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

Basińska-Szafrańska, Anna

doi:10.1007/s00228-020-03048-y

Cited by 6 publications

(10 citation statements)

References 102 publications

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“…This study supports the hypothesis [25] that one of the possible reasons for early relapses may be customary premature conclusions of detoxification, followed by delayed drug elimination and the related withdrawal crisis.…”

Section: Discussionsupporting

confidence: 88%

“…However, this rule works only if it is the actual concentrationdecline process that is extended (stage III here), occurring below the satiating (and not an over-accumulated) concentration level. As has been discussed elsewhere, in typical trials, this may not be the case [25].…”

Section: Discussionmentioning

confidence: 86%

“…Eventually, after achieving a non-optimal plateau, which transiently drives adaptation in the direction opposite to the treatment goal, effective elimination can start, but with a marked delay and from an excessive level. Thus, a later crisis may not mean a weaker crisis if the delayed elimination end results not from extension of the elimination process but from the delayed start only [25].…”

Section: Discussionmentioning

confidence: 99%

“…However, it has been recorded in the past, although not commented on [12,13,[21][22][23], that when detoxification is typically [24] preceded by replacing abused drugs with a slowly eliminating substitute BZD, then the crucial low-concentration phase may be involuntarily shifted far beyond drug withdrawal. Hence, it might be expected [25] that a delayed low-concentration phase would result in delayed withdrawal syndrome after the cessation of medical assistance. In such conditions, relapse becomes highly likely.…”

Section: Introductionmentioning

confidence: 99%

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

Basińska-Szafrańska

2021

Eur J Clin Pharmacol

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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.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Basińska-Szafrańska

2021

Eur J Clin Pharmacol

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“…In our sample we observed a total of 191 subjects who required a supportive therapy, representing the subgroup with the highest clinical complexity. Furthermore, serum BZD concentration monitoring could help to make detoxification more reliable and effective [ 21 ], especially in this subgroup. Moreover, it should be noted that the detoxification treatment was used safely in pregnant women, who achieved complete detoxification, with no malformation or other pregnancy/neonatal negative outcomes.…”

Section: Discussionmentioning

confidence: 99%

Phenobarbital use in benzodiazepine and z-drug detoxification: a single-centre 15-year observational retrospective study in clinical practice

Sartori,

Crescioli,

Brilli

et al. 2022

Intern Emerg Med

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Given the increase in benzodiazepine (BZD) and Z-drug (ZD) use disorder, this study described the use of phenobarbital (PHB) as detoxification in clinical practice. A 15-year observational retrospective study was performed on medical records of BZD-ZD use disorder patients detoxified with PHB at the Toxicology Unit and Poison Centre, Careggi University Hospital, Florence (Italy). A multivariate logistic regression was used to estimate odd ratios (ORs) and related 95% confidence intervals (CI) of “treatment failure” considering demographic and pharmacological characteristics. “Hospitalisation length”, “PHB discharge dose”, and “BZD-ZD free status” at discharge were also calculated. During detoxification, out of 355 patients (57% of men), with a mean age of 42.92 years, only 20 (5.6%) treatment failures were recorded: 19 were discharged against medical advice or due to misbehaviour, and only one for PHB-related non-serious skin rash. Analysis showed a higher probability to be BZD-ZD free at discharge for subjects who reported to be employed (OR 2.29; CI 95% 1.00–5.24), for those who abused oral drops of BZD-ZD (OR 2.16, CI 1.30–3.59), and for those treated with trazodone (OR 2.86, CI 1.14–7.17) during hospital stay. A hospitalisation length of > 7 days was observed for patients with opioid maintenance therapy (OR 2.07, CI 1.20–3.58) for substance use disorder, and for those treated with more than 300 mg/day of PHB equivalents at hospital admission (OR 1.68, CI 1.03–2.72). Our results suggested that PHB can be considered a valuable detoxification option for different types of BZD and ZD use disorder patients.

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

Basińska-Szafrańska

2022

Eur J Clin Pharmacol

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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.

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

Cited by 6 publications

References 102 publications

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

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

Phenobarbital use in benzodiazepine and z-drug detoxification: a single-centre 15-year observational retrospective study in clinical practice

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

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