Need Advice - Having Very Adverse Reactions to Promethazine (Phenergan)

[Wayne]

i was given Amitriptyline (Laroxyl), I was in a semi-coma for 24 hours (Although I did take only half the dose that was prescribed)...

A quick update tonight, which is just about the time I'm supposed to have all the Promothazine out of my system. Whether that's the case or not, I'd say I'm about 80-90% back (whew!), with various symptoms at differing stages. The most problematic at this point is the continuing tinnitus, which is only about 50-60% back. But I think it's realistic to expect more improvements. I'll likely update more tomorrow sometime.​

@pattismith, thanks for sharing your experience with Amitriptyline. In the past few days, I ran across the following snippet. I think what it says about Amitriptyline is the likely explanation for what you experienced all those years ago. Your story would seem to be another pretty loud warning for anybody with ME/CFS about anything that can create anticholinergic effects in the body.

I was taken by the cavalier attitude in the last sentence of the second paragraph. The first symptom that showed up for me was noticeable and unusual brain lapses; within about 20-30 min. of taking the Promothazine.

"Anticholinergic drugs work by blocking the effects of acetylcholine, a substance that transmits messages in the nervous system. In the brain, acetylcholine is involved in learning and memory. In the rest of the body, it stimulates muscle contractions.

A wide range of drugs—including tricyclic antidepressants like amitriptyline (Elavil) or doxepin (Deptran, Silenor, Sinequan)—have strong anticholinergic effects, which means they can have side effects like memory problems and confusion. These effects are more pronounced in older people, so these antidepressants are reserved for younger people.

The selective serotonin reuptake inhibitors (SSRIs), like citalopram (Celexa) and duloxetine (Cymbalta), are commonly used to treat depression in people of all ages. Some of them have stronger anticholinergic side effects than others, but over all they have a relatively low anticholinergic effect."

​

 

[zzz]

First of all, @Wayne, I'm very glad to hear that you're feeling much better. That was an unusually strong anticholinergic toxicity reaction that you had, especially from one dose of promethazine. Unfortunately, our sensitivity to drugs is all too common, and there was really no way you could have known ahead of time that taking one dose of promethazine would have that effect on you. Many, many drugs have anticholinergic activity, including virtually all antihistamines, but in most drugs the amount of this activity is quite low, and often unnoticeable.

As you pointed out, physostigmine is the recommended treatment for a severe anticholinergic toxicity reaction. Due to the strength of this drug, and the severity of the symptoms it treats, it is not recommended that it be given outside a hospital setting. Seizures can be treated outside the hospital with benzodiazepines, such as clonazepam, which would only be needed on a short-term basis. Physostigmine is generally used only if benzodiazepines are unsuccessful in controlling seizures.

Ingesting small amounts of choline or choline-rich foods can help reduce the symptoms of anticholinergic toxicity in many cases. However, there is a danger in ingesting too much choline, as excessive choline can result in the condition known as cholinergic crisis. Although cholinergic crisis is the exact opposite of anticholinergic toxicity, its symptoms are somewhat similar - this is known as a U-shaped curve. People who have autoantibodies to the muscarinic receptor have to be especially careful here, as it is very easy for them to switch between anticholinergic toxicity and cholinergic crisis. Both states can be fatal in the extreme, so it is important that if someone experiences a strong anticholinergic toxicity reaction or experiences a strong cholinergic crisis, help be sought immediately in the ER, unless the symptoms rapidly decrease on their own.

I should also clarify a bit about how half lives work. A half life is just the amount of time it takes half of the amount of a drug to be excreted from your system or metabolized into something harmless. As you can keep on dividing the number of molecules of a drug in half almost forever, it can theoretically take years before every single molecule of the drug is cleared from the body. For this reason, a standard rule is that 5.5 half lives is enough to reduce the amount of a drug in the body to an insignificant amount; after 5.5 half lives, only about 2% of the original dose will remain active, and that's usually not enough to notice. For severe overdoses, more than 5.5 half lives may be required. It is almost never necessary to wait that long before the drug's actions become unnoticeable, but it is good to know that that although the concentration of the drug in the system drops rapidly, it doesn't get cleared out completely in the short term. This is almost never a problem, though.

Determining half lives is also problematic because drugs typically have different half lives in the blood and in the tissues. The tissue half life is the most relevant, but it is also the hardest to determine. Many drugs list only a half life in the blood plasma, which often significantly understates the lasting power of the drug in the tissues. One source says that promethazine has a life life of 5 to 14 hours; another says 10 to 19 hours. Due to the fact that we tend to be more sensitive to drugs than most people, it's good to use the higher number to be safe. So if a half life of 19 hours is correct, then it will take about 104 hours, or 4 1/3 days, for the activity of the drug to drop into insignificance. Even then, 2% of the drug is left in the body, but that number continues to drop off with time, and should not be a problem.

 

[Wayne]

Determining half lives is also problematic because drugs typically have different half lives in the blood and in the tissues. The tissue half life is the most relevant, but it is also the hardest to determine. Many drugs list only a half life in the blood plasma, which often significantly understates the lasting power of the drug in the tissues.

Thanks @zzz for your comprehensive post with so much good information. I very much appreciated the insights on the half life of drugs in blood plasma vs. tissues.

I think this is reflected in my own situation, where my symptoms had improved significantly, but they actually regressed again a bit yesterday. My knee went out on me, and I wasn't able to do many of the things that were keeping me afloat, like walking, doing clay foot baths, taking plenty of charcoal, etc.

I also started going into a PEM episode, which I attribute to the "unnatural energy" I feel was being churned up by my misfiring neurons by the anticholinergic activity. The energy did seem to help me keep going for a few days, but eventually burned me out. I'm actually surprised I'm doing as well today as I am.

I was still having a very hard time yesterday with sleep, and decided I needed to try something to address that. I occasionally take a 1/4 tablet of Tylenol 4 (w/ codeine), and have noticed it helps me sleep, and grounds me in some interesting ways. I also had some clonazepam and valium laying around from years past, and wondered whether I should try a "speck" of that.

Being so wary of benzos, I decided on the 1/4 tablet of Tylenol 4. It turned out to be a good decision, and I was able to sleep much better (which is why I'm doing so much better today). But my dreams are still feeling very strange. And I wake with tinnitus being at its worst. The waves of anxiety that initially felt so crippling still come and go, but at a much lesser intensity.

So I do believe this stuff is still in my system, and am hoping to do a detox foot bath, castor oil pack, and other things today. I just ran across the following, which I think would be a VERY good thing for somebody to know who may be experiencing unexpected anticholinergic toxicity. I'm wondering whether I should consider this, given the end stage I find myself in. I might just give it another day or so.

"Physostigmine is one of only a few drugs that can be used as an antidote foranticholinergic poisoning. Nicotine also counteracts anticholinergics by activating nicotinic acetylcholine receptors."​

 

[Wayne]

The list below was from THIS ARTICLE:

We have identified drugs with high, moderate and low anticholinergic (AC) action in brackets. The greater the AC activity the more worrisome the cognitive impact. The rankings are somewhat arbitrary and controversial since some research categorizes these drugs differently. This is our best assessment at this time. It may change as better research is conducted.

• Amitriptyline (Elavil) [high AC activity]
• Atropine [high AC activity]
• Benztropine (Cogentin) [high AC activity]
• Chlorpheniramine (Actifed, Allergy & Congestion Relief, Chlor-Trimeton, Codeprex, Efidac-24 Chlorpheniramine, etc.) [high AC activity]
• Chlorpromazine (Thorazine) [high AC activity]
• Clomipramine (Anafranil) [high AC activity]
• Clozapine (Clozaril) [high AC activity]
• Cyclobenzaprine (Amrix, Fexmid, Flexeril) [moderate AC activity]
• Cyproheptadine (Periactin) [moderate AC activity]
• Desipramine (Norpramin) [high AC activity]
• Dexchlorpheniramine (Polaramine) [high AC activity]
• Dicyclomine (Bentyl) [high AC activity]
• Diphenhydramine (Advil PM, Aleve PM, Bayer PM, Benadryl, Excedrin PM, Nytol, Simply Sleep, Sominex, Tylenol PM, Unisom, etc.) [high AC activity]
• Doxepin (Adapin, Silenor, Sinequan) [high AC activity]
• Fesoterodine (Toviaz) [moderate to high AC activity]
• Hydroxyzine (Atarax, Vistaril) [high AC activity]
• Hyoscyamine (Anaspaz, Levbid, Levsin, Levsinex, NuLev) [high AC activity]
• Imipramine (Tofranil) [high AC activity]
• Meclizine (Antivert, Bonine) [high AC activity]
• Mepenzolate (Cantil) [high AC activity]
• Nortriptyline (Pamelor) [high AC activity]
• Olanzapine (Zyprexa) [high AC activity]
• Orphenadrine (Norflex) [high AC activity]
• Oxybutynin (Ditropan, Oxytrol) [high AC activity]
• Paroxetine (Brisdelle, Paxil) [low AC activity]
• Perphenazine (Trilafon) [high AC activity]
• Prochlorperazine (Compazine) [moderate AC activity]
• Promethazine (Phenergan) [high AC activity]
• Protriptyline (Vivactil) [high AC activity]
• Pseudoephedrine HCl/Triprolidine HCl (Aprodine) [moderate to high AC activity]
• Scopolamine (Transderm Scop) [high AC activity]
• Thioridazine (Mellaril) [high AC activity]
• Tolterodine (Detrol) [high AC activity]
• Trifluoperazine (Stelazine) [high AC activity]
• Trimipramine (Surmontil) [high AC activity]

Other Drugs that May Have Some Anticholinergic Activity

• Alprazolam (Xanax) [low AC activity]
• Amantadine (Symmetrel) [low AC activity]
• Baclofen [moderate AC activity]
• Brompheniramine [high AC activity]
• Carbamazepine (Tegretol) [moderate AC activity]
• Carbinoxamine (Arbinoxa) [moderate to high AC activity]
• Carisoprodol (Soma) [moderate AC activity]
• Cetirizine (Zyrtec) [moderate AC activity]
• Cimetidine (Tagamet) [moderate AC activity]
• Clemastine (Tavist) [moderate to high AC activity]
• Clidinium & chlordiazepoxide (Librax) [low to moderate AC activity]
• Clorazepate (Tranxene) [low AC activity]
• Codeine [low AC activity]
• Colchicine [low AC activity]
• Darifenacin (Enablex) [moderate to high AC activity]
• Digoxin (Lanoxicaps, Lanoxin) [low AC activity]
• Dimenhydrinate (Dramamine, Gravol, etc) [high AC activity]
• Diphenoxylate plus atropine (Lomotil) [moderate to high AC activity]
• Disopyramide (Norpace) [low to moderate AC activity]
• Flavoxate (Urispas) [moderate AC activity]
• Fluphenazine (Prolixin) [moderate AC activity]
• Furosemide (Lasix) [low AC activity]
• Hydrochlorothiazide (Esidrix, Dyazide, HydroDIURIL, Maxzide & literally scores of other medications for high blood pressure) [low AC activity]
• Loperamide (Imodium) [moderate AC activity]
• Loratadine (Alavert, Claritin) [moderate AC activity]
• Loxapine (Loxitane) [moderate AC activity]
• Maprotiline [low to moderate AC activity]
• Meperidine (Demerol) [moderate AC activity]
• Methocarbamol (Robaxin) [moderate AC activity]
• Methotrimeprazine (Nozinan) [moderate AC activity]
• Nifedipine (Adalat, Procardia) [low AC activity]
• Olanzapine (Zyprexa) [moderate AC activity]
• Orphenadrine (Norflex) [moderate AC activity]
• Quetiapine (Seroquel) [moderate AC activity]
• Procyclidine (Kemadrin) [moderate AC activity]
• Propantheline (Pro-Banthine) [moderate to high AC activity]
• Ranitidine (Zantac) [low AC activity]
• Solifenacin (VESIcare) [low to moderate AC activity; more research necessary]
• Thiothixene (Navane) [high AC activity]
• Tizanidine (Zanaflex) [high AC activity]
• Tramadol (Ultram) [low AC activity]
• Trihexyphenidyl (Artane) [high AC activity]
• Trospium (Sanctura, Spasmex) [high AC activity]

Here's a graph from a different website...

 

[Wayne]

Below is a link to a very good and comprehensive article on Antcholinergic Syndrome. It's fairly lengthy, and I only copied and pasted the "Treatment" section. I wish I had known about this treatment information 8 days ago when I awoke with all my severe symptoms, as the drug that antedotes AC Syndrome can work within minutes.

I'm still experiencing significant symptoms after more than a week now, and if I'm not substantially improved by tomorrow, I may look into doing an antidote with Physostigmine. It's apparently the only drug available for that purpose, though I'm keeping some kind of nicotine in mind as well.

ANTICHOLINERGIC SYNDROME: PRESENTATIONS, ETIOLOGICAL AGENTS, DIFFERENTIAL DIAGNOSIS, AND TREATMENT​

Treatment

Treatment for anticholinergic toxicity primarily involves reducing or stopping anticholinergic agents, engaging in supportive therapy (eg, IV hydration, nutrition, and, if needed, medications for symptoms of delirium), admission to a monitored bed due to cardiac complications, and in severe cases the use of physostigmine to reverse the effects of the anticholinergic agent.12,35-37

Physostigmine is a tertiary amine that rapidly crosses the blood-brain barrier and is an acetylcholinesterase inhibitor. Physostigmine improves both the central and peripheral symptoms associated with anticholinergic toxicity.12,35 It has been used to treat anticholinergic delirium since the mid-1800s and is preferred over other cholinergic agents due to its rapid onset of action and short half-life.12,14,33,48

Because physostigmine has a short half-life, a patient may need to be given repeated administrations of the medication if symptoms recur.12,14,35,48 If symptoms are due to anticholinergic toxicity, improvement occurs rapidly, often within minutes.12,35 The usual dose of physostigmine is 1-2 mg given IM or 0.02 mg/kg IV, with the patient being observed for 30 minutes afterwards for either improvement or the development of cholinergic symptoms such as arrhythmias.12,14,35

Rapid improvement following physostigmine injection is evidenced by improved cognition, decreased tachycardia, and dryness of the mouth. Mydriasis may take days to fully resolve, even with continued physostigmine treatment.12 Pilocarpine, a miotic medication, is helpful to determine if mydriasis is related to anticholinergic effects or another cause.​

 

[RWP (Rest without Peace)]

@Wayne

Sorry your symptoms are still hanging on. Hope the new approach helps.

RWP + PWR

 

[Wayne]

I'm waking up today, feeling like I've pulled back from the precipice.

I wrote the above about 5 days ago, and unfortunately, shortly afterwards I found myself heading back toward the precipice. Many of my symptoms came back in force, with the most prominent ones being tinnitus, extreme anxiety and agitation, and inability to connect with my brain and emotions, etc. It felt like my dysfunctional brain and neurological discombobulation kept going around in an endless loop, with no end in sight, despite all my best efforts to break out of that loop.

Then two nights ago, I had another seizure, though less serious than the first one. It started while I was asleep (like the first one), but this time it started while I was in a dream experience. I was with my Osteopathic doctor in the dream, and as I went into the seizure, he asked me what this was all about. As I began to explain, he then started making some efforts to help me, though I don't recall what they were.

I went into town today to purchase some Huperzine A, which apparently acts like a cholinesterase inhibitor, something that would stop the unnatural breakdown of acetylcholine in my brain and body. I would consider it a more natural version of the prescription drug Physostigmine, but without the danger of severe side effects. I learned that ginkgo biloba, nicotine, and TCH (?) also prevent the breakdown of acetylcholine. I'll be doing a separate post on these at some point.

I took my first dose of Huperzine A, and then decided to stop by my Osteopathic doctor's office. Though he's notoriously hard to get in to see, I discovered there had been a cancellation and I could get a visit in 1 1/2 hours. He almost exclusively does cranial sacral work these days, and after hearing my story, was eager to get started on me. He quickly evaluated that on a scale of 1/2 - 10, I was at a 1/2. He said there was absolutely NO movement or rhythms in my body--I think he even used the word "dead" in some manner. I could relate, as I'd been feeling the past few days that I was in the "end game" of my life.

It didn't take long before the extreme anxiety and rigidity in my system began to ease up. And it continued unabated for the next 20 minutes or so. It felt like I was coming back to life, even to the point of feeling like a human being again, with normal emotions and relatively coherent thoughts. He said he's always been impressed how quickly I come back after experiencing various kinds of setbacks. In addressing my main concern, he thought that the tinnitus I've been experiencing will begin to abate as well, as a good number of his patients have gotten relief from it.

I'm expecting a pound of ginkgo biloba to arrive in the mail tomorrow, which apparently has many more benefits for the brain than just protecting the acetylcholine. Daniel Amen (doctor) who specializes in brain health and has done literrally thousands of brain scans, says some of the best scans he's taken are from people who regularly take ginkgo biloba. So I'm looking forward to taking this, as I feel my brain and nerves are going to need a lot of support as I continue to make my way through this extraordinary odyssey.

For now, I'm feeling feeling a tremendous amount of relief. And am hopeful again that I can really start moving inexorably forward from this point on.​

 

[pattismith]

This experience was horrible, I hope you will learn something positive out of it.

Along my way, I happened to learn myself a lot from the drugs side effects I had, even though it took me some time to find the right answers....Trials and errors is our karma

I may try Ginko Biloba too, it sounds a good idea

 

[RWP (Rest without Peace)]

Wow, Wayne. How awful this has been! We're hoping that the two new items will help.

RWP + PWR

PS: PWR takes Ginkgo daily, though a very small amount (1 drop tincture, and only in the a.m.) because it can keep her awake.

 

[Wayne]

I hope you will learn something positive out of it.

Two Week Update

Well, it's been two weeks now since I first took that Promethazine, and this whole experience continues to challenge. I'd have to say it's been two of the most challenging weeks of my life, and felt at times I was scrambling to use all of my wits to keep body and Soul together. Never did so many castor oil packs, epsom salts baths, coffee enemas, grounding, and more in such a compact period of time.

I've noticed a certain cycle when the drug seems to move through my system as it (presumably and hopefully) is moving out of my body. About every two days (evenings) I'll notice the tinnitus increase in volume. Then I'll start feeling seriously anxious, or agitated, depressed, etc., in a way that I rarely experienced prior to this all starting. When I take a look in the mirror, my face is very red.

This is when I do a coffee enema to help flush this toxicity out of my body. It's felt like an amazing blessing to have become so familiar with doing them, and to at this time be able to experience the remarkable relief they can provide. They've considerably helped alleviate some of these difficult symptoms of anticholinergic toxicity. -- Fortunately, these 2-day cycle episodes seem to be getting less intense as time goes by.

I've come to believe that my knee went out on me three days into this in such a serious way because of what this drug was doing to my muscles (which need acetylcholine to operate at all). A lot of involuntary muscle movements, cramps and spasms I was experiencing (I believe) ended up pulling my knee out of it's normal location.

I've not had a normal appetite since this all started, and have now lost 12 lb. I'm mostly on a liquid diet of bone broth, sauerkraut juice, teas (with a touch of coconut oil & stevia), and occasional this's and that's, like an avacado or apple. I'm adding about 6 egg yolks daily to the bone broth, and consider it my main "comfort food". It seems to calm my system down, and keep some of the symptoms abated for a while.

Unfortunately, most times when I eat a little bit of just about anything, I tend to get a tickle in my lungs, and I start coughing in an unusual way. It seems the drug may have affected my lungs in some manner, as respiratory symptoms are listed as potential side effects.

I've learned much more about tinnitus, but won't go into detail here. I'll just mention however, that the tiny hairs in our inner ear all have acetylholine receptors. So if they were all of a sudden "starved" for it by this drug, it would seem to explain why tinnitus can get triggered as it did.

I ordered a concentrated gingko biloba extract, specifically designed to treat tinnitus. It's main actions are its ability to increase the microcirculation in the inner ear, AND, scoop up the excess glutamate that is generally created with inner ear turmoil. In other words, tinnitus appears, to some degree, to be "excitotoxicity" in the inner ear. I'm mentioning this, because I would think GB's ability to do this would be of interest to anybody with ME who experiences excitotoxicity in their brains.
-
Interestingly, there's actually been some positive things I've experienced in the course of this ordeal. After a few days, I feel my overall functionality has actually notched up a bit. Being forced into somewhat of a partial fasting mode seems to have given me some of the benefits of fasting.

My OI/Dysautonomia definitely seems to be better. I'm guessing that that may be due to the 6 egg yolks I'm eating, which is keeping my acetylcholine higher than it was in the past. I'm also taking Huperzine A, which keeps acetylcholine from breaking down.

I've come to believe I had such severe reactions to this drug because I had abnormally low acetylcholine levels to begin with, which may not be uncommon for pwME. I think however, that was likely only part of the problem. To reference your post @pattismith, I think my continuing experimenting with keeping my acetylcholine levels higher could pay off well for me in the end. I guess this would be the proverbial silver lining.

Though challenges remain, I feel I've at least regained a semblance of equanimity I've striven so hard to maintain over the decades of dealing with ME. But this whole experience has really stretched me. -- Now, if only I could get more than 4 hours of sleep. I just read a testimonial today by a man who says 5-6 drops of CBD oil helped him tremendously with sleep. I'll likely pick some up tomorrow.

Best to All, Wayne​

 

[RWP (Rest without Peace)]

@Wayne

Thanks for updating us. Wish this could be over for you sooner. Glad a few things are going in the right direction.

RWP + PWR

 

[pattismith]

it sounds scary that you still suffer from this drug!
Let's hope you will be able to sleep better and eat more soon

Here you have a list of acetylcholinesterase reversible inhibitors:

https://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor

Rosmarinic acid is in the list (in many plants, there is a wiki link with a list of plants where you can find it)

 

[dannybex]

Hi @Wayne,

I'm just seeing this thread now. Not sure if your tinnitus is still hanging around, but just wanted to mention that IMO, the reaction may possibly more related to it's antihistamine properties than anything else.

One of the ways H1 antihistamines work is by reversing/inhibiting what happens when histamine is released -- dilating the blood vessels being one of the them. These drugs do the opposite, constrict blood vessels -- hence, the common symptom of sedation/sleepiness, dry mouth, etc. One of the other symptoms is indeed tinnitus.

I haven't been able to take that type of antihistamine in probably 15+ years, as every time I do, they give me a horrible case of restless legs -- again, because of it's affects on circulation. Other antihistamines are tolerable, although I avoid them in general.

I've also had tinnitus off and on for about 30 years. It's gone away from time to time, but over the last 7-8 years has been worse. It developed into pulsatile tinnitus probably 10 years ago, at which time the ear doctor said that probably meant I was developing some arterial plaque. His guesstimate then was 10%. It got better...the pulsing stopped for about 3-4 years, but has been worse again for the past 2 years.

It's worth noting that salicylates inhibit vitamin K2 synthesis in various ways, and in my case, I ate a high salicylate diet for waaaaay too many years. Easier to do that one might think. But because tinnitus can be caused by salicylates, I'm wondering if that's because of it's interference w/K2? Just a guess.

Anyway, aside from your vagus nerve hypothesis (which definitely is an issue w/ME/CFS) I hope some of these ramblings are helpful. It would be very odd if it's still going on. There is a case history of a gentleman who suffered serious effects after a Promethazine injection on this page.

Hope you can or have figured it out.