Help with Amitriptyline & Ketamine Cream

I am trying the compounded Amitriptyline & Ketamine cream. My doctor said I can use it up to six times a day. However, it isn’t practical for me to use it on my hands during the day because I am afraid to touch anything and leave residue. My hands are so much worse at bedtime anyway, so I put it on before I go to bed. But I have some questions about this cream and am hoping some of you with experience can help me.

  1. Is it supposed to provide immediate relief, or is it a gradual relief? I am finding it difficult to tell if it helps me or not. There is definitely not an immediate relief for me. Maybe it shortens my flares, but I am not really sure of this.

  2. Does the cream help any of you when you are cold, or is it just to be used when you are having the hot flares? I don’t think I have Raynaud’s but my hands and feet do get icy cold at times. They are sometimes blue but never white. Sometimes they are icy cold but they look red hot.

  3. Is it possible that just using the cream over a few days or weeks on a regular basis will help prevent flares or at least help to manage your pain level? If so, then how often should I apply the cream and for how many days/weeks?

I was really excited about trying this cream, but it’s so expensive and not covered by my insurance. I am just trying to decide if I should stick with it or move on to something else.

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i didn’t have any luck with compound topicals. i believe my freezing and burning are deeper than a topical solution.

your pharmacist would be better able to answer this for you.

i don’t believe it was meant to prevent flares.

I have just ketamine 10%gel. It does work well to calm a flare and reduce pain for me. It is not ment to prevent flares. I let it soak in for 5-10 mins and then I can wash my hands if needed. Washing after it has provided some relief does not diminish results. I use a small amount, more isn’t any better then enough to cover area. My gel doesn’t spread easy, so I put a bit of lotion on at the same time.

The cream is meant to reduce flares. Amitriptyline is both a sodium channel blocker and serotonin antagonist. If your EM does not come from either of these problems then it will not reduce flares, however, the ketamine in the cream will reduce the pain during flares.

In one of the Mayo papers on amit/ket topical, it reads

"Although we expected no effect on the other manifestations of erythromelalgia, specifically the redness and high temperature of the affected limbs, 2 patients [out of 5] noticed improvement in those symptoms also, possibly through a decrease in neurogenic inflammation or modulation of efferent nerve fibers to skin vessels (or both). "

It goes into detail about the proposed anti-pain mechanism of the ket / amit topical.

I did very badly with 10% ketamine + 2% amitriptyline. I found lower percentages to be better, and actually did better with just amitriptyline. However for me there is a period of burning before the (partial) pain relief so in the end I scrapped it to focus on oral medication. It sucks that these compounded creams are $. I wanted the topical to work very badly!

btw, like therese, i too mixed it with a lotion to help it spread.

When I used it I had some kind of allergic reaction as it caused the worse flare of my life and destroyed the skin on my feet. My understanding is it is supposed to be mainly a numbing cream.

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Here’s what I can tell you from my mom’s tests. But she may be different. First I have a theory that Antagonistic effects of Risperdol caused my moms EM. We know risperdol affected and caused her problem, but we are not sure my serotonin theory of how the antagonistic effects of the Risperdol was the cause or if it was something else. That is my theory not necessarily upheld or agreed to by any doctor. That being said, Amitriptyline does effect Serotonine six of the seven receptor sites which are affected by Risperdol with it’s own antagonistic effects. (those seven sites control things like temperature regulation and blood flow and vascular constriction, you can look up the side effects and see them listed in Wikipedia.) Amitriptyline used in the mix to lesson the reaction you may get from the Ketamine which can be considered a very risky drug. Some a very few people who have EM claim Amitriptyline caused their EM, or made it worse. So although it’s being used to lesson psychological effects of ketamine it could be an added risk factor. I think the slight burning some experience with this mix is from the Amitriptyline working the Serotonin receptors like Risperdal did on my mom. I firmly believe that Risperdal is dangerous for some people and will give them EM and Amitriptyline may almost be as bad, but may be more reversible. I believe if they can damage nerves and affect you’re feet by producing flares you should stop taking those nerve medications immediately to avoid any further or worsening EM damage. (JUST MY OWN non-professional warning.)

My own theory, not a medical person theory, mind you but it’s just mine, is that the Amitriptyline may cause a partial flare before the ketamine kicks in. If you feel warming, that’s a bad sign for you’re condition in my “NONMEDICAL” opinion. Ask your doctor, and confirm any treatment step, remember all the usual disclaimers apply to my post, I’m just a caregiver.

As far as the Ketamine, it’s used to control pain and stop the pain. It actually is a tranquilizer but may have mental side effects so if you suffer from some kind of mental illness, like Manic Depression, it can lead to manic episodes. Low topical doses in studies may not even be measurable in the blood stream which means low doses of Ketamine may not have much effects on your mind, so that may make them less risky as a topical dose for EM folks.

The Tricyclic antidepressant effects of amitriptyline is being used to moderate possible psychological effects of the ketamine, that’s why they mix it in. My mom only tried the mix of both at the lowest doses three times as a mixed cream.

She cannot use cooling Gel based creams that hold in heat and cause flares but she can use some creams. So I took a cream she could use to the compounding pharmacist and asked him to use a base like that for her Ketamine cream test doses and he did.

She used a cream that matched the cream formulation in Camile Beckman’s French Vanilla cream, in other words a non-greasy cream, not a gell or something that will retain heat. The compound pharmacy can decide what base to put the medication in.

Most people in test studies that tried the mixture had better results with larger doses, but often smaller doses or the smallest doses are tried at first. Some compound pharmacies try to start with a large dose.

My mom got good results after both feet had the cream on the first time. She felt warmth but had other side effects from the Amitriptyline that matched the side effects it might give like heart rhythm things and other shacking which she didn’t like and one nightmare. But I realized her side effects were likely more from the Amitriptyline than the Ketamine. So I convinced her doctor to try prescribing a cream that only had Ketamine in it. She takes Ativan as well which is a nerve pill but she takes it for pain, so that might help her possible mental reactions, at least that was my hope. And she had less side effects without the amitriptyline in the mix, but she had other side effects which was a loss of some muscle control and more shakiness in her walk and gate. So we stopped it after three test doses.

For my mom’s condition flares still occurred but the pain and effect of them was greatly reduced. The first doses were more effective but she may have developed a tolerance to them (which may seem unlikely but it’s possible, our test was short). You have to bear in mind Ketamine will enhance the effect of other opioid pain killing drugs and make them more powerful. It will cause an additive effect and mom was also on Fentanyl and Norco when using the cream so those pain medications were multiplied with the Ketamine cream. In her case recovery from a flare was more like 10 minutes in cool water vs an hour without the cream.

In her first tests she said her pain went down to a 3 level and was so low she didn’t notice the pain. In her case she still had flares, but the pain from them was reduced. Chilling was required to bring the swelling down even with the ketamine cream, but flares were controlled faster.

I’d estimate the pain killing effect with the 0.5% ketamine cream was probably equivalent to having something like a 250mg fentanyl pain patch on, which of course would never be acceptable and cause heart failure and death. My mom had as much as a 100 mg pain patch in the past which was to much for her. She had 75mg which was quite strong (this with norco or vicodin in the past.) But she was on 50mg pain patch when she did the ketamine cream tests. They were as effective as a tibial nerve block with lidocaine which is a localized pain block test she also tried with foot doctors. The ketamine cream for her was as effective as a surgical injection of lidocaine to numb the foot which we also tested.

She said the Ketamine was in a completely different class than the Fentanyl , norco 10/325 and Motrins which she normally takes.

Mom’s tests failed as far as being able to use the cream long term. We decided to try it the second time, because of the first tests being so effective. We had less side effects but the side effects of her seemingly being weaker and less able to walk was a concern for us.

The Ketamine however is also used in some cases as a way to get people off Opiods by some doctors. It’s rare and barely used on humans now because of the risks of it. Being related to PCP and LSD has it’s drawbacks. It’s used more as a tranquilizer for animals than humans now. The ketamine as a cream may not enter the bloodstream as much as an injection would which is what those who are getting high are doing, they are ingesting the ketamine in some way. The ketamine tropically won’t enter the blood stream as much, but in some tests higher doses would enter the bloodstream in measurable amounts and that might cause more side effects. I’d say in general from what the doctors told us, for my mom, starting out with a lower dosage is a more cautious approach and probably a better way to approach it. A lower dose version may cost less as pharmacies are charging by the amounts of drugs being required to put the medication together.

The Ketamine opiod reset effects lasted perhaps a month or two from the first test making moms other opiod drugs more effective and hitting her pain harder, also causing more drowiness side effects as they are stronger now to her. After the second Ketamine cream test, still 0.5% but only that in the cream her opiod tolerance was reset and it seems to me that it was a permanent reset in that the pills now hit her harder. This was a good side effect in my mind as far as I can tell. At least it made the need for opiods now be reduced. We have not reduced her overall dosage on opiods since the test as far as max that can be prescribed but we have thought about doing that a few times. She ends up taking fewer doses. She also dropped weight to 113 from 145 since a hospital stay in the last few years. So being lighter in weight the opiod drugs may hit her harder so it’s hard to quantify in a purely scientific way how much the Ketamine “reset” helped vs weight loss.

Mom is 80 years old now and has had EM since 2002. The Ketamine cream doesn’t cure the EM, but helps you deal with the pain. It’s important to take any side effect seriously and use caution when trying these new drugs which are not widely used. This of course is my lay advice as a person and caregiver. I’m not giving medical advice but sharing our experience.

My mom also takes half doses of her pill prescriptions every 4 hours instead of every 8 hours. This doubles the hassle of taking pills but it provides perhaps a little bit of protection against overdose in the event she forgets and takes a second dose. That is probably a good thing to think about if your taking opiods, as opiod overdose can kill people.

She takes them to have the pills not hit her as hard, but the half dose idea to me seems to be a good idea for added safety as well. I hope this helps a bit.

I also want to say my mom did get excited a bit with the first test of ketamine cream and felt it was very close to being a cure. She was planning on doing all the things she felt she could not do, which was a good sign. Her chattiness and positive feelings was a little manic however and it could have been a mental side effect she was getting from the mix. That wasn’t to bothersome to us, and those times of discussion were about 10 to 15 minutes max. She was excited with the progress, but wasn’t super mobile from the results she got more sleep. She did go out and after the first test, she claimed her feet felt like they were coated in varnish. She also said her feet felt like they were in a state of ephoria. I have never heard of someone saying their feet felt “high” before this.

So that was some of her side effects, some good some bad.

Profile of ketamine isomers: anaesthesia and analgesia
Ketamine consists of 2 isomers, S(+)‐ketamine and R(–)‐ketamine with comparable pharmacokinetic
profiles, but different clinical effects. The anaesthetic properties of S‐ketamine have been described
to be 3 times more potent than R‐ketamine.7 Equianaesthetic doses of racemic ketamine, S‐ketamine
and R‐ketamine have different side effect profiles. S‐ketamine produces significantly less agitation,
disorientation, pain, and anxiety; R‐ketamine gives significantly less nausea and dizziness.7 Rketamine,
compared with S‐ketamine leads also to more rapid recovery of psychomotor skills.8
Analgesic effect of S‐ketamine is approximately 4 times more potent compared with R‐ketamine.9 In
equianalgesic doses intravenously, proprioceptive disturbances are reported twice more frequently
after administration of S‐ketamine compared with R‐ketamine, in chronic pain and experimental
pain.9 10 11
For anaesthetic purposes, the side effect profile of S‐ketamine seems preferable; for the
management of pain, subanaesthetic doses of R‐ketamine seems superior.

Wanted to include this quote from a study which was done about ketamine cream. It seems there are two types of Ketamine. One is better for chronic pain, the other may have less side effects. What I found interesting about the study is it mentioned this, but when I talked to the compounding pharmacist he had no idea which kind was being used by the pharmacy. Didn’t know if it was one type or the other or if the two kinds were actually mixed in the ketamine he used. I found that to be interesting. Apparently the study may have more info from the companies that produce the stuff than what your local pharmacist may have.

I have been on this for about 2 yrs now. At first it helped for about 2weeks then it did nothing but sometimes made it worse so my pharmacist added lidocaine and carb (not sure how to spell it) and that helped for 2-3 weeks then stopped. He then makes it in a liquid for that I apply with an eye dropper (this works well for me). In my case he has to alternate and be creative every month. Like for example just make ketemine and amytriptyline. Then next time add lidocaine and vise versa.
I apply this on my feet and I don’t like it cause it’s sticky and dirt attaches easily. I wear flip flops all the time. Oh I almost forgot to mention…my pharmacist has also added a compound of asprin 10% cream. Believe it or not asprin is a antihistamine and antihistamines help with redness and swelling. So far that’s been helping out quite well.

I know you said it was on cream, but did the article state that or was it just on ketamine in general. Many of those side effects would not come from a topical cream but rather if taken systemically. Technically they are the same, they are enantiomers of each other, same chemical twisted in a different way. I think they both would help but I think that if the cream really works, it might be due to a strong response to amitriptyline as it has sodium channel and serotonin blocking properties. It would be interesting to see how people who get relief from the cream respond to just amitriptyline. It would also help with insurance purposes.

Yes that is correct Joe. Many of the sideeffects are seen when the ketamine is measurable in the blood stream and often that is not the case with ketamine when it’s being put on as a cream.

The amitriptyline has been used by some perhaps along with other medications as well to be added meaning they took it perhaps in oral form and it either helped or had no effect or made it worse. Sometimes with EM when we look at the seemingly true raw stats of what people report about 1/3 will respond positively or negatively and another 1/3 will have no response to any single treatment. In theory according to medical literature from neurologists for example if the cause is not known the treatment may be very different for different rare diseases. So as different people may have different manifestations and causes or unknown causes there is no one solution that solves all the EM problems.

Ketamine can seemingly be applied topically with less side effects but it was reported as more effective for some em patients in at least one test group when it was strong enough to reach the blood stream.

Amitriptyline as a help or cure for EM I should really say just something to help it alone would actually be a different topic. Not to split hairs but it would be working on someone em symptoms in Peoria oh a much different way and I believe it is not being used in the cream mixture of ketamine and amitriptyline as a pain killer at all. It’s being used to reduce psychiatric reactions one might have from the ketamine because ketamine can give a person a high or a bad trip.

Ketamine likely won’t give bad side effects as a cream for most doses according to the study it said it would be a very reduced risk. To a normal person however a doctor would say be careful and don’t apply it on someone and touch it, because you don’t want to get it. Some doctors may be very wary of ketamine and say don’t touch the cream at all if your applying it to a patient.

I think there are two different kinds of EM generally. This is my own 5eory of course and there are probably many kinds of it as it can be related to many kinds of neuropathy or mixed neuropathy prob,EOS and there are a hundred kinds of neuropathy in theory everyone in the world could potentially have a different mixed version of poly-neuropathy and no two might be exactly alike.

For me and this is my layman theory as a casual observer there are those who get EM but have mixed symptoms with other nerve problems or something else which causes flares but also may cause a time when flares are not present and feet or hands may even be naturally cold. Those kinds of EM patients have an EM flare but also other problems and the EM flare may even be temporary. An example of an EM flare which may be temporary would be an EM flare that a diabetic would have. They may have EM flares as nerves are dying from lack of blood as capillaries are filled with sugar residual or sticky plaques to put it in layman’s terms. As they lose nerves the nerves die and their body will react and flares may happen. But over time their small fiber nerve death causes the foot to go completely numb. They will eventually still have flares and swelling because the body default response to not knowing if something is going on wrong like no nerve feedback is to send more blood to heal the injury. So they will have swollen and horrible looking feet but they won’t feel it because the feet are numb as the nerves died.

Then there are those with mixed ailment problems they may have neuropathy and Reynards syndrome. They will get em flares perhaps but also have cold chilled feet and hands. Their disease may cycle and the EM component may be a mystery to them.

I think people with mixed symptoms often benefit from aspirin tramedol therapy. They may respond well to those therapies.

Then we have some who have EM flares and only EM flares. They never have cold feet normally. Or feel that their feet are normal. They may actually have normal foot and skin temperatures if you measure it but they feel like the foot is burning and swelling may result as the body tries to send more blood down there. They may not have any circulation problems and blood flow and heart issues are not a problem. They just have a kind of pure form of hot flare o key EM. In theory according to doctors if heat is added to the foot for burning foot flares will happen and pain will be worse. And the only thing to remove the flares is environmental chilling of the feet.

The medicine helps you feel a pain reduction but only environmental chilling will help. But in some cases perhaps people are push8ng their em around with other medications that trigger Reynards like symptoms. The people with pure EM or only hot EM flares and no mixed symptoms will not respond to aspirin or trmedol. This of course is only my theory and guesswork. I don’t know that I have enough data to verify this and it’s only a guess.

I have another theory at least for my mom’s version of EM but I don’t know if it’s really proper or even a good one and that is the sensitivity of the scale of her temps are out of sync with the reality because many nerves have been damaged and the brain is making up signals that aren’t there and rescaling the network. Kind of like losing say 90 percent of the resister leads in a volume control. The brain may remap the few remaining nerve impulses that are received and only a few say one may act like ten signals being fired off. But the other nine nerves are gone. If the brain is guessi)g and remapping it would be like a broken knob or volume control on an old radio that goes from level 1 volume abruptly up to level ten with hardly any volumes in between.

If the EM patient brain is making up signals and remapping the signals lost then a small brush against one nerve might trigger a kind of small fiber neuropathy overreaction like ten nerves we struck.

This of course is just a theory but it may be why my mom often says her pain is level seven or level ten. She doesn’t say other levels are being felt because her pain volume knob is broken to use a broken radio analogy. How can one help someone with dead or permanently damaged nerves?

Some think nerves can be rebuilt and fixed maybe giving them high doses of cynbalts will help may be the guess of one neurologist willing to give it a try. Others may suggest neurontin. It becomes a kind of trial and error guesswork thing.

In theory the neurologist can figure out and find out the best way to treat nerve damage but it doesn’t always work out.

I think some maybe a very few maybe less than 1 percent may get em from pills like amitriptyline or Risperdol. This because of 5ht receptor damage. But this may not be the problem most em patients face.

A path many tasks is aspirin trmedol.

Then opioids, maybe Effexor, amitriptyline, neurontin, lyrica which is neurontin once it’s processed but has more dosage levels and finally other therapies like ketamine when all others have failed.

Ketamine orally is for more severe cases of pain for people like cops type 2 or what used to be called RSD. They may used or try ketamine therapy which is very dangerous and experimental in an attempt to do a ketamine coma reset of their brain.

We are not talking about taking ketamine orally for EM. People who get ketamine in other ways either got it for operations in Vietnam during the war or for other diseases which gives more severe side effects because it’s hitting the brain harder being in the bloodstream.

We don’t want to go there that’s for sure.

It’s also important to note than compounding pharmacists can work for companies and be of a mind to try more and experiment more. They may add all kinds of mixtures to a compound. Many medical doctors will be very wary of doing that. They may take a conservative approach.

So my summary is to be careful and watch out for side effects. I’m. It saying you should not try to find out and suggest new things to try to the doctors but remember some medications can have very severe side effect and make the EM even worse.

As one neurologist said to me. We have to be careful of this medication referring to mom’s opiods, “because one of the side effects is death.”

There are literally millions of people with burning feet flares which may be just temporary or due to diabetic diseases. I think many of the marketed stuff pushed toward them like nerve renew stuff won’t likely help a person with just EM flares. A lot of stuff is unknown and some of my thoughts indeed many of them are just my opinions so people have to discuss this with their doctors and likely go through a long slow process to figure out what best works for them.

I’ve also not mentions mexiletine which helps some who havethe genetic form of em. That often requires a lack of opiods and is given in heart cardiac doses to work with EM but may be given in much smaller doses for neuropathy which won’t help most em patients. The higher doses of that heart medication have to be monotored often in a hospital setting and the patient may have to be off all opiods to take that drug. That is also a path some with the genetic version of EM end up on.

It didn’t work for me, it kind of burned. I use 10% Lidocaine from compounding pharmacy, it helps me quite a bit.

Sharon - how long does each application last? Thanks.

Thanks everyone for the replies. I guess I will give up on this cream because I just can’t tell that it’s helping.

Ketamine doesn’t cause euphoria or mania. It’s a tranquilizer. When taken systemically it creates a dissociative trance like state. (I may know this from experience as a teenager. :joy:)

Ketamine in a sufficient dose causes the exact opposite of mania — profound impairment that makes you temporarily unable to interact with others or the world around you.

So any euphoria was not a side effect of the cream directly. It may have been amplifying the opioids, as you said.

Very interesting. Thanks for the info.

Hey Marci -

Not sure how long you tried it. Remembered this post -

“I tried the ketamine cream a few years ago and it didn’t seem to help. But I didn’t try for as long as you did [10-15 days]…so maybe I will give it another try! Thanks for posting this information.”



Obsessive Googler

@watchman I do a lot of research. Being a person with mixed complicated diagnosis of nephropathy, neuralgia’s and vascular dysfunction. I believe your observations are accurate. I do benefit from Tramadol. So far has been the best Sodium Channel Blocker I have currently available to me and functions for pain control. The addition of topical Ketamine gel 10%, antihistamines, Triamcinolone Acetonide cream (cortisone) .1% , plus cooling methods all help. My observation is that either rotating topicals or mixing topicals helps best. Not sure if this is because body finds a way around blocking pain signals or the mechanism of action changes. However I find both Aspirin and Lidocaine to be irritating.
Whats most concerning for me is circulation and blood flow issues. Not being able to exert myself or bend over with out throbbing lightheadedness. Heart rate increase and sometimes blood pressure increase. I have low blood pressure historically which has been an issue with vasovagile responses to high levels of pain. Feeling like I need to be working with a doctor that understands channelopathy.

I am waiting results of genetics testing for SCN9A gene mutations and will have a punch test preformed soon to check for Small Fiber Neuropathy.

I really need to find out what is Primary and Secondary to my current list of illness and chronic pain. Have always been chemical sensitive and have failed 16 medications. My Current doctors are not knoweledge able in prescribing Mexiletine; not sure If i would even tolerated it, so not wanting to fight to hard too for trial before finding out if I have IEM. Not sure how to not need pain medications like Tramadol for the trial either because I have a lot of different chronic pain and have not found other medications my body will tolerate. I did try LDN but failed for 2 reasons increase in blood pressure induced permanent migraine, Pain level increased, EM flares and Trigeminal Neuralgia flare.
Trigeminal Neuralgia
Occipital Neuralgia
Migraine Headaches
Allergies/Sinus Rhinitis - food, environmental
Neck Arthritis Degenerative discs
Raynauds Syndrome
Spondylothithis @L5
Fracture @L5
Foraminal arthritis and stenosis
livedo reticularis

Looking for help, and helping others with my story gives me a sense of purpose!
Thanks for sharing about your mom! She is lucky to have you!

I’m not sure how to answer this. I think it might be different for each person. I ran out of Lidocaine and was surprised how much my feet were red and burned.

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