Use of a long-acting substitute in detoxification from benzodiazepines: safety (accumulation) problems and proposed mitigation procedure.

OBJECTIVE: In the majority of approaches, detoxification of patients with benzodiazepine (BZD) addiction is preceded by conversion to long-acting BZDs. Resulting BZD accumulation, however, is neither monitored nor prevented. An unrecognized shift of the key low-concentration phase beyond the nominal treatment period may underlie delayed unassisted crises and treatment failures. This open, single-arm, semi-naturalistic study examines the anti-accumulation paradigm to minimize the high-concentration treatment phase and to regain time for medical assistance during the low-concentration phase. METHODS: In 133 of 165 patients with BZD dependency, after conversion to diazepam by titration up to the satiation state, the loading dose and satiating concentration were recorded. The subsequent anti-accumulation procedure consisted of aggressive daily dose reductions under laboratory feedback (serum BZD concentration, radioimmunoassay) until accumulation stopped. The final overaccumulation ratio (OA) and maintenance-dose/loading-dose ratio (MTN) were estimated. The post-conversion peak-concentration/loading-dose ratio was illustratively compared with the concentration/dose ratio in 32 long-term diazepam users demonstrating the natural plateau. RESULTS: Despite gender- and age-related differences in loading and maintenance doses and in satiating and peak concentrations (higher in younger and male patients), their quotients remained similar. The MTN ratio had an average value of 0.29 and a median value of 0.25, with OA ratios of 1.54 and 1.39, respectively. The concentration/dose ratio was approximately 3 times lower than that in regular diazepam users. With effective elimination starting (on average) from the 6th day, the treatment, including post-elimination recovery, lasted on average 52 days. CONCLUSIONS: The MTN values show how harmfully popular tapering schedules intensify and extend the high-concentration stage during alleged detoxification, leading to unrecognized delays in elimination, and delayed withdrawal crises. The common errors are discussed. An individual MTN, estimated from laboratory feedback (the anti-accumulation paradigm), expeditiously moves patients to the onset of actual detoxification. This action regains time to maintain medical assistance until treatment is properly completed.

Delayed crises following benzodiazepine withdrawal: deficient adaptive mechanisms or simple pharmacokinetics? Detoxification assisted by serum-benzodiazepine elimination tracking.

OBJECTIVE: Rapid relapses after successful withdrawal occur even in apparently motivated benzodiazepine (BZD)-dependent patients. Regardless of known personality or biological (re-adaptation) issues, the aim of this open-label, single-arm, seminaturalistic study was to search for any detoxification errors contributing to failures. METHODS: The data came from 350 inpatients. Based on serum-BZD evolution criteria, the procedure was divided into four stages: substitution, accumulation, elimination and post-elimination observation. After switching the patients to a long-acting substitute (diazepam), to prevent data falsification due to unwanted overaccumulation, the doses were expeditiously reduced under laboratory feedback until accumulation stopped. With the start of effective elimination, the tapering rate slowed and was individually adjusted to the patient's current clinical state. The tracking of both serum-BZD concentration and the corresponding intensity of withdrawal symptoms was continued throughout the entire elimination phase, also following successful drug withdrawal. Detoxification was concluded only after the patient's post-elimination stabilization. RESULTS: Regardless of various initial serum-BZD concentration levels and the customized dose-reduction rate, and despite the novel lab-driven actions preventing initial overaccumulation, elimination was systematically proven to be protracted and varied within the 2- to 95-day range after the final dose. Within this period, withdrawal syndrome culminated several times, with varying combinations of symptoms. The last crisis occurrence (typically 2-3 weeks after withdrawal) correlated with the final serum-BZD elimination. The factors that prolonged elimination and delayed the final crisis were patient age, duration of addiction, adjunct valproate medication and elimination stage start parameters growing with former overaccumulation. CONCLUSIONS: The low-concentration detoxification stage is critical for patients' confrontations with recurring withdrawal symptoms. Underestimated elimination time following drug withdrawal and premature conclusions of detoxification expose patients to unassisted withdrawal crises. Concentration tracking defines proper limits for medical assistance, preventing early relapses.

High levels of benzodiazepines after treatment of moderate alcohol withdrawal syndrome: the problem of incomplete detoxification.

Purpose: Some alcohol-dependence relapses occur soon after a concluded detoxification treatment. A popular agent used in that treatment is diazepam, which effectively relieves withdrawal symptoms due to its long half-life and affinity to the same receptors. It is hypothesized here that these attributes, after nominally completed detoxification, result in, respectively, persisting benzodiazepine (BZD) influence and a distorted (optimistic) clinical presentation. This could contribute to later reemergence of withdrawal symptoms caused by delayed final elimination of BZDs, as the evidence puts into doubt the concept of a gentle self-taper of a long-acting drug. Methods: Serum-BZD concentration levels were measured with a radioimmunoassay at the end of routine treatment of moderately- intense alcohol withdrawal syndrome. These data were cross-referenced with individual diazepam administration schedules, including the maximal daily dose and the day of its administration, and the day of overall diazepam cessation. Results: Most patients revealed clinically relevant serum-BZD levels. These correlated with the doses but also with the day of maximal- dose administration and the day of diazepam withdrawal. Conclusions: The confrontation with actual abstinence comes after detoxification. Delayed elimination of diazepam may be a contributing factor in the re-emergence of symptoms and early post-detox relapses. The optimization of the procedure has been discussed in terms of concentration evolution and known treatment schedules. Maximal initial dosage compression and further decisive counteracting the tendencies of diazepam towards accumulation increase the patient's chance of going through the low-concentration crisis under medical assistance.

Metabolic diversity as a reason for unsuccessful detoxification from benzodiazepines: the rationale for serum BZD concentration monitoring.

PURPOSE: Many harms secondary to benzodiazepine (BZD) dependence force users towards detoxification treatment. However, even strongly motivated patients tolerate the process badly or experience early relapse. The detoxification procedure has not yet been standardized. The objective of this paper is to examine the hypothesis that faulty detoxification routines may have caused some failures. METHODS: The detoxification approaches found in the literature were compared stage by stage. The review was used to identify possible common, across-the-board systematic errors. RESULTS: The presented literature review confirms that the widespread divergence in the BZD metabolism rate is effectively neglected during detoxification routines. Without laboratory measurements, these differences, additionally interfered with by auxiliary drugs, undermine not only the scheduled but even the symptom-driven procedures. An initial substitution with a long-acting BZD, although recommended, may lead to over-accumulation. This excess, varying between patients and incompatible with the current tapering stage, may lead to repeated overestimation of the patient's adjustments to reduced doses. Consequently, the patient's good clinical presentation at withdrawal, resulting in a conclusion of detoxification, may actually reflect a persistently high serum BZD concentration. The low-concentration stage, if shifted past the end of treatment, exposes patients to unexpected, unassisted withdrawal crises. With laboratory feedback, these crises, unlike the symptoms related to deficient re-adaptation mechanisms, could be prevented. Moreover, by minimizing the high-concentration phase, time can be saved for properly assisted low-concentration challenges. CONCLUSION: A customized detoxification procedure driven not only by the intensity of withdrawal symptoms but also by serum BZD monitoring may prevent some failures. As the standard regimen, it would make detoxification from BZDs more reliable and effective.