New Hypnotics

How good is the new hypnotic zopiclone? A new GABA(A) agonist (promoter) deserves watching. GABA is of course one of the chemicals felt to inhibit central nervous system activity, the shield against glutamate which activates the nervous system. Glutamate and aspartate are excitatory amino acids, while GABA and glycine inhibit the central nervous system.

In current usage, the term “hypnotics” has largely been applied to the benzodiazepines specifically and nearly any sedative generally. Hypnotics are often used in Central Pain to allow some sleep. It is probably fair to say the field of hypnotics is becoming crowded. Candidates include valium and clonazepam as well as indeplon, zaleplon, zolpidem, zopiclone and eszopiclone.

Recently, zopiclone has been marketed as eszopiclone and in other forms. Like the benzodiazepines such as clonazepam, zopiclone acts on the GABA(A) alpha (1) subunit associated receptor. However, due to the work of Mikkelsen and others, scientists are very suspicious that more than one subtype of this GABA(A) receptor exists. The reason is that at lower doses benzodiazepines may SUPPRESS the hypothalamus and adrenal cortex to reduce corticosteroids, whereas at higher doses, albeit with more sedation, they may actually result in HIGHER circulating levels of cortisone. Two-step receptors are possible, but two or more SEPARATE receptors are more likely. Any pain benefit is generally dose related and although not major, is used as an adjunct to other meds by many Central Pain subjects.

This paradox, low dose=low cortisol, high dose=high cortisol, with a drug known to suppress the cortisol control centers, suggests two mechanisms and hence more than one subtype of GABA(A) alpha (1) subunit. It is important to remember that for a given neurotransmitter or neuroprotein, DIFFERENT receptors often exist, sensitive to ONLY ONE portion of a very long molecule. Thus, it is the receptor which must be studied most, not the neurotransmitter. A comparison might be that electricity runs the house wiring, but what matters most is what is plugged into the socket. Sometimes differing receptors can be attaching very close to each other in a huge protein molecule, and even be linked to each others activity, as they deform the configuration of the molecule slightly.

Zoplicone, which induces fos* gene activity in the paraventricular nucleus of the hypothalamus (which regulates the pituitary which regulates the adrenal cortex, which regulates cortisol) is being promoted heavily as a new drug, but we have not received enough information to conclude it induces sleep better in central pain than clonazepam. Zopiclone has been found to have a mild dose related analgesic effect, but then so does clonazepam. What IS interesting that in the few reports received, is that those WITHOUT CP seem to continue to prefer Ambien for sleep, but those WITH Central Pain may find eszoplicone better, which indicates the anti-hyperalgesic effect, even if modest, may be greater than appreciated.

Many who have written consider clonzepam of some significant help with their central pain. We await more input before commenting on the zopiclones, including eszopiclone, marketed as Lunesta (copyrighted name), which is being promoted heavily. It remains to be seen if this drug is better for most or for just a few or for no one in particular with Central Pain as compared to clonazepam or other benzodiazepines. There is always a price to be paid for sedation, and the claims that no drowsiness results from zopiclone seem subject to question, particularly in those over sixty years of age. Many with severe CP find heavy sedation essential before any hope of sleep may be achieved.

We love drug companies, they are the mainstay of medical research for the most part, but of course they have administrators who hope to turn a profit. This can lead to overenthusiastic claims if the company is not careful. In the past, following the success of amitryptyline (Elavil), a host of similar tricyclics were produced, many claiming superior treatment for Central Pain, the effect being achieved perhaps largely through sedation, although these drugs are not commonly called hypnotics. Despite the extensive number of articles, some published in distinguished journals, including even complicated paradigms and algorhythms as to precise way to choose from among the tricyclics, there is no solid evidence any of the tricyclics are better for Central Pain than Elavil, which is very inexpensive by comparison.

Are the differences and advantages between the tricyclics real or not? We simply do not know, as conclusive double blind studies have not been performed. Similarly, while certain of the hypnotics probably will be shown to have some edge, it is not clear that any one particular drug will gain a clear advantage in the medical trials, despite the fact that some will win in the marketplace. None of them are particularly effective at stopping pain, but having some sleep is essential to surviving the severe forms of CP.

The warnings on the dangers of sudden withdrawal from eszopiclone indicate some significant events of withdrawal symptoms during drug trials. It is also being reported that no episodes of tolerance (decreasing effectiveness with time, requiring progressively higher doses) were noted, but this may be doubtful in light of the general feeling that tolerance does occur with hypnotics, particularly with prolonged use.

We are happy to see the drug companies rework and tweak molecules as they please, but would prefer the money to be devoted to new classes of drugs, inasmuch as adequate benzodiazepines already exist. Specifically, we can hope for safe, deliverable blockers of the Nav 1.3 ion channel, the CaV2.2 calcium channel, and the newly discovered T3 Calcium channels. The silver bullet is always more desirable than the mortar shell, if side effects are to be avoided.

*accurately or not, fos activity, which is actually a fairly early chemical step, and not actually very specific, is taken as indicating that genes in fos postive areas have been turned on or upregulated.