Ketamine and Cluster Headache

Brian E McGeeney, MD, MPH, MBA

What is ketamine?

Ketamine was introduced into clinical practice in 1964 as an anesthetic. Ketamine was found to induce analgesia (relief of pain), amnesia and at a sufficient dose to induce loss of consciousness. The term dissociative anesthetic is used to describe ketamine and refers to subjects who appear awake but not responsive to sensory stimulation, while maintaining breathing. More modern anesthetic agents have taken over from ketamine, although it is still used in veterinary medicine. One major difference between ketamine and opioids is ketamine does not inhibit the breathing drive. Most of the opioid related deaths occur because of inhibition of the unconscious natural drive to breathe.

What evidence is there about use of ketamine for cluster headache?

There are no controlled studies and no official recommendations. Therefore we form hypotheses about usefulness or not from individual experiences. Such conclusions do not constitute proof but can be compelling. Based on my experience for years I am convinced that ketamine nasal spray (KNS) is a useful second or third-line abortive agent for individual attacks of cluster headache (CH), with a possible role in prophylaxis also. Many patients using KNS notice a reduced frequency of attacks.

Does my doctor need a special license to prescribe ketamine?

No. Most physicians have the standard DEA license which covers schedule 2-5 drugs including ketamine. Every physician can prescribe, whether they will or not another matter.

Is ketamine a controlled substance?

All medications that require a prescription are ‘controlled substances’. From the Controlled Substance Act 1970, medications are grouped into 5 different Schedules reflecting their purported medical usefulness and potential for abuse. Schedule 1 substances cannot be prescribed, and Schedule 2 agents include the standard opioids such as oxycodone, morphine and stimulants like methylphenidate (Ritalin). Schedule 3 medications include ketamine and this schedule allows refills. Some countries control ketamine like opioids.

Is nasal ketamine available at street pharmacies?

Up to 2019 the answer was no. In March 2019 the U.S. Food and Drug Administration approved Spravato (esketamine) nasal spray, in conjunction with an oral antidepressant, for the treatment resistant depression in adults. Molecules of ketamine (like many molecules), exist structurally in 2 forms, mirror images of each other. Esketamine is one of these forms. Hence esketamine is ketamine. Spravato costs about $5,000 for the first month, and $2,500 a month thereafter and would not be covered by insurance for cluster headache (and likely difficult to get covered for its indicated use also). This is the only form of ketamine that a typical street pharmacy would have, whereas KNS from a compounding pharmacy would be $100 a month or less.

What is a compounding pharmacy?

The main function of compounding pharmacies is to provide drugs prescribed by physicians for patients with needs that cannot be met by commercially available drugs. Medications which are available are formulated in ways which are not commercially available, such nasal sprays, suppositories etc. Strictly speaking there is no commercially available nasal ketamine, only esketamine! Not all compounding pharmacies will work with ketamine due to its Schedule 3 status, but most will.

What about IV infusion of ketamine?

In recent years there has been a great expansion of clinics offering intravenous infusions of ketamine for depression. This is much more costly than KNS and is not going to be covered by insurance for CH (and often not for depression as well). Further, the clinical experience is more profound, and can be anxiety provoking unless anti-anxiety medications are given (benzodiazepines).

What is the addiction potential?

Ketamine like many medication can result in overuse, and use despite harm. The risk of this is clearly less than opioids but remains possible with all people, especially those who are abusing other drugs.

What are the side effects?

Ketamine has a wide margin of safety. Caution is advised with all medications that can cause drowsiness. More than 20% of people who use ketamine for recreational purposes are estimated to have urinary tract symptoms but this is much less common in those who use ketamine for medical purposes only. Cases of ulcerative or interstitial cystitis (bladder inflammation) have been reported in individuals with long-term abuse of ketamine. A high KNS dose in excess of what is needed can induce distortion of time and space, hallucinations and mild dissociative effects. Even larger doses result in a more severe dissociation commonly referred to as a ‘K-hole’, with intense detachment. Most people would dislike these effects.

What should a prescription for nasal ketamine for cluster headache say?

Besides stating ketamine nasal spray the prescription should state the concentration, volume and administration instructions. In my practice for a long time I used 50mg/ml (40 mls volume but can vary), with 2-3 sprays each nostril for relief of a cluster headache attack, every 8 hours as needed. Many patients who successfully use KNS need to use more sprays and I now feel that a more concentrated solution is likely better such as 75mg/ml or 100mg/ml. Most of the ketamine is broken down by the body before reaching the bloodstream. Of note each Spravato device for depression delivers 2 sprays only and the concentration is 140mg/ml.

How do I bring this up with my doctor without appearing to be a drug addict?

Well, are you? Asking your provider what they know about the use of nasal ketamine in CH is a start. You could ask them to look into it. A good option is to bring along an article which covers this use (see references).

Do I have to stop other medications?

No. Typically medication adjustments are not needed.

How do I use nasal ketamine for cluster headache?

Administer sprays to both nostrils at the onset of an attack. Both nostrils are used as the medication works by getting into the general circulation not by local action. The user needs to practice and fine tune dose to effect. Cessation of an attack requires less than the dose required to become very drowsy or go unconscious! Nevertheless, one should not drive or operate machinery after dosing, with a preponderance of caution. Many patients notice that ketamine has a prophylactic affect as well. Tolerance develops rapidly, meaning with repeated use the clinical effect lessens. For this reason I require patients to give themselves holidays from KNS, such as one day a week and one week a month.

Can I use sumatriptan, oxygen or other abortive treatments if I use ketamine nasal spray?

Yes.

How dose ketamine work, if it does work?

Ketamine in the blood rapidly finds its way into the brain where the important actions occur. We have known for a long time that ketamine causes a blockade of the glutamate N-methyl-D-aspartate (NMDA) receptor which is widely expressed in the brain. There are also other effects on different receptor families. Interestingly ketamine was first synthesized as a replacement for the related compound phencyclidine (PCP, ‘angel dust’). The important sites of action in connection with CH are not known. Cluster headache is a brain disorder and there are likely multiple pharmacological opportunities to break an attack with medications that act broadly on the brain.

References

McGeeney BE. Cluster Headache Acute Therapies. Practical Neurology May 2019. (includes ketamine nasal spray)
Winstock AR, Mitcheson L, Gillatt DA, Cottrell AM. The prevalence and natural history of urinary symptoms among recreational ketamine users. BJU Int 2012; 110: 1762–66.