Twas the night before Christmas, when all through the house
Not a creature was stirring, not even a mouse;
The stockings were hung by the chimney with care,
In hopes that St. Nicholas soon would be there
The children were nestled all snug in their beds,
While visions of sugar-plums danced in their heads;
And mamma in her ‘kerchief, and I in my cap,
Had just settled down for a long winter’s nap
The use of sedatives for hypnotic purposes has been a source of concern for over a century. Initially the benzodiazepines looked like a step forward. They were sold as better hypnotics than older sedatives like the barbiturates. But combining benzodiazepine hypnotics with benzodiazepine anxiolytics from 1960 through to 1990 helped trigger the benzodiazepine addiction crisis. People were being saturated with benzos around the clock, making dependence almost inevitable.
Primary care doctors came under fire in the late 1980s, with threats of legal action against them, usually stemming from key opinion leaders (psychopharmapartialists) advocating the new SSRI kids on the block. Family doctors were encouraged to convert anxious patients (cases of Valium) into depressed ones (cases of Prozac).
At the same time, they were encouraged to prescribe the shorter acting Z-hypnotics rather than benzodiazepines. Even though Z drugs, zopiclone, zolpidem and zaleplon, act on benzodiazepine receptors, industry pretty effectively persuaded doctors they were entirely different to benzodiazepines. They aren’t.
Z drugs brought another set of problems. The benzodiazepine crisis mistakenly put a premium on shorter acting drugs. The Z drugs were much shorter acting. They helped people fall asleep but also woke them up again a few hours later – just as alcohol does. They also triggered sleep walking, sleep eating, sleep driving, and sleep homicide.
Z drug concerns opened a niche for Seroquel (quetiapine) – a niche that Mellaril (thioridazine) once occupied. Both are sedative tranqulizers, closely related to clozapine (which began life as a sleeping pill).
Mellaril killed many people by causing QT interval problems before its use was restricted and it was later discontinued. Seroquel and Clozapine also cause QT interval problems. One of latest concerns is that Seroquel combined with opioids may lead to premature deaths with a company whistleblower recently claiming Astra-Zeneca have known about this problem for years.
Another “fake” hypnotic option has been pregabalin and gabapentin. These drugs, which act on the same GABA system as the benzodiazepines, and are addictive, have crept into use as hypnotics on the back of their marketing for pain-management. They have a limited use in a small number of neuropathic pains but are now being prescribed widely in primary care for pain in general. As some patients seem initially happy when they take them, doctors have loosened up about using them especially at night when pain has been cast as one of the main reasons people can’t get to sleep.
This leaves us in an extraordinary position. Many family doctors react now with extreme caution when asked to prescribe a benzodiazepine. They only hand out homeopathic doses and refuse to prescribe for longer than a few weeks. This would be fine if they handled SSRIs, Seroquel and Pregabalin the same way but they don’t.
If forced to take diazepam, fluoxetine (or any other SSRI), or quetiapine (Seroquel), or pregabalin for a year, I would immediately opt to take diazepam and I’d imagine most mental health workers would too – yet this is the drug with the darkest reputation among both family doctors and the public at large.
Insomnia is not the same as sleeplessness. Insomnia is a complaint about sleep not a statement about how much sleep you aren’t having. The benzodiazepines bring this out most clearly in that people taking them report a better night’s sleep when according to sleep recordings they only fall asleep minutes earlier. They report getting up fewer times during the night but it seems they simply don’t remember getting up when they have taken a benzodiazepine.
The propaganda behind the marketing of hypnotics stresses that sleeplessness kills – both physiologically kills and in practice kills because we make mistakes. The captain of the Exxon Valdez was supposedly over-tired when he crashed the tanker leading to the worst oil spill before Deep Horizon – some of whose crew were probably missing sleep also or maybe on pregabalin.
But missing sleep and functioning for over-extended periods of time is not the same as insomnia. Insomnia – the belief you are having poor sleep – almost cannot be cured with a pill.
Medication can sedate. And for millennia in the face of crisis, we have knocked ourselves out with substances and equally recognized that doing this for more than a short period of time brings problems.
Enter Stage Left
Suvorexant (brand name: Belsomra) is the next stanza in the Hypnotic Before Christmas. This new drug claims to help sleep by blocking the waking mechanism rather than by sedating.
Work on the basis of narcolepsy, as outlined in Pandemonium and Pandemrix and Pandemrix and Narcolepsy brought the existence of orexins to light. Suvorexant is an orexin receptor antagonist which has been approved for the treatment of “insomnia” in a range of countries from 2014 onwards.
In clinical trials participants in the treatment group were able to fall asleep 5.2 minutes quicker and slept 10.7 minutes longer than those in the placebo group. When suvorexant is taken daily, plasma level remains high even during daytime a few days after commencement.
At the moment we know almost nothing about its interaction with other medicines like antidepressants, benzodiazepines, anticonvulsants, antipsychotics or opioids – many of which are likely to be co-prescribed with it.
In addition to triggering arousal, orexins promote the growth of normal cells and inhibits the growth of tumor cells. Blocking it is tricky.
In clinical trials, drowsiness, memory impairment, parasomnias (nightmares, sleepwalking etc.), narcolepsy-like symptoms (including cataplexy, hypnagogic hallucination, sleep paralysis) and suicidal ideation all increased in a dose-dependent way.
Drowning not Waving
In clinical trials, there were more deaths on suvorexant than treatment as usual. One death in particular stands out – written off by the company as just a bizarre accident.
The woman in question drowned while swimming in the sea. There are a lot pointers in the case that what happened was she developed cataplexy – emotion-induced paralysis – part of the narcolepsy syndrome. This is the feature of narcolepsy that made it so hard to investigate the condition in dobermans prone to narcolepsy because the emotion of sex caused them to slump on the job – Pandemrix and Narcolepsy.
There are probably tons of other things about narcolepsy that will shed light on the effects of Belsomra and vice versa – effects of Belsomra that will shed light on narcolepsy. Our Narcolepsy sufferer in Pandemonium was almost as incapacitated by sleep apnoea as by narcolepsy. This was puzzling. Women are much less likely to get sleep apnoea than men. But the Belsomra trials threw up breathing problems including sleep apnoea, so this may be much more part of narcolepsy than we have previously recognized.
New Year Resolutions
It would be nice to think doctors would have a New Years resolution not to believe fairy-tales quite so quickly and not to leap on the next sleigh that turns up but unfortunately while they might wish it, this is a resolution that ain’t going to last more than a few days into the New Year.
When something strange happens to you on the latest new drug – if you start hallucinating reindeer – the first thing you should think is the drug caused it. And if your doctor says the clinical trials don’t show this happening, tell him you have some difficult news for him – there is no such thing as Santa.