New treatment for Depression: Nebulized Ketamine (NebKet)

By Brian Stanton, MD August 4, 2017

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Ketamine, a 60 year old drug long out of patent, has been demonstrated to be highly effective in treating Major Depression, a widespread and debilitating disorder. It offers a largely side effect-free alternative to chronic oral antidepressants which are ineffective in many patients and come with a host of side-effects. It is also a vastly safer and cheaper alternative to ECT, which is known to cause significant memory problems for patients.

After initial research at the National Institute of Health (NIH) and pioneering work at a handful of clinics using Ketamine infusions began about 10 years ago, thousands of patients have been helped by this simple procedure. Dozens of clinics are popping up around the country now helping to make the technique easier to access. That’s great news for the hundreds of thousands of still suffering victims of this disorder, but a new problem is now emerging which is a serious impediment to treatment. The problem is cost. Ketamine is not covered by any insurers for the treatment of depression at this time. The drug itself is ridiculously cheap at about $1 per infusion.

However, the cost of an infusion can be pricey and prices around the country can mysteriously differ by a factor of 10 or more. However, there are limits to how much the cost can be reduced in the current paradigm. The cost is in the labor and clinic space where a person can receive the infusion in a comfortable, safe and supportive environment and has staff with the clinical skills and equipment to administer IV infusions. That does not come cheap. Patients suffering from depression are in general not a wealthy group. How many can easily lay out $1000/infusion? The average patient is often in a state of financial ruin after years of difficulty maintaining personal relationships or even being able to hold onto a job.

I am a recently retired anesthesiologist who after 30 years of trying to convince people not to hemorrhage to death at 3 in the morning (and other assorted delights), simply had to slow down and leave this arduous work to more intrepid souls. I found myself still reading the journals and became fascinated by the new Ketamine clinics many of which are run by my brethren. One day I got an idea on how to deliver Ketamine to patients without an IV using an Asthma Nebulizer. I thought at first, this is a simple notion and surely others will take up this method, and prove its efficacy. However, my perusal of the websites for the various clinics has not shown anyone to date using the technique. Finally, I decided to try it myself by obtaining a nebulizer and trying it on some volunteer patients. The happy news is, as any anesthesiologist with a knowledge of pharmacokinetics might easily predict, it works. The implications for cost and convenience (which also translates into cost) is highly significant for this patient population.

A few words now about the pharmacokinetics in words I am hoping non-technical people will find easy to understand. The gold standard for introducing a pharmaceutical into the body is IV infusion and this certainly applies to Ketamine as well. An IV is placed in a convenient vein using sterile equipment and the infusion is performed by a precision computer controlled device, either a “syringe pump” or a “drop counter” as is frequently found at patient’s bedsides in the hospital setting. An exact number of milligrams can be set to infuse at a precise rate, usually tailored to the patient’s weight and health status. Control of the rate is important because overdose of Ketamine (which belongs to the hallucinogen family along with PCP, LSD, Psilocybin and Mescaline) can result in possibly nightmarish hallucinations in select individuals and should be assiduously avoided.

Standard Ketamine is dispensed in most hospital pharmacies to the Anesthesia and ER staff as an injectible liquid, containing 10mls of Ketamine 50mg/ml. When given IV a little goes a long way, and 1 ml (50mg) per session is usually sufficient for the treatment of depression when given carefully over a 45-60min infusion. If you take this same dose and give it in one shot to a patient, the drug becomes a powerful ‘dissociative’ anesthetic. Their eyes will glaze over, they will not respond to command or move for about a half hour. The reason Anesthesiologists and Emergency Physicians love this drug is that the drug has minimal effect on the patient’s breathing or blood pressure. This is particularly true of the sickest, riskiest patients e.g. trauma victims and women hemorrhaging while delivering their babies. It is because of this huge safety factor that Ketamine is used as an intramuscular dart to sedate wild animals like lions and tigers, since the animal goes into a trance like state with little danger to its overall health. I can only venture a guess as to what a tiger experiences when he emerges from the sedation wildly hallucinating, but at least he is alive and well, safely able to roam his forest again.

IV administration maybe the gold standard, but it comes with its own list of risks and complications. These include infection, hematoma, that is, continued bleeding from the vein under the skin after either ‘spearing’ the vein through when attempting to place the IV or later after removing a properly placed catheter from a vein that continues bleeding. Also, IV’s can be inadvertently disconnected with subsequent blood loss, infiltration can occur (where medicine is infused into the subcutaneous tissue instead of into the vein), and more rarely blood clots, nerve damage and thrombophlebitis. In addition, some patients are positively terrified of needles. Causing massive anxiety just prior to giving Ketamine is not a great idea since the drug is a hallucinogen and tends to ‘magnify’ the emotional state of the patient. Furthermore, there is a growing awareness in the medical profession that ‘veins are precious’. Huge numbers of patients are presenting in hospitals who have had multiple hospital admissions and thus multiple vein sticks, whose peripheral veins are now extremely fragile and limited. Any technique that can preserve the veins in these patients is highly valuable. This goes double for any patient with a history of IV drug abuse.

Other methods of administration are currently being offered at select clinics, each, in this author’s opinion, distinctly inferior to the IV method. These methods are Nasal Spray, Sublingual, Electrical skin patches, Oral and Intramuscular.

The nasal spray is a decent method that has the virtue of allowing patient self-administration but suffers from significant flaws. Absorption from the nasal mucosa is all over the map, irritation of the mucosa from frequent spraying results in nasal congestion and venoconstriction, resulting in highly limited absorption, plus the patient must hold the sprayer to their nose, squeeze it and inhale nasally at a consistent rate, which gets progressively more difficult as the sedation sets in.

Sublingual administration of Ketamine (putting it under the tongue) also suffers from wildly variable absorption rates as do Oral administration and Intramuscular (injecting it into a muscle). Variable absorption means considerable risk that the patient will either get too little over too long a time (leaving the patient only mildly affected over many hours) and therefore not get the therapeutic effect or far worse, they run the risk of getting all the drug at once and ending up like our ‘tripping’ tiger. IM (intramuscular) is an especially egregious method touted at some clinics, strictly for the convenience of the staff, and is in this author’s opinion, just plain malpractice.

As for patches and electrical skin patches, these devices use special patches and/or electrophoresis to deliver a drug through a skin patch. The devices are expensive and I do not have the impression that they deliver a sufficient therapeutic dose in the case of Ketamine, but rather appear to deliver subtherapeutic dosages continually over a period of days. This medium is typically used for and is more suited to delivery of birth control medications, pain medicines, and anti smoking drugs where low doses delivered essentially continually are required. Some clinics are using them to treat patients with Chronic Regional Pain Syndromes (CRPS) but I am unable to comment on their efficacy for that application.

Asthma nebulizers are simple, inexpensive devices used by asthma patients for decades to self-administer bronchodilators. The injectable form of Ketamine dispensed by hospitals works just fine in a nebulizer, converting it into a potent mist. Imagine if Asthma patients had to go to a clinic for an IV infusion, every time their asthma acted up. For that matter, there are many other classes of patients who can be quickly trained to monitor their glucose, administer insulin, do special exercises, change their own dressings etc. I believe Ketamine can easily be adapted to this approach by treating patients in clinics, training them to load the drug into the nebulizer and self-administering on perhaps a once-per-month basis.

So why am I writing this article specifically for a non-medical audience? It is because my volunteer patients are now calling me and saying that they can’t find physicians willing to prescribe this widely available, inexpensive and effective treatment. Physicians are a scrupulously conservative group and this is a new use for an old drug, which has no backing from a pharmaceutical manufacturer. Some patients have said their doctors refused to prescribe because the side-effects are unknown. This argument is just silly. There is no known lethal dose of Ketamine. Contrast that with drugs like narcotics or insulin which can easily kill a patient if the drug is either abused or a miscalculation is made. Self-administration by nebulizer of Ketamine is not going to be a big money maker for any drug company (Ketamine is cheap and long out of patent) or for the average doctor. However, if some intrepid Physicians, CRNA’s, APRN’s or PA’s out there with prescribing power start writing these prescriptions, they might find it to be a very nice supplementary income stream. E.g., charge $50/visit for checkups and renewals without any of the expense and heartaches associated with filing with insurance companies, and avoid the risks, time and expense of IV infusions. Collect 1000 patients and bingo, nice income stream. Initial sessions should be conducted under the auspices of the clinic setting, with patients self-administering in their homes after that. My fellow physicians, I implore you to please take up this practice for obvious ethical reasons as well as buttering your own bread a bit. Its a win-win for everyone.

For self-administration, obtain a stand-alone nebulizer unit. Stand alone meaning not hand-held. Instead, the device sits on a table top with some plastic tubing leading to the nebulizer chamber, which is attached to a plastic mask that you place over your face and fix in place with a bit of elastic. Ketamine is highly sedating and you cannot be expected to hold anything up to your face for the whole session. Safety wise, if you feel that the strength is a bit too much for you, you can simply pull the mask off your face. The nebulizer technique is quite wasteful of the drug compared to the IV technique, using about 5 times as much Ketamine. This is because much of the vapor is expelled to the room and thus not inhaled. I recommend trying to breath by mouth and avoiding nasal breathing as much as possible as Ketamine can be absorbed into the nasal mucosa and then slowly absorbed, lengthening the recovery time after a treatment.

The procedure has a huge safety margin compared to other methods, including IV infusion. All other methods can lead to a scenario in which the entire dose is delivered at once, a highly undesirable outcome even if rare. The nebulizer can only hold about a 50-60 min quantity (about 10mls), so the session is automatically ended when the drug runs out. Plus, as previously stated, patients can simply pull the mask off or turn the switch off on the device to limit further absorption if need be. In order to get the liquid out the glass ampule, patients will also require a 10ml syringe and either a needle or even better, a needleless cannula that prevents the user from accidentally sticking themselves. Ketamine wears off fairly quickly after a session, but I strongly recommend emptying your bladder just prior to a session as Ketamine seems to make people want to pee, and you should plan on sitting in your chair and NOT WALKING for at least a half an hour after a completed session. Ketamine causes profound ataxia resembling alcohol intoxication and can cause you to slur your speech and stumble like a drunk. Ideally patients would be best off to have a friend or family member present to observe and assist. Patients should absolutely not drive or operate machinery for 3-4 hrs after a session. However please feel free to invest in the stock market, as you won’t possibly be any stupider than the current population of investors.

I have noted a few mild disadvantages to the nebulizer technique. It requires about 5 times as much Ketamine as the IV, increasing the cost from slightly over a dollar to about $6. The onset of effect is slightly slower than IV (perhaps 4-5mins). The recovery period is longer, about 10-20 mins longer. Patients will ‘taste’ the ketamine which does not occur with IV (an slightly unpleasant medicine like flavor hard to describe) and little droplets can form on your nose, so you may want to have a hanky handy.

Any discussion of Ketamine invariably brings up Ketamine’s reputation as a drug of abuse. Ketamine is used at concerts and raves and has found application as a date rape drug. It is easily obtainable on the internet and from drug pushers of various stripes, and this association has tarnished the drug’s reputation. This is of course true of other legal and highly useful drugs such as narcotics, benzodiazepines and Propofol (one of the most widely used drugs in Anesthesia which became famous when it killed Michael Jackson). It should be noted that the dosages used for the treatment of depression are minuscule compared to what interests abusers, and that black market prices are actually vastly cheaper. This is why Ketamine clinics do not appear to attract people with nefarious aims as the doses and costs render them useless to that population. Unfortunately, the often high cost of legal Ketamine is driving patients to the black market. However, snorting or swallowing illegal rave drugs doesn't produce the same results as Ketamine infusions and also is associated with the risk of buying a drug of questionable quality under risky circumstances which may be cut with some other substance, or not even Ketamine at all. Ketamine makes people feel incredibly weird. The patients that benefit from Ketamine do not appear to ‘like’ the experience, but rather endure it for the sake of the substantial therapeutic benefits which typically kick in within a day or so of treatment.

To summarize, this author is suggesting to patients, physicians, clinics and medical and pharmacy boards around the world to seriously consider this alternative method of Ketamine administration which avoids the risks, costs and inconvenience of the IV method while delivering an almost identical benefit.

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