DÄ internationalArchive1-2/2015The Problems of Long-Term Treatment With Benzodiazepines and Related Substances

Review article

The Problems of Long-Term Treatment With Benzodiazepines and Related Substances

Prescribing Practice, Epidemiology, and the Treatment of Withdrawal

Dtsch Arztebl Int 2015; 112: 1-7. DOI: 10.3238/arztebl.2015.0001

Janhsen, K; Roser, P; Hoffmann, K

Background: Benzodiazepine abuse and dependence have been recognized and widely discussed for more than 40 years. With more than 230 million daily doses prescribed in Germany per year, the burden of reimbursement on the statutory health insurance carriers is high, albeit with a slight decline from year to year. At present, about 50% of all prescriptions in Germany are issued privately, even for patients who have statutory health insurance.

Methods: We selectively review the literature on the epidemiology and treatment of benzodiazepine dependence and abuse in Germany.

Results: Estimates of the number of benzodiazepine-dependent persons in Germany range from 128 000 to 1.6 million. Most estimates take no account of the large number of private prescriptions (i.e., those that are not reimbursed by the statutory health insurance scheme), while many exclude prescriptions for elderly persons, for whom these drugs are frequently prescribed. For the outpatient treatment of benzodiazepine withdrawal, it is recommended that the drug should first be switched to an equivalent dose of another benzodiazepine with an intermediate or long-acting effect; the dose should then, in general, be reduced weekly. In case of consumption of a high dose (≥ 20 mg diazepam equivalent), hospitalization and the additional administration of carbamazepine or valproic acid are recommended. Flumazenil treatment can improve withdrawal symptoms and leads to higher abstinence rates. Antidepressants should be given only if the patient is depressed. The dependence potential of non-benzodiazepine drugs such as zolpidem and zopiclon must also be borne in mind.

Conclusion: Benzodiazepines are generally highly effective when first given, but they should generally be given only for strict indications and for a limited time. If these drugs still need to be given beyond the short term, timely referral to a specialist is indicated, and possibly also contact with the addiction aid system.

LNSLNS

Misuse and dependency problems with benzodiazepines have been a familiar phenomenon for about 40 years (1, 2, e1). For this reason, pharmaceutical companies and the German Federal Institute for Drugs and Medical Devices (BfArM) have restricted the standard period of use to 2–4 weeks since the 1980s. However, 4–5% of members of statutory health insurance companies receive at least one prescription for a benzodiazepine (BZD) or benzodiazepine derivate (Z-drugs: zolpidem, zopiclone) per calendar year. Furthermore, in 13–14% of these patients, 90 and more defined daily doses (DDDs) are prescribed (3). According to a recent projection by Holzbach, the prevalence of misuse and dependency in Germany is 5% (4). When considering patient related and prescription related parameters, Holzbach determined a proportion of patients whose intake could be described as very problematic of 2.8%, and of patients whose intake could be described as problematic of as high as 17.5% (5). In older users, the proportion whose intake is problematic is higher than 20% (6).

In the outpatient setting, members of statutory health insurance schemes receive prescriptions for an annual 25.6 million DDDs of benzodiazepine hypnotics, 103.7 million DDDs of benzodiazepine tranquillizers, 0.5 million DDDs of clomethiazole, and 3.7 million DDDs of clonazepam (79). These prescription figures at the expense of statutory health insurance funds have been falling for years.

In addition to this, 74.6 million DDDs of Z-drugs are prescribed to members of statutory health insurance schemes (6), as are 22.0 million DDDs of tetrazepam, which was mainly used as a muscle relaxant, and whose license approval has been suspended since August 2913 because of severe skin disorders, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, DRESS syndrome, and others (e2, e3). Prescriptions in both groups have increased in recent years, at the expense of the statutory health insurers. Cumulatively, annual prescriptions amount to 230.1 million DDDs. Currently, 90 benzodiazepine-containing preparations—including Z-drugs—are included in the German drug directory (“Rote Liste”; e4), which account for 20 individual substances.

In its main indications—which include the treatment of predelirium, delirium tremens, and acute withdrawal symptoms, as well as therapy for states of confusion, agitation, and restlessness in elderly patients with organic brain syndrome—clomethiazole is to be used only in the inpatient setting (e5).

Several studies give rise to the assumption that since the end of the 1990s (at least), benzodiazepines and Z-drugs have been prescribed often, and increasingly also to members of statutory health insurance schemes, by means of a private prescription (912). The prescription volume of benzodiazepines fell from 12.7 million packets in 1993 to 2.0 million packets in 2012, but the proportion of private prescriptions in 2012 was 55.3%—in a setting of 87% of members in statutory health insurance schemes in the population. Even more conspicuous was the trend in prescriptions of Z-drugs: the volume increased from 2.2 million packages in 1993 to 8.9 million in 2011 (7.9 million in 2012). In 2011, the proportion of private prescriptions amounted to 49.5% (9).

According to the current law on prescriptions of medical drugs, hypnotics and tranquillizers can be prescribed for up to four weeks at the expense of the statutory health insurers—in individual cases this period can be extended if sound reasons exist. Continued prescription with the cost borne by the statutory health insurers is conceivable in individual cases, where certain criteria are being met (for example, in a setting of existing dependency). However, this is the subject of controversial discussion (13). In principle, it is possible, by using data from the statutory health insurers, to identify doctors who issue prescriptions with erroneous indications or who prescribe vast volumes, and to counsel them on their prescribing behavior. But the high proportion of private prescriptions currently substantially hampers such a targeted approach.

The case study accompanying this article describes the course of a complicated case of benzodiazepine withdrawal treatment (eBox). Initially prescribed for insomnia, benzodiazepines and clomethiazole had been prescribed to the case patient by her doctor for about 10 years. Ultimately, three months of detoxification treatment on an inpatient basis was required to stabilize the patient. On this background, our article provides an overview of the rates of BZD and Z-drug misuse and dependency. Furthermore, we explain how to carry out the withdrawal treatment and discuss prescription practice.

Case report
eBox
Case report

Methods

In order to obtain information on the epidemiology of the misuse of BZDs and Z-drugs and dependency, we conducted a selective literature search in PubMed (Table 1). The search was limited to German-language and English-language publications since 2004.

PubMed search algorithm, July 2014
Table 1
PubMed search algorithm, July 2014

Studies on how to carry out withdrawal treatment in BZD dependency were searched in PubMed in the category “medical subject headings major topic” (MeSH major topic), using the following search terms: “benzodiazepines/adverse effects” and “substance withdrawal syndrome/therapy”. We restricted our search to German-language and English-language publications from the past five years. Both searches were conducted in July 2014.

Results

The selective literature search regarding the epidemiology identified 46 matches, of which four publications were relevant (4, 5, 14, 15). We categorized as relevant studies that contained information about the epidemiology of benzodiazepine dependency. Table 2 provides an overview of these publications, to which prevalence data were added from the Epidemiological Survey on Substance Abuse (ESA) (16, e6), the German Federal Health Survey (17) and the German Center for Addiction Issues (e7). The data from the 2012 Epidemiological Survey on Substance Abuse show that for the whole population as enumerated in the census 2011 (e8), about 1.1 million persons aged between 18 and 64 years were dependent on hypnotics or tranquillizers by 31 December 2011. According to the data from the German Federal Health Survey 1998, the number of people aged 18–79 with dependency on hypnotics/tranquillizers is as high as 1.6 million (18). Holzbach’s group considered clinical aspects by dividing dependency into three phases (3, 4). The volume of problematic drug provision (yellow to black phase—that is, longer than 6 months on 3.33 mg and more diazepam equivalent/day) in Germany is reported to be 800 000 patients. These figures are based on data from prescriptions covered by the statutory health insurers and include prescriptions for older patients. Since the end of the 1990s at least, evaluations of data from statutory health insurance companies have meant that the prescribed amounts are likely to be underestimates because of the high proportions of private prescriptions (10).

Selected publications on rates of benzodiazepine/Z-drug misuse or dependency in Germany
Table 2
Selected publications on rates of benzodiazepine/Z-drug misuse or dependency in Germany

Several international guidelines on the therapy of benzodiazepine dependency exist (19–21, e9, and others), which mainly relate to outpatient withdrawal treatment of patients without high-dose consumption. A 2006 Cochrane review (22) was updated in 2013 (e10) and is currently subject to further revision. The German Medical Association’s guidance on medical drug dependency (23) and the 2006 guideline by Poser and colleagues (20) provide a detailed overview of the treatment of medication dependency. Holzbach published information on withdrawal treatment (3, 24, e11) that exceeded the scope of the former two publications.

The PubMed search on benzodiazepine withdrawal identified 22 matches, of which seven were relevant. Three of these dealt with the role of pregabalin (25, e12, e13), two with flumazenil (26, 27), one with cognitive behavioral therapy (e16), and one compared interventions with increased frequency of contacts between doctor and patient (28).

For the purposes of outpatient withdrawal treatment, it is widely recommended that patient’s medication is swapped to an equivalent dose of an intermediate-acting to long-acting benzopdiazepine, such as oxazepam or diazepam. The dose should be reduced weekly, over 4–10 weeks, by 10–25% of the dose that had been taken for a long period of time (24, 20, e16) (Figure). Oude Voshaar and colleagues showed in a meta-analysis (e17) that the recommendations regarding how to proceed in this scenario differ widely—they range from sudden withdrawal of the substance to stepping down intake over a year. In clinical practice, there certainly is an increased risk for withdrawal seizures. It remains doubtful whether concomitant medication with anticonvulsants is able to reduce these to a satisfactory degree.

Flow diagram of benzodiazepine withdrawal
Figure
Flow diagram of benzodiazepine withdrawal

For patients with high-dose consumption, of a diazepam equivalent dose of 20 mg or higher, inpatient treatment is recommended when starting withdrawal treatment, but additional treatment with carbamazepine or valproate is also advised (24). Potential problems arising in this setting are due to different equivalence data (3). Other concomitant medications—such as buspirone, beta blockers, and clonidine—do not seem to affect withdrawal treatment conclusively (e17). The use of antidepressants is recommended only in patients with comorbid depressive symptoms (e18). There are indications that flumazenil has a positive effect on withdrawal symptoms and results in a higher rate of abstinence (26, 27, e14). The Figure shows different withdrawal treatment options. Table 3 provides an overview of typical withdrawal symptoms. At this point we wish to remind readers again of a possible rebound effect of previously subclinical underlying psychiatric conditions.

Benzodiazepine withdrawal symptoms
Table 3
Benzodiazepine withdrawal symptoms

The importance of psychotherapeutic interventions has generally been assessed as positive (28, e15, e17), although Oude Voshaar et al. (e20) found in a comparative randomized controlled trial that, after a year, merely reducing the dose in a controlled fashion was superior to a combination with cognitive behavioural therapy in terms of the abstinence rate. However, this difference did not reach significance. Table 4 provides an overview of the effectiveness of selected interventions.

Effectiveness of different interventions in benzodiazepine dependency
Table 4
Effectiveness of different interventions in benzodiazepine dependency

Conclusion

Although treatment with benzodiazepines has many benefits, it became obvious quite soon after their introduction to the market in the 1960s that the risk of dependency should not be underestimated (3, e11). The fact that this was known not only to the medical profession but also to the wider population found its reflection in diverse culture historical episodes. One example is the 1966 song “Mother’s Little Helper” by British Rock band The Rolling Stones.

It should be pointed out that for a long time, the pharmaceutical industry played down the importance of the risk of addiction—not least again, when the Z-drugs were introduced. Their potential for dependency/addiction has been explicitly emphasized by different parties (3, 29, e21).

It is impossible to imagine certain medical disciplines without these groups of medications—for example, emergency medicine, anesthesiology, but also epileptology, and psychiatric emergencies (30, e22, e23, e24). According to the data of the German Federal Health Survey, users list among the most common reasons for taking these drugs insomnia (50%) and inner restlessness, nervousness, and states of agitation and tension (25.9%) (17). In the case study accompanying this article, the initial prescription was issued for insomnia.

Because of a lack of data, one can only speculate about the motivation for prescribing benzodiazepines and related substances for longer periods than those recommended in the medication guidelines. It can be assumed that the good effectiveness in terms of the target symptoms creates great affinity in patients towards their medication—even before manifest dependency develops. Patients therefore put pressure on their doctors who prescribe the drug to them. Those affected fear that their initial symptoms might return. This is also reflected in the comment that in many cases, prescriptions are issued at patients’ explicitly expressed wishes (31). Furthermore, most patients are likely to have gone through a prolonged history of suffering before they were given benzodiazepine medication, so they desire rapid intervention and need it too. Since, for example, care in the psychotherapeutic setting is still associated with long waiting times, this means that patients’ needs are insufficiently met. Another group of persons includes patients with primary polysubstance dependencies, but no concrete data are available in terms of what proportion this group accounts for.

As early as in 1984, Binder and colleagues reported on 157 cases of benzodiazepine dependency and in this context used the term “epidemic” (32). In addition to adjuvant administration in pain therapy (33, e25), psychiatric diagnoses are the primary indications for benzodiazepine medication. The mechanisms or individual risk factors that determine whether a patient develops high-dose dependency or—with comparatively low dosages of benzodiazepines—low-dose dependency are currently not known. Martinez-Cano and colleagues found in a study of 153 patients with benzodiazepine dependency a particularly high risk for high-dose dependency for triazolam and lorazepam. They explained this mainly on the basis of pharmacokinetic and pharmacodynamic factors (34). High-dose dependency has, however, been documented for all benzodiazepines, including the Z-drugs (12, 35, e26). In persons with high-dose benzodiazepine dependency, addiction-specific comorbidities are apparently less common than in consumers of low-dose benzodiazepines (36, e27).

Without any doubt, doctors are crucially involved in the long-term prescribing of benzodiazepines. It can be assumed that the majority of consumed benzodiazepines were not obtained on the black market but were prescribed by doctors. This problem was identified and made the focus of discussion early on (32, 37, 38, e28, e29), but the consequences are not yet reflected in doctors’ prescribing behavior. Even after the prescribing options for different benzodiazepines were restricted, no effect was seen in this regard. For example, for flunitrazepam, prescriptions became possible only with a narcotics prescription. A recent survey among Germany’s primary care physicians, which asked questions about their prescribing of hypnotic substances in the shape of private prescriptions, provides interesting insights: the doctors named primarily the regulations of the medication guideline and prescriptions on request as reasons for why they issued private prescriptions to patients who were members in statutory health insurance schemes (31). Furthermore, 80.4% out of 458 survey participants were of the opinion that Z-drugs were more effective and—including their addiction-forming potential—less likely to cause adverse effects than benzodiazepines. The literature does, however, not provide any evidence base for this assumption (39). To date, data on the distribution of persons who are dependent on high-dose benzodiazepines are lacking. Since the prescribing problems are set within a legal gray area, substantial methodological problems arise—but the need for research is evident.

In our view, the prevention of inappropriate long-term prescribing, motivation for withdrawal, as well as carrying out outpatient or inpatient withdrawal therapy, are necessary measures to prevent inappropriate long-term use and long-term prescriptions. On the one hand, doctors and users will have to be better informed in this context, but sufficient treatment capacity is also required. The German Medical Association in collaboration with the Drug Commission of the German Medical Association in 2007 published guidance for medical practice, entitled “Medikamente—schädlicher Gebrauch und Abhängigkeit [Medical drugs—harmful use and dependency]” (23). The German Medical Association and the Association of Statutory Health Insurance Physicians for Hamburg in February 2011 published joint guidance for prescribing benzodiazepines and their analogues (4). This recommendation should be adhered to, even in situations where a patient forcefully expresses their request for a prescription (40). The Association of Statutory Health Insurance Physicians for Westphalia-Lippe also passes the guidance and comprehensive additional information regarding the prescribing of benzodiazepines to its members. The association also provides details of whom to contact for advice, for patients and doctors. With regard to the prevention and therapy of medication dependency, the current guideline of the German Medical Association explicitly points out that primary care physicians and other specialists in private practice, especially psychiatrists, need to collaborate closely. Here lies a potential that has hitherto been insufficiently used and which might improve healthcare.

Conflict of interest statement

The authors declare that no conflict of interest exists.

Manuscript received on 11 April 2014, revised version accepted on
28 October 2014.

Translated from the original German by Birte Twisselmann, PhD.

Corresponding author
Dr. med. Knut Hoffmann
LWL-Universitätsklinikum Bochum
Klinik für Psychiatrie, Psychotherapie und Präventivmedizin
Ruhr-Universität Bochum
Alexandrinenstr. 1–3, 44791 Bochum, Germany
knut.hoffmann@wkp-lwl.org

@For eReferences please refer to:
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eBox:
www.aerzteblatt-international.de/15m0001

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e19.
Lugoboni F, Quaglio G: Exploring the dark side of the moon: the treatment of benzodiazepine tolerance. Br J Clin Pharmacology 2013; 1–3.
e20.
Oude Voshaar RC, Gorgels WJ, Mol AJ, et al.: Predictors of long-term benzodiazepine abstinence in participants of a randomized controlled benzodiazepine withdrawal program. Can J Psychiatry 2006, 51: 445–52. MEDLINE
e21.
Lader M: History of Benzodiazepine Dependance. J Subst Abuse Treat 1991; 8: 53–9. CrossRef MEDLINE
e22.
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e23.
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e24.
Mavrogiorgou P, Brüne M, Juckel G: The management of psychiatric emergencies. Dtsch Arztebl Int; 108: 222–30. VOLLTEXT
e25.
Mickel C: 3 things to consider before relying solely on point of
care tests for determining benzodiazepine use in chronic pain. Pain Physician 2012; 15: E151–8. MEDLINE
e26.
National Institute for Clinical Excellence: Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia. www.nice.org.uk/guidance/ta77 (last accessed 2 December 2014).
e27.
Johansson BA, Berglubnd M, Hanson M, Pöhlen C, Persson I: Dependence on legal drugs among alcoholics. Alcohol Alcohol 2003; 38: 613–8. MEDLINE
e28.
Faust B: Doctors and detailers: the benzodiazepine scandal. Austr Nurses J 1991; 20: 12–3.
e29.
Lader M: Benzodiazepines revisited-will we ever learn? Addiction 2011; 106: 2086–109. MEDLINE
LWL-Klinik Bochum, Department of Psychiatry, Psychotherapy, Psychosomatic and Preventive Medicine, Ruhr University Bochum: PD Dr. rer. pol. Janhsen, Prof. Dr. med. Roser, Dr. med. Hoffmann
Faculty of Health (Department of Medicine), Witten/Herdecke University: PD Dr. rer. pol. Janhsen
Flow diagram of benzodiazepine withdrawal
Figure
Flow diagram of benzodiazepine withdrawal
Key messages
PubMed search algorithm, July 2014
Table 1
PubMed search algorithm, July 2014
Selected publications on rates of benzodiazepine/Z-drug misuse or dependency in Germany
Table 2
Selected publications on rates of benzodiazepine/Z-drug misuse or dependency in Germany
Benzodiazepine withdrawal symptoms
Table 3
Benzodiazepine withdrawal symptoms
Effectiveness of different interventions in benzodiazepine dependency
Table 4
Effectiveness of different interventions in benzodiazepine dependency
Case report
eBox
Case report
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