolam) with equivalent dosing of a longer-acting drug (eg, clonazepam), which may provide for a milder withdrawal syndrome during the taper.
The following is a commonly used benzodiazepine equivalence schedule. Diazepam 10 mg is approximately equivalent to the following drugs and doses :
Alprazolam - 1 mg
Chlordiazepoxide - 25 mg
Clonazepam- 0.5-1 mg
Lorazepam - 2 mg
Oxazepam - 30 mg
Temazepam - 20 mg
The weekly tapering dose can be calculated by firstly converting the current prescription to an equivalent diazepam dosage. It should be noted, however, that although a gradual taper, with longer weeks and long half-life benzodiazepines, 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 reduce their original prescription converted to diazepam then further converted every 2 weeks to 75%, 50% 25%, 12.5%, and 0% of the original dose.
Anticonvulsant agents that do not demonstrate cross-dependence with sedative-hypnotics (ie, 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 currently support the use of carbamazepine as a treatment for detoxification from benzodiazepines and use of gabapentin and topiramate in the treatment of benzodiazepine detoxification.
Treatment of severe sedative-hypnotic withdrawal
If a patient who has been using sedative-hypnotics on a long-term basis presents with advanced withdrawal (eg, elevated vital signs, delirium), 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, determine the level of tolerance by giving pentobarbital, 200 mg by mouth and wait 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.
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.
Short-acting medications, instead of phenobarbital, 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 midazolam, diazepam, or lorazepam, depending on rapidity of reversal of effects required. 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.
General principles for discontinuation therapy
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. For pediatric patients, dexmedetomidine is also showing promise for discontinuation therapy.
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.
For those patients taking benzodiazepines as sleep aids, emerging research suggests that 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.
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 (eg, mood or psychotic disorders).
Poison centers may be contacted to obtain information about other possible unknown substances being used, especially in overdose situations.
Keep nothing by mouth if patient is unconscious.
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