D Zullino, A Miozzari, M Preisig
anticonvulsant, benzodiazepine withdrawal, detoxification, gabapentin, substance abuse
D Zullino, A Miozzari, M Preisig. Gabapentin-Assisted Benzodiazepine Withdrawal In A Multidrug Dependent Patient. The Internet Journal of Pharmacology. 2005 Volume 4 Number 2.
There is an increasing interest in anticonvulsants for the treatment of benzodiazepine withdrawal, and among the newer substances gabapentin seems particularly promising due to its gabaergic and its glutamate-antagonistic activity. We present the case of a rapid benzodiazepine-withdrawal controlled successfully with gabapentin.
The most often recommended method for benzodiazepine withdrawal is slow tapering (1), which, however, requires a constant motivational management and is therefore often associated with poor treatment retention. This may be particularly true for multidrug users, who usually prefer to withdraw all substances at once and will not stand for long lasting procedures.
There are different theoretical rationales for using anticonvulsants in substance abuse patients. One important argument is their lack of addiction potential. A further rationale is in part based on evidence supporting the role of kindling in withdrawal syndrome, which has been proposed as a model for understanding withdrawal syndromes (2). Many of the withdrawal phenomena have been linked to modulations of the glutamatergic and/or the gabaergic system. Kindling and learning as well as behavioral sensitization has been described in this context as particular forms of long-term potentiation, which share some neuronal structures and neurophysiological processes. Each of these phenomena has been reported to be established and reinforced during repeated intermittent stimulation, e.g. during application of addictive drugs.
Some data on carbamazepine show an effect on a number of behavioral effects of benzodiazepine withdrawal (3). Adjunctive carbamazepine reduces iatrogenic benzodiazepine withdrawal severity in placebo-controlled studies (4,5,6). Similarly, two studies found that carbamazepine reduced benzodiazepine withdrawal in benzodiazepine-abusing populations (7, 8). Despite encouraging case reports of valproate in the treatment of benzodiazepine withdrawal, this could not be confirmed by controlled trials (9, 10). We also have reported recently on the use of topiramate in opiate and in benzodiazepine detoxification(11,12,13).
Gabapentin, a drug used as adjunctive therapy in the treatment of partial seizures, lacks the shortbacks of benzodiazepines in the treatment of drug dependent patients, such as risk of drug interactions and abuse potential. It has recently been suggested to have some efficacy in the treatment of mild to moderate alcohol withdrawal (14,15,16,17).
Gabapentin is eliminated via renal mechanisms, which may be of particular utility in patients with hepatic dysfunctions. It furthermore does not interact with liver enzymes thus decreasing the risk of pharmacokinetic interactions. Although it has no direct effect on GABA receptors or transporters, it has been shown to increase GABA turnover in various regions of the brain. It binds to subunits of the L-type calcium channels and increases the synthesis and nonsynaptic release of GABA in the brain (18,19,20). Moreover, it may influence the synthesis of glutamate (20). It has been hypothesized that gabapentin may, through its GABAergic activity, restore the feedback inhibition from the nucleus accumbens after alteration through repeated cocaine use (21).
Crockford et al. (22) have recently presented a case of benzodiazepine detoxification aided by the use of gabapentin. Their patient, a 49-years old woman with a history of panic disorder and generalized anxiety was dependent on alprazolam and furthermore abused butalbital and diphenhydramine. Gabapentin was given to facilitate clonazepam-based treatment.
We report the case of a gabapentin-assisted detoxification in a patient who, in addition to benzodiazepine dependence, had a long history of alcohol, opiate and cocaine abuse.
A 30 year old patient had been abusing alcohol since the age of 15, opiates and cocaine since 19, and high-dose benzodiazepines since 25. She has a history of recurrent depression, which has been treated during the last year with citalopram 20 mg/d. She had undergone several opiate and cocaine detoxifications between 20 and 25 years, experiencing regularly severe withdrawal symptoms like nausea, vomiting, irritability and insomnia. After 8 years of repeated methadone treatments she succeeded to withdraw from illegal drugs 4 years ago, to attend a therapeutic community during 8 months, and not to consume illegal drugs since then. She, however, reports a subsequent significant increase of alcohol and benzodiazapine consumption. She was therefore hospitalized 4 times for alcohol detoxification during the last 3 years, always exhibiting severe withdrawal symptoms including important tremor, agitation and anxiety, needing high doses of benzodiazepines.
Whereas infectious hepatitis as well as HIV-infections were excluded prior to the current inpatient detoxification, the hepatic sonography showed signs of a beginning cirrhosis. During the previous 12 months she was hospitalized twice due to acute pancreatitis. As she presented a considerable alcohol consumption of about 15 standard drinks per day, combined with a consumption of oxazepam 240mg per day, she was proposed to be firstly admitted for alcohol detoxification in the alcohol detoxification unit. The alcohol detoxification was performed adapting the oxazepam dose, stabilizing it finally at 15 mg q.i.d. The withdrawal syndrome was characterized by slight tremor, insomnia and fluctuating anxiety and agitation.
After one week of stable oxazepam dose at 15 mg q.i.d. the patient was transferred to our specific inpatient detoxification program at the Psychiatric University Hospital. The urine screening at admission showed no recent intake of cannabis, cocaine and opiates. As the patient requested a rapid benzodiazepine detoxification, and as she had not tolerated carbamazepine and topiramate during previous hospitalizations, gabapentin was proposed to her. She was informed about the experimental nature of the treatment, as an adjunctive treatment to the benzodiazepine tapering.
Oxazepam was rapidly tapered out over 4 days. Concomitantly, the patient was administered gabapentin 500mg the first day, 800mg the second day, and 900mg from the third to the ninth day. It was then tapered out until day 12. During his 14-day hospitalization the patient experienced as withdrawal symptoms only transient insomnia, which responded well on zolpidem 10mg and trimipramine 50mg. While she was closely monitored with regard to other benzodiazepine withdrawal symptoms, especially vegetative symptoms, no further withdrawal signs were observed.
At discharge the patient did receive no more medication beside the antidepressant treatment with citalopram. She has not relapsed with regard to any of the substances during the subsequent month.
While a slow tapering of benzodiazepines may take several months until complete detoxification, our case confirms a previous report (22) suggesting that gabapentin treatment can be a more rapid alternative, even in patients with a history of multidrug dependence including cocaine and opiate abuse. Besides transient insomnia, all typical withdrawal symptoms were prevented by gabapentin in our case. The course of our case was quite similar to that reported by Crockford et al.. Both patients also described a “benzodiazepine-like” effect even after definitive wash-out of the benzodiazepines. The maximum gabapentin dose given in our patients was 900 mg/d compared to 600 mg/d in Crockford's case, and the dose was well tolerated by the patient, who had previously only poorly tolerated carbamazepine and topiramate.
Different mechanisms underlying the efficacy of gabapentin in benzodiazepine withdrawal can be considered. Although it has no direct effect on GABA receptors or transporters, it has some GABA-ergic activity, which may be sufficient to compensate the benzodiazepine-related GABA activity. E.g. it has been hypothesized that gabapentin, through its GABAergic activity, may restore the feedback inhibition from the nucleus accumbens after alteration through repeated drug use (21). Furthermore, gabapentin has been reported to influence the synthesis of glutamate (20). Indeed, the role of glutamatergic mechanisms in synaptic plasticity and long-term behavioral adaptation to drugs has repeatedly been emphasized (23).
In addition to its increasingly corroborated efficacy in the treatment for alcohol detoxification, gabapentin seems to become a promising alternative in benzodiazepine detoxification, for benzodiazepine monodependence as well as for patients with multiple drug abuse.
Daniele Zullino Service d'abus de substances Hôpitaux Universitaires de Genève Rue verte 2 CH – 1205 – Genève Tel.: + 41 22 372 55 60 Fax: + 41 22 328 17 60 e - mail: Daniele.Zullino@hcuge.ch