Doctors, please have a cider before you prescribe benzodiazepines to your patients.

Abstract
This article reviews the history, the use and misuse of benzodiazepines. A small trick, CIDER, is introduced to help doctors to remember and to follow the Revised Guidelines on the Proper Prescription and Dispensing of Dangerous Drugs by Registered Medical Practitioners.


The History
Librium was the first benzodiazepine to be marketed, by Roche in March 1960, after its approval by the FDA in February 1960. Its discovery was by no means accidental, unlike the discoveries of many wonder drugs. It was one of the research products by Dr. Leo Sternbach in an attempt to find a substitute for the phenothiazines, which were the treatment of choice for anxiety at that time. However, the many side-effects and the addictive potential of phenothiazines tended to limit their use in ambulatory patients. The pharmaceutical companies were actively looking for new substitutes to continue their share in this porfitable market.
In 1963 Valium was introduced as a more potent tranquilizer. The third benzodiazepine, Serax, was introduced in June 1965. (1)


The Use

Since their introduction, benzodiazepines became the most commonly prescribed group of psychotropic drugs.
However one should be reminded that in fact the labeled uses of benzodiazepines are confined to alcohol withdrawal psychosis, anxiety, insomnia and muscle spasm.
Common unlabeled uses include atonic seizures, atypical absence seizures, infantile spasms, myoclonic epilepsy adjunct treatment, neonatal abstinence syndrome, night terrors, opioid withdrawal symptoms, panic disorder, sedation in pediatric patients, tension headache and tremors. (2)


The Misuse
The recognition of the development of drug dependency, withdrawal symptoms and thus abuse potential of benzodiazepines has raised much concern after the exponential increase of their uses in the 1970s.
Use for as short as 2 weeks had been reported to cause dependence.
Withdrawal syndrome can be very difficult to deal with especially for patients predisposing to chemical dependence. However, paradoxically, many of them are in fact the target group of patients for the prescription of benzodiazepines.
It is quite common for any articles concerning benzodiazepines in journals or magazines to be flooded with response letters from “angry patients” who claimed to have sufferred from benzodiazepine dependence and withdrawal synddrome.
I think many doctors would also have the experience of encountering patients telling you that they have been taking some benzodiazepines daily for over 20 years. They are quite satisfied with the fact, living with the drug, and resist any suggestion of tailing off them.

To combat these problems, many regulations and guidelines have been developed by various authorities to regulate and to guide the use of benzodiazepines by doctors.
There has been a recent increase in the public’s awareness of mood disorders, anxiety disorders and problems of insomnia. Patients tend to be more ready to seek help for these problems from the general practitioners and their family physicians. This might result in an increase in the use of benzodiazepines. It is time to review some of these guidelines, among which the “Revised Guidelines on the Proper Prescription and Dispensing of Dangerous Drugs by Registered Medical Practitioners” promulgated by the Medical Council of Hong Kong will concern us most.


The Precautions

General
To use benzodiazepines only when indicated, in the lowest dose, for the shortest duration possible.

Abuse potential and risk of dependence
The abuse potential and risk of development of drug dependence of a particular benzodiazepine is inversely related to its half-life and directly related to the duration of continuous use.
Benzodiazepines with short half lives will be of higher risks of being abused and drug dependence. Hence they should be prescribed with care (or to be avoided) especially for the at risk groups.
(Benzodiazepines with short half life (<6 hr): Midazolam (Mayne), Triazolam (Halcion);
Benzodiazepines with intermediate half life (around 12 hr): Alprazolam (Xanax), Loramet, Lorazepam (Ativan), Bromazepam (Lexotan), Temazepam;
Benzodiazepines with long half life: Clonazepam (Rivotril), Estazolam, Flunitrazepam (Rohypnol), Chlordiazepoxide (Bralix), Diazepam (Valium), Flurazepam, Nitrazepam, Pinazepam (Domar).)

To use benzodiazepines intermittently or on a p.r.n. basis instead of continuous use can also help to lower the risk of developing dependence.

Treatment of Anxiety
Benzodiazepines are indicated for the short-term relief (two to four weeks only) of anxiety that is severe, disabling or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness.
The use of benzodiazepines to treat short-term ‘mild’ anxiety is inappropriate and unsuitable. (3)

Treatment of Insomnia
Benzodiazepines should be used to treat insomnia only when it is severe, disabling, or subjecting the individual to extreme distress

Treatment of panic disorders
With panic disorders (with or without agoraphobia) resistant to antidepressant therapy ,a benzodiazepine (lorazepam 3–5 mg daily or clonazepam 1–2 mg daily [both unlicensed]) may be used.

Treatment of depression
Benzodiazepines should not be used as the sole agent in the treatment of depression.
A benzodiazepine may be used as short-term adjunctive therapy at the start of antidepressant treatment to prevent the initial worsening of symptoms. (4)


The Regulations

In Hong Kong the prescription and supply of benzodiazepines by doctors is mainly governed by the Dangerous Drugs Regulations (Cap. 134) and the Professional Code and Conduct. Regulations 5 and 6 of the Dangerous Drugs Regulations (Cap. 134) criminally sanction for any failure to keep proper records and requirements as to registers of dangerous drugs supplied. These have received much attention and most doctors should be familiar with, or at least be aware of, them after the repeated convition of doctors in breach of the Regulations and the report of such cases in the HKMA Newsletter.

While breaching the Dangerous Drugs Regulations would result in criminal consequences, a breach of the Professional Code and Conduct would result in diciplinary action. Part III Section 11 of the Code conerns with the “Supply of dangerous or scheduled drugs”. Subsection 11.1 states that: “ Medical practitioners are advised to acquaint themselves with the Guidelines on the Proper Prescription and Dispensing of Dangerous Drugs promulgated by the Medical Council. Disciplinary proceedings may be taken in any case in which a medical practitioner prescribes or supplies drugs of addiction or dependence otherwise than in the course of bona fide and proper treatment.”

The “Revised Guidelines on the Proper Prescription and Dispensing of Dangerous Drugs by Registered Medical Practitioners” was promulgated by the Medical Council of Hong Kong in October 2003.
Section (A), (2) and (3) state that “These guidelines reflect currently accepted professional standards on the use of such agents in the local context, and are intended to provide general guidance to medical practitioners for the promotion of good clinical practice.
The Practice Directions under Section (E) should be followed. Breach of these directions may be construed as improper use of dangerous drugs.”
Section (E), (1) concerns the “Practice Directions for use of benzodiazepines”
Since the test for professional misconduct is “a fall short of accepted professiomal standards”, and the Guidelines reflect the currently accepted professional standards on the use of such agents in the local context; failure to follow the guidelines would highly likely to result in a successful conviction of professional misconduct. (5)


The “CIDER”

It is important for doctors to pay attention to these guidelines and to be familiar with them so as not to get caught by them.
I have designed a small trick to remember them (for those concerning benzodiazepines only):

The word CIDER is used to remember the essential points of the guideline:

C- Complete history, physical examination, investigation and diagnosis.

I- Inform your patients about your diagnosis, plan of management, duration of treatment, other treatment alternatives, and the side effects and abuse potential of the medication.

D- Document your findings, plan of management and most important, the justification of prescribing benzodiazepines to this particular patient

E- Evaluate the patient’s abuse potential (eg. History of substance abuse, alcoholic), judge it against the therapeutic benefits, and document it in your notes

R- Reassess the need for continual treatment regularly, (monthly, as recommended) and tail off whenever possible. (Remember to document this)

Refer the patient to specialist care when necessary.


So, doctors, please have a CIDER before prescribing benzodiazepines to your patients!


(The Origins of Cider
It’s almost impossible to pinpoint the origins of cider. The existence of apples is easier to establish, but when it comes to actual cider making, documentary evidence remains frustratingly patchy.
Most cider is made from fermented apple juice. Natural cider has nothing added and relies, for fermentation, upon the wild yeast present in the apples. For mass-produced ciders, a yeast culture is added in order to achieve consistency. Although much of today’s cider is produced from apple concentrate, many traditional cider-makers use only cider apples, cultivated specifically for the purpose.) (6)

Reference
1. Dilip Ramchandani. The Librium Story. History Notes, Psychiatric News.
2. First Databank
3. Advice form Committee on Safety of Medicines
4. BNF
5. The “Revised Guidelines on the Proper Prescription and Dispensing of Dangerous Drugs by Registered Medical Practitioners”
6. History-of-cider.com