Assessment of Pharmacological Treatment Quality: Comparison of Symptom-triggered vs. Fixed-schedule Alcohol Withdrawal in Clinical Practice

• Abstract
• Introduction
• Methods
• Patient sample
• Fixed-scheduled treatment with diazepam (FS)
• Symptom-triggered treatment with clomethiazole (ST)
• Statistics
• Results
• Discussion
• References

Abstract

Introduction: Despite the fact, that symptom-triggered alcohol withdrawal treatment is recommended by German guidelines on alcoholism, many hospitals continue to use fixed-schedule protocols, as they have been successfully applied for many years.

Methods: This retrospective study compared all patients’ records of alcohol withdrawal treatment from October 2010 to November 2011 at Magdeburg’s University Department of Psychiatry (n=120). A symptom-triggered protocol with clomethiazole (AESB, n=46) was used in parallel with the existing fixed-schedule protocol with diazepam (n=74).

Results: The symptom-triggered group showed less need of pharmacological treatment duration (p<0.001) and cumulative dosage of medication compared to the fixed-schedule protocol (p<0.006). No difference was observed regarding the need of clonidine or haloperidol (to treat blood pressure derailment or delirium) and the incidence of epileptic seizures.

Discussion: Based on the shorter treatment duration and a similar rate of complications our department has switched to the symptom-triggered protocol to improve the quality of patient care.

Introduction

Treating patients with alcohol addiction remains one of the core clinical duties of psychiatric hospitals in Germany. Depending on the location and setting of the psychiatric hospital, up to 50% of all patients admitted via emergency protocols suffer from alcohol use disorder. Interestingly, this high ratio of admissions due to alcohol has not increased during the last decades, but had already been reported by Kraepelin in 1883 [1]. Clinically, patients are either admitted due to intoxication with ethanol and might experience alcohol withdrawal symptoms (AWS) when alcohol blood levels drop during detoxification or they are admitted due to existing AWS requiring alcohol withdrawal treatment (AWT). Once patients show signs of AWS, it needs to be managed medically to avoid severe complications such as delirium tremens, which untreated still has a high risk for death [2]. During AWT, GABA-ergic medications such as benzodiazepines or clomethiazole are given to substitute ethanol [3]. Administration of GABA-ergic medications either follows a fixed-schedule protocol (FS) or a newer approach that is symptom-triggered (ST). During symptom-triggered AWT, the severity of specific withdrawal symptoms is measured and medication is given based on a calculated clinical score while a fixed-schedule protocol follows the administration of a fixed dosage of medication in a given time interval that is prolonged or tapered over the course of days [4]. Internationally, the Clinical Institute Withdrawal Assessment (CIWA) or its revised form is very common [5], whereas German hospitals often use a modified German version of the CIWA called “Alkoholentzugssymptombogen (AESB) [6] as this protocol is also published in a prominent German textbook of psychopharmacology [7].

Many studies support the idea that symptom-triggered AWT reduces time of treatment and cumulative dosage of medication needed [8] [9] [10] [11]. Thus, symptom-triggered treatment is recommended in the newly published German guidelines on alcoholism [12]. However, other studies did not show an advantage of symptom-triggered over fixed-schedule treatment protocols [13] [14]. Therefore, many hospitals in Germany continue to use their older fixed-schedule protocol, which they have used effectively regardless of whether or not a switch towards a symptom-triggered approach that could improve health care even further.

In 2010, the symptom-triggered AESB protocol was introduced in our department, and it was used in parallel with the pre-existing, fixed-schedule, in-house protocol from October 2010 to November 2011. The current study is a retrospective analysis of all records of patients treated during this period of time.

Methods

Patient sample

The sample consisted of all alcohol-addicted patients (according to ICD-10) admitted to our hospital as inpatients for alcohol withdrawal treatment (AWT) between October 2010 and November 2011. We analyzed the medical records of these patients. During this period of time, different attending physicians used 2 different treatment protocols for AWT. Demographic and clinical data and baseline laboratory values were well matched as summarized in [Table 1]. Accordingly, carbohydrate-deficient transferrin (CDT) – a good indicator for heavy alcohol consumption – was not significantly different between the tested cohorts [15].

There were 178 admissions of patients who developed AWS during the study period. 120 admissions were first admissions within the study period, fulfilled all inclusion criteria and had no exclusion criteria.

Inclusion criteria were:

• AWS on admission with or without seizures or delirium tremens

• Initial alcohol intoxication with motivation for AWT during detoxification

• Age between 18 and 75 years

Exclusion criteria were:

• Severe concurrent somatic disease, trauma or surgery

• Pregnancy

• Addiction to other psychoactive drugs, especially benzodiazepines (excluding nicotine)

• Patients who did not have AWS severe enough to be treated pharmacologically

Patients were excluded based on the following reasons: second or more AWT during the assessment period (n=48) and benzodiazepine addiction (n=3). Clomethiazole (CMZ) was switched to diazepam (DZP) treatment in 7 patients to be able to administer medication intravenously (n=4) or because of diarrhea as a side effect of CMZ treatment (n=3). The cases that included both CMZ and DZP in their treatment were excluded from the statistical analysis. 74 patients received FS with diazepam vs. 46 patients who received ST with clomethiazole ([Fig. 1]). Add-on therapy with carbamazepine was applied in 2 patients of the FS cohort and in 16 patients of the ST cohort (Fisher’s exact test p<0.001).

All patients received intravenous thiamine substitution of 100 mg daily for the first 3 days of their admission followed by oral substitution of 300 mg per day for the remaining days of AWT to prevent Wernicke-Korsakoff syndrome. To guarantee compliance, our nursing staff controlled all medications administered.

Fixed-scheduled treatment with diazepam (FS)

This FS protocol has been the standard protocol used at our hospital. Patients in this group received their medication according to this protocol as soon as they showed the first withdrawal signs. In general, once detoxification was started, patients received 5 mg diazepam every 2 h on the first day of detoxification. Sometimes, when withdrawal was severe, they could be administered 10 mg of diazepam bihourly. Once patients were stable on this fixed dose of DZP (usually after 24–48 h into detoxification treatment), they were still checked every 2 h but diazepam was tapered to 5 mg every 4 h. Once stable on this dosage, periods of checks and medication were stretched even further to 5 mg every 6 h. Finally, 5 mg were administered 3x daily for one day, 2x daily for one day, and a final 5 mg on the morning of the last day. Starting doses, intervals of checks as well as reduction of medication were individually determined by the physician based on the general clinical impression of each patient, however not based on a published standard. Likewise, the first administration of medication was set as the statistical start of the withdrawal treatment and the time point of the last administration of DZP was considered as the statistical endpoint of the AWT.

Symptom-triggered treatment with clomethiazole (ST)

Symptom-triggered treatment with CMZ was based on the AESB protocol [6]. In this protocol 10 different symptoms of withdrawal (blood pressure, heart rate, tremor, paroxysmal sweats, nausea/vomiting, anxiety, agitation, orientation, disturbances/hallucinations and seizures) are measured. Depending on the item a score from zero to 2/4 or 5 points can be reached. Patients have to reach 5–7 points in order to receive one capsule of CMZ, 8–10 points resulted in 2 capsules and 11 points or more resulted in 3 capsules. Symptoms were measured every 2 h for the first 4 days, every 3 h on the 5^th day, every 4 h on the 6^th day and intervals were prolonged by 2 h each additional day. Statistically, the first and last administration of medication was defined as the start and end of the withdrawal treatment.

Both groups were compared regarding overall duration of drug treatment as well as their average drug dosage per day and their overall cumulative drug dosage. 5 mg of DZP were set as equivalent to 1 capsule of CMZ (192 mg) as published in the German guidelines on medication of addiction. As the guidelines were published in 2006 and are out-of-date, no direct citation link can be provided. The guidelines were published under the register number 076/009 of the Association of the Scientific Medical Societies in Germany (http://www.awmf.org/en/awmf.html). Systolic and diastolic blood pressure and heart rate had been compared on admission and during the AWT. All documented side effects and complications have been recorded and analyzed, in particular delirium tremens, seizures, as well as additional medication with clonidine or haloperidol.

Statistics

Statistical analyses were performed with R statistics 3.2.2. Categorical data were analyzed with Fisher’s exact test. Student’s t-test was performed for demographic variables (i. e., age, body mass index (BMI)). The normal distribution of the samples was tested by the Shapiro-Wilk test. Laboratory data and outcome measures did not follow a normal distribution. Thus, non-parametric Mann-Whitney U test was used to calculate group differences between FS and ST regarding these data. As a second step, we compared the subgroups of CMZ-treated patients in the ST group with or without add-on treatment with carbamazepine in order to rule out a positive effect of this co-medication as a relevant confounding factor.

Results

As shown in [Table 1] and [Fig. 2], the ST group had a significantly shorter duration of medical withdrawal treatment (FS=116.0 h [Q1: 94.0 h; Q3: 137.0 h; n=74], ST=62.0 h [Q1: 40.8 h; Q3: 92.5 h; n=46], U Test p<0.001). Patients in the ST group also needed significantly less cumulative dosage of medication (FS median=130.0 mg [Q1: 103.8 mg; Q3: 165.0 mg; n=74], ST median=90.0 mg [Q1: 58.8 mg; Q3: 151.3 mg, n=46], U Test p<0.006).

No difference was observed regarding the additional application of clonidine medication, which is an indicator of hypertensive derailment during treatment (FS=4/70; ST=0/46; exact Fisher-test p=0.297). Similarly, the need for additional haloperidol medication – an indicator of manifested or suspected beginning of delirium tremens – did not differ between the treatment groups (FS=23/51; ST=8/38; Fisher-test p=0.133). The incidence of epileptic seizures as a complication of alcohol withdrawal was not significantly different across the tested cohorts (FS=1/73; ST=1/45; Fisher-test p=1.000).

As a second step, we compared the subgroups of CMZ-treated patients in the ST group with or without add-on treatment with carbamazepine in order to rule out a positive effect of this co-medication as a relevant confounding factor contributing to the good outcome of symptom-triggered alcohol withdrawal treatment. As summarized in the Supplementary Table, both subgroups did not differ regarding the duration of medical alcohol withdrawal treatment (U Test p=0.620), required cumulative dosage of medication (U Test p=0.393), clonidine (exact Fisher-test p=1.000) and haloperidol treatment (exact Fisher-test p=0.101) or the incidence of epileptic seizures as a complication of alcohol withdrawal (exact Fisher-test p=0.348).

Discussion

In our retrospective analysis of 2 different treatment protocols, the symptom-triggered AESB protocol was superior to a fixed-schedule protocol. This is in line with many previous publications [8] [9] [10] [11] and further supports the recommendation of the German guidelines for alcoholism to use a symptom-triggered protocol. In our study, clomethiazole was used as the only medication in the symptom-triggered group. While clomethiazole is also recommended as the first-line standard medication by the German guidelines, it is not available in many countries. In addition, recent studies challenged the German recommendation of clomethiazole as the medication of choice, as they showed that benzodiazepines are equally effective and not inferior for AWT compared to clomethiazole [16] [17]. Therefore, we think that the observed superiority of the AESB over our old in-house protocol is based on the type of treatment protocol and not based on possible differences of the 2 medications used. Although we cannot completely rule out the possibility that clomethiazole itself might be superior to diazepam, the fact that some patients received carbamazepine on top of clomethiazole had no effect on the group results.

The naturalistic character of this study is a major limitation as our data is neither controlled nor randomized. Ideally, a prospective study with 4 different groups would be needed to finally investigate the question of whether a benzodiazepine or clomethiazole and/or a symptom-triggered or fixed-schedule protocol is best for treating AWS. Given the high costs of such a prospective study, it is very unlikely to find sufficient sponsoring for such a trial.

In recent years, the idea of reducing costs of inpatient treatment in psychiatry has become more and more prominent, and a recent study showed that simply by implementing a symptom-triggered treatment protocol, costs of AWT were reduced by over 50% without loss of treatment quality [18].

In Germany, the costs of AWT are currently covered by compulsory health insurance. Depending on the insurance company and the severity of the patient’s addiction, treatment may usually be reimbursed for up to 10 days. AWT with a symptom-triggered protocol will shorten the time of medical withdrawal treatment compared to a fixed-scheduled protocol and enable the patient to participate in further motivational treatment strategies.

Currently a new reimbursement system for inpatient psychiatry is being developed in Germany and daily reimbursements will decrease over time of inpatient treatment [19]. Although this new system is being criticized by many psychiatrists as well as the German Association of Psychiatry, Psychotherapy and Psychosomatics (DGPPN), and a new analysis showed that it will most likely not improve efficiency but rather decrease quality of care [20], many hospitals are faced with the need to restructure their daily clinical routine to adjust to this new system and the possible dilemma, that this might have negative consequences for patient care. Therefore, it is of uttermost importance to focus on core responsibilities of psychiatrists and to define those areas that can be delegated to other professions without reducing treatment quality [21], especially as psychiatry is faced with another big problem of a shortage of psychiatrists and psychiatric residents [22]. Reducing the medical part of withdrawal treatment thus not only enables the patient to spend more time in psychological treatment but also decreases the time the patient needs to be closely monitored by a physician.

Based on these results and considerations, the symptom-triggered AESB protocol seems to be superior to the fixed-scheduled protocol as treatment duration is shorter, and patients need less cumulative medication without increasing the risk of complications (blood pressure derailment, delirium, epileptic seizures). Furthermore, the AESB protocol is well standardized and easy to follow by psychiatric nurses.

Conflict of Interest:

The authors declare no conflict of interest.

^* These authors contributed equally to this paper

• References

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Correspondence

• References

• 1 Kraepelin E. Compendium der Psychiatrie. Leipzig: Ambr. Abel Verlag; 1883
  Search in Google Scholar
• 2 Perry EC. Inpatient management of acute alcohol withdrawal syndrome. CNS Drugs 2014; 401-410
  PubMedSearch in Google Scholar
• 3 Caputo F, Bernardi M. Medications acting on the GABA system in the treatment of alcoholic patients. Curr Pharm Des 2010; 16: 2118-2125
  CrossrefPubMedSearch in Google Scholar
• 4 Manasco A, Chang S, Larriviere J et al. Alcohol withdrawal. South Med J 2012; 105: 607-612
  CrossrefPubMedSearch in Google Scholar
• 5 Sullivan JT, Sykora K, Schneiderman J et al. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 1989; 84: 1353-1357
  CrossrefPubMedSearch in Google Scholar
• 6 Lange-Asschenfeldt C, Müller MJ, Szegedi A et al. Symptom-triggered versus standard chlormethiazole treatment of inpatient alcohol withdrawal: clinical implications from a chart analysis. Eur Addict Res 2003; 1-7
  PubMedSearch in Google Scholar
• 7 Benkert O, Hippius H. Kompendium der Psychiatrischen Pharmakotherapie. Berlin Heidelberg: Springer-Verlag; 2015
  CrossrefSearch in Google Scholar
• 8 Cassidy EM, O’Sullivan I, Bradshaw P et al. Symptom-triggered benzodiazepine therapy for alcohol withdrawal syndrome in the emergency department: a comparison with the standard fixed dose benzodiazepine regimen. Emerg Med J 2012; 802-804
  PubMedSearch in Google Scholar
• 9 Duby JJ, Berry AJ, Ghayyem P et al. Alcohol withdrawal syndrome in critically ill patients: protocolized versus nonprotocolized management. J Trauma Acute Care Surg 2014; 938-943
  PubMedSearch in Google Scholar
• 10 Sachdeva A, Chandra M, Deshpande SN. A comparative study of fixed tapering dose regimen versus symptom-triggered regimen of lorazepam for alcohol detoxification. Alcohol Alcohol 2014; 287-291
  PubMedSearch in Google Scholar
• 11 Daeppen J-B, Gache P, Landry U et al. Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med 2002; 162: 1117-1121
  CrossrefPubMedSearch in Google Scholar
• 12 Mann K, Hoch E, Batra A. S3-Leitlinie, Screening, Diagnose und Behandlung alkoholbezogener Störungen. Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften. Internet http://www.awmf.org/uploads/tx_szleitlinien/076-001l_S3-Leitlinie_Alkohol_2016-02.pdf last update: Feb. 28, 2016
  PubMed
• 13 Maldonado JR, Nguyen LH, Schader EM et al. Benzodiazepine loading versus symptom-triggered treatment of alcohol withdrawal: a prospective, randomized clinical trial. Gen Hosp Psychiatry. 2012: 611-617
  PubMedSearch in Google Scholar
• 14 Elholm B, Larsen K, Hornnes N et al. Alcohol withdrawal syndrome: symptom-triggered versus fixed-schedule treatment in an outpatient setting. Alcohol Alcohol 2011; 318-323
  PubMedSearch in Google Scholar
• 15 Bianchi V, Premaschi S, Raspagni A et al. A comparison between serum carbohydrate-deficient transferrin and hair ethyl glucuronide in detecting chronic alcohol consumption in routine. Alcohol Alcohol 2015; 266-270
  PubMedSearch in Google Scholar
• 16 Bonnet U, Lensing M, Specka M et al. Comparison of two oral symptom-triggered pharmacological inpatient treatments of acute alcohol withdrawal: clomethiazole vs. clonazepam. Alcohol Alcohol 2010; 68-73
  PubMedSearch in Google Scholar
• 17 de Millas W, Ganzer F, Kuhn S et al. Oxazepam versus clomethiazol in alcohol withdrawal treatment. Eur Addict Res 2010; 179-184
  PubMedSearch in Google Scholar
• 18 Murdoch J, Marsden JA. “symptom-triggered” approach to alcohol withdrawal management. Br J Nurs 2014; 198-202
  PubMedSearch in Google Scholar
• 19 Haring B, Kutschis M, Bleich S et al. The new reimbursement for psychiatry and psychosomatics – challenges, opportunities and risks of the new financing system. Fortschr Neurol Psychiatr 2014; 30-38
  Thieme ConnectPubMedSearch in Google Scholar
• 20 Vollmann J. The new financial compensation system PEPP: an ethical analysis. Nervenarzt 2014; 1410-1418
  PubMedSearch in Google Scholar
• 21 Jordan W, Bleich S, Cohrs S et al. Definition des Kernbereichs ärztlicher Tätigkeit im psychiatrisch-psychotherapeutischen Fachgebiet – Voraussetzung für jede Delegation. Psychiat Prax 2011; 8-15
  Thieme ConnectPubMedSearch in Google Scholar
• 22 Jordan W, Adler L, Bleich S et al. Ärztemangel im psychiatrischen Krankenhaus – Zukunftssicherung durch Neuordnung des ärztlichen Dienstes. Psychiat Prax 2011; 16-24
  Thieme ConnectPubMedSearch in Google Scholar

• Supplementary Material