Approach Considerations
Outpatient care
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.
Inpatient care
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.
Medical Care
Treatment of sedative-hypnotic overdose
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
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 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]
Treatment of mild-to-moderate sedative-hypnotic withdrawal
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]
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Alprazolam - 1 mg
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Chlordiazepoxide - 50 mg
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Clonazepam- 0.5 mg
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Lorazepam - 2 mg
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Oxazepam - 30 mg
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Temazepam - 20 mg
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] .
Treatment of severe sedative-hypnotic withdrawal
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]
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. [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]
Consultations
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.
