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

Abstract

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.

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

“…The detoxification procedure included 4 stages [ 5 ]. Substitution Following popular approaches, the detoxification was preceded by replacing the formerly used BZDs with a standard long-acting BZD.…”

“…To date, these delayed/protracted crises have been attributed to individual inertia of biological readaptation processes. However, the first large-sample study using serum BZD concentration tracking revealed that the timing of the last of consecutive withdrawal crises, which was often (45%) the strongest one, was correlated with the time at which the concentration reached zero [ 5 ]. These results are in line with both older small-sample studies on BZDs [ 6 – 8 ] and modern views on discontinuing medications at all [ 9 ].…”

“…These results are in line with both older small-sample studies on BZDs [ 6 – 8 ] and modern views on discontinuing medications at all [ 9 ]. It has also been shown that a BZD concentration of zero occurs with a variable but usually marked delay after drug withdrawal [ 5 ]. The related crisis, seemingly late and surprising to the patient, may then trigger a relapse.…”

“…Some determinants of delayed elimination relate to how detoxification is performed [ 5 ]. One determinant is the moment when the concentration decrease begins.…”

“…The anti-accumulation paradigm was developed as an accessory action during the study on the BZD elimination course and related withdrawal crises [ 5 ]. It was intended to stop accumulation as hindering elimination assessment.…”