Benzodiazepine Withdrawal Syndrome - Management - Medications and Interactions

Medications and Interactions

While some substitutive pharmacotherapies may have promise, current evidence is insufficient to support their use. Some studies found that the abrupt substitution of substitutive pharmacotherapy was actually less effective than gradual dose reduction alone, and only three studies found benefits of adding either melatonin, paroxetine, or trazodone and valproate in conjunction with a gradual dose reduction.

• Alcohol, even mild to moderate use, has been found to be a significant predictor of withdrawal failure, probably because of its cross tolerance with benzodiazepines.

• Antipsychotics are generally unresponsive to benzodiazepine withdrawal-related psychosis. Antipsychotics should be avoided during benzodiazepine withdrawal as they tend to aggravate withdrawal symptoms, including convulsions. Some antipsychotic agents may be more risky during withdrawal than others, especially clozapine, olanzapine or low potency phenothiazines (e.g., chlorpromazine), as they lower the seizure threshold and can worsen withdrawal effects; if used, extreme caution is required.
• Barbiturates are cross tolerant to benzodiazpines and should be avoided.
• Benzodiazepines or cross tolerant drugs should be avoided after discontinuation, even occasionally. These include the nonbenzodiazepines Z-drugs, which have a similar mechanism of action. This is because tolerance to benzodiazepines has been demonstrated to be still present at four months to two years after withdrawal depending on personal biochemistry. Re-exposures to benzodiazepines typically resulted in a reactivation of the tolerance and benzodiazepine withdrawal syndrome.
• Buproprion, which is used primarily as an antidepressant and smoking cessation aid, is contraindicated in persons experiencing abrupt withdrawal from benzodiazepines or other sedative-hypnotics (e.g. alcohol), due to an increased risk of seizures.
• Buspirone augmentation was not found to increase the discontinuation success rate.
• Caffeine may worsen withdrawal symptoms because of its stimulatory properties. Interestingly, at least one animal study has shown some modulation of the benzodiazepine site by caffeine, which produces a lowering of seizure threshold.
• Carbamazepine, an anticonvulsant, appears to have some beneficial effects in the treatment and management of benzodiazepine withdrawal, however, research is limited and thus the ability of experts to make recommendations on its use for benzodiazepine withdrawal is not possible at present.
• Flumazenil has been found to stimulate the reversal of tolerance and the normalization of receptor function. However, further research is needed in the form of randomised trials to demonstrate its role in the treatment of benzodiazepine withdrawal. Flumazenil stimulates the up-regulation and reverses the uncoupling of benzodiazepine receptors to the GABA_A receptor, thereby reversing tolerance and reducing withdrawal symptoms and relapse rates. Limited research and experience and possible risks involved, the flumazenil detoxification method is controversial and can only be done as an inpatient procedure under medical supervision.

A study into the effects of the benzodiazepine receptor antagonist, flumazenil, on benzodiazepine withdrawal symptoms persisting after withdrawal was carried out by Lader and Morton. Study subjects had been benzodiazepine-free for between one month and five years, but all reported persisting withdrawal effects to varying degrees. Persistent symptoms included clouded thinking, tiredness, muscular symptoms such as neck tension, depersonalisation, cramps and shaking and the characteristic perceptual symptoms of benzodiazepine withdrawal, namely, pins and needles feeling, burning skin, pain and subjective sensations of bodily distortion. Therapy with 0.2–2 mg of flumazenil intravenously was found to decrease these symptoms in a placebo-controlled study. This is of interest as benzodiazepine receptor antagonists are neutral and have no clinical effects. The author of the study suggested the most likely explanation is past benzodiazepine use and subsequent tolerance had locked the conformation of the GABA-BZD receptor complex into an inverse agonist conformation, and the antagonist flumazenil resets benzodiazepine receptors to their original sensitivity. Flumazenil was found in this study to be a successful treatment for protracted benzodiazepine withdrawal syndrome, but further research is required. A study by Professor Borg in Sweden produced similar results in patients suffering from protracted withdrawal. In 2007, Hoffmann–La Roche the makers of flumazenil, ackowleged the existence of protracted benzodiazepine withdrawal syndromes, but did not recommended flumazenil to treat the condition.

• Fluoroquinolone antibiotics have been noted by Ashton and confirmed elsewhere as increasing the incidence of a serious CNS toxicity from 1 to 4% in the general population, for benzodiazepine-dependent polulation or in those undergoing withdrawal from them. This is probably the result of their GABA antagonistic effects as they have been found to competitely displace benzodizepines from benzodiazepine receptor sites. This antagonism can precipitate acute withdrawal symptoms, that can persist for weeks or months before subsiding. The symptoms include depression, anxiety, psychosis, paranoia, severe insomnia, parathesia, tinnitus, hypersensitivity to light and sound, tremors, status epilepticus, suicidal thoughts and suicide attempt. Fluoroquinolone antibiotics should be contraindicated in patients who are dependent on or in benzodiazepine withdrawal. NSAIDs have some mild GABA antagonistic properties and animal research indicate that some may even displace benzodiazepines from their binding site. However, NSAIDs taken in combination with fluoroquinolones cause a very significant increase in GABA antagonism, GABA toxicity, seizures, and other severe adverse effects (see fluoroquinolone toxicity).
• Imidazenil has received some research for management of benzodiazepine withdrawal, but is not currently used in withdrawal.
• Imipramine was found to statistically increase the discontinuation success rate.
• Melatonin augmentation was found to statistically increase the discontinuation success rate for people with insomnia.
• Phenobarbital, (a barbiturate), is used at "detox" or other inpatient facilities to prevent seizures during rapid withdrawal or cold turkey. The phenobarbital is followed by a one- to two-week taper, although a slow taper from phenobarbital is preferred. In a comparison study, a rapid taper using benzodiazepines was found to be superior to a phenobarbital rapid taper.
• Progesterone has been found to be ineffective for managing benzodiazepine withdrawal.
• Propranolol was not found to increase the discontinuation success rate.
• SSRI antidepressants has been found to have little value in the treatment of benzodiazepine withdrawal.
• Trazadone was not found to increase the discontinuation success rate.