Study: Sub dissociative dose of ketamine with haloperidol versus fentanyl on pain reduction in patients with acute pain in the emergency department; a randomized clinical trial

This study came in through my notifications today, but it was published two weeks ago on Clinical Pain Advisor.

I also remember seeing this study being discussed on social media and online forums a few weeks ago.  I meant to write it up then, but better late than never.

Basically, this study was pitting ketamine against fentanyl IV for acute pain relief in the ER.  All the patients had moderate to severe pain (greater than 5 out of ten on a ten-point scale) and they were randomly assigned to receive 2.5 mg haloperidol with 0.3 mg/kg ketamine or 1 microgram/kg fentanyl. Patients were assessed for pain at 5, 10, 15, and 30 minutes after injection, the need for rescue medication, and for adverse effects.

I mean, immediately I’m wondering why you would think that giving someone, who is already in moderate to severe pain, a medication (ketamine) that most people find gives them unpleasant hallucinations is a GOOD idea.  Especially when the only reason to do this is a fear of addiction which, in the case of IV fentanyl in the ER, is a vanishingly small risk.

Also, why would you still think it’s a good idea when you now have to give them ANOTHER medication, an anti-psychotic with a serious side effect profile of its own, to get rid of the hallucinations and agitation that you have just induced with the ketamine?

Um…I know I’m not a medical scientist or a doctor, but really?  This person is in terrible pain, let’s give them a hallucinogen that we know causes agitation in 87% of patients.

Does this not seem like A Bad Idea?

If we were creating addicts in the ER from IV fentanyl, I’d understand this approach.  But we’re not. Millions of people have been given IV fentanyl for pain, for surgery, for many reasons. And the vast majority of them did NOT become addicted.  That’s clear. It’s obvious.  People get fentanyl as part of surgical procedures every day.  It’s safe. It does not cause addiction.

People may be confused about prescriptions for oral opioids given in the ER causing addiction, or diversion of medication. I would still argue this is uncommon, but this is what people are thinking of when they are thinking that opioids treatment in the ER leads to addiction. 

IV fentanyl as a treatment for acute pain is very low risk.  That’s not in question.  The study authors agree.

So why then?

I can’t see the benefit in finding an alternative therapy where we have a perfectly good therapy. 

Yes, for people who can’t take opioids, or who have previous addiction issues and do not want opioids.  For them, this is valuable. But there is no way that ketamine should become the first-line treatment for severe, acute pain in the ER. 

Simple common sense says giving two drugs, one to ameliorate the horrendous side effects of the first drug, is not as good as giving one drug, which has few side effects, has been used successfully for decades, is well understood, and gives very effective pain relief.

I’m not a doctor or a scientist, so I may well be wrong. I would welcome people who have more education and experience in this area to please comment.

But here’s my thoughts:

The only reference I could find was on UpToDate, for IV analgesic and sedative dosing regimens for managing pain, agitation, and delirium in the ICU.  It’s unlikely this is the best resource. Bite me, google.

https://www.uptodate.com/contents/image?imageKey=PULM%2F79667

UpToDate says the starting dose of fentanyl for severe pain is 1 to 2 mcg/kg.  And then 0.35 to 0.5mcg/kg every 30 mins to an hour intermittently, to maintain the pain relief.

The study gave the participants 1mcg/kg, which is the minimum dose.  Seems likely that many people wouldn’t get good pain relief from the minimum dose.  It seems to me that if they weren’t achieving good pain relief from 1mcg/kg, then the study participants should have given another 1mcg/kg, as would happen in the ER in the real world.  That is, if they were intending to give the pain-relieving properties of fentanyl a fair representation.  Seems that they purposefully used an underpowered dose of fentanyl, which would almost guarantee the alternative treatment would be found to be superior.

Underdosing is just one very common technique that I have noticed researchers use to make the study of opioids’ pain-relieving effects seem inferior. There was a study a few years ago where they pitted a tiny dose of oxycodone against an NSAID at a typical dose. Of course, the opioid gave very poor pain relief because it wasn’t a therapeutic dose!  So the study made it look like nsaids give better pain relief than oxycodone. Until you looked carefully at the study and the dosing they used.  

Anyone who has ever been in severe pain knows that an NSAID does NOT give better relief than oxycodone. Not ever. 

But back to THIS study.  They had to keep the ketamine at the low end of the dosing range so that it was in the “sub dissociative” range.  The funny thing is that a lot of people still experience hallucinations and agitation at this dose. If this were truly the “sub-dissociate” dose, why would you even need the haloperidol, the anti-psychotic, to manage the side effects? Cos you’re saying this is a dose that won’t cause these side effects…then you’re saying that you have to give another drug to manage those same side effects.   

Hmmmm. 

I know I’m not a scientist, but c’mon. Make it make sense.

Either ketamine at this dose causes agitation, hallucination, delirium etc and it requires haloperidol to manage those side effects, or it does not. Obviously, if you’re giving the haloperidol, the study designers are acknowledging its common to experience psychotic side effects with ketamine at this dose. Otherwise, you wouldn’t need the haloperidol. You can’t have it both ways.

Also, haloperidol sedates the patient. I’m wondering if they were truly getting pain relief, or if they were just being sedated into silence and compliance.  I don’t know the answer.

I can’t read the whole study, because I can’t afford to pay $50 for the privilege.  But I found another study where they pitted ketamine without haloperidol against morphine for acute pain relief in the ER.

IN THIS study, 87% had psychotic side effects from the ketamine.  Wow…87%. That’s a lot. And I’ve had ketamine, it was the most unpleasant drug experience I have ever had. By a long way. I had to beg them to stop it.  Your mileage may vary, but I was led to believe my experience is very common. And the study linked above supports this.

But this study says that only 4 people had “emergence symptoms” which would be hallucinations and agitation from ketamine. Pain Clinical Advisor acknowledges that there were more adverse events with ketamine, but it’s buried in the text.

But again, I am not a scientist.  I’m just a patient. So I went to social media and online forums to see what actual doctors and researchers had to say.

Firstly, there was pretty good consensus that ketamine is every bit as addictive as fentanyl.  And that giving people in pain “Special K’ was no less risky than giving them ‘hillbilly heroin’.  I thought ‘hillbilly heroin’ was oxycodone, but I take the point.

An ER doc commented on the addictive risk of fentanyl as follows:

“1) fentanyl’s effects are short-lived and should rarely be used for acute pain in hemodynamically stable patients and 2) the risks of using parental opioids to treat acute pain in ED patients range from trivial to nonexistent.”

And the Addiction medicine doctor who posted the study agreed that the risk of addiction is very low.   So that seems to negate the whole purpose of this study.

An Advanced Life Support Paramedic  commented that “using a short-acting opioid for this RCT of ALTO seems disingenuous;”  (RCT=Randomised controlled trial,  ALTO-Alternative to opioids)

And added:

“I’d be really interested in a study comparing Fentanyl to a Fentanyl/Ketamine combo. Anecdotally I have great success with this combined approach to analgesia vs single agent therapy with Fentanyl. Also, I think 1 mcg/kg Fentanyl is too conservative a dose.”

Which gels with what I discovered when I googled fentanyl doses.  At least one medical professional who uses fentanyl for the relief of severe pain every day agreed that a dose of 1mcg/kg is an inadequate dose. That’s a pretty big flaw in the study’s design.

He also refers to studies that show that using ketamine with opioids has an ‘opioid sparing’ effect. That is, you can use lower doses of opioids for the same pain-relieving effect if you use ketamine as well.  The rates of adverse events are significantly higher, however.   And again, ketamine is known to be a drug that people love to abuse. Are we really gaining anything here?

And then there’s still the addition of haloperidol, which has some serious risks and side effects of its own.

A little bit about haloperidol:

“Haloperidol is an anti-psychotic and mood stabilizing medication that is inexpensive and widely used for people with conditions including schizophrenia and bi-polar disorder. It works in part by blocking the receptor for the neurotransmitter dopamine 2, involved in motor, motivational and reward-seeking behavior, in coordination with dopamine 1.

While haloperidol helps many people with serious mental health conditions, its list of potential side-effects and adverse events is long. For example, it has been found to increase risk of sudden heart failure and death in dementia patients, leading the U.S Food and Drug Administration to issue a black-box warning against its prescription to manage agitation in seniors with conditions including Alzheimer’s.”

source: https://www.scripps.edu/news-and-events/press-room/2020/20201007-subramaniam-haloperidol-induced-catalepsy.html

Again, I can’t read the actual studies, so I can’t confirm how many people endured unpleasant hallucinations and ‘agitation’.  “Emergence phenomena” would relate to severe symptoms, but even mild hallucinations can be very unpleasant. It really should be reported in the abstract, in my opinion. But they are out to prove that ketamine is superior to fentanyl, so they are glossing over the adverse events.

What researchers choose to put in their abstracts and titles can be very misleading.  Read only the title and the conclusion, as most people will, and you’ll come away thinking that ketamine and haloperidol is a much better option than fentanyl.  But is that what the study actually showed?

Not in my opinion.

And even the researchers could not conclude that ketamine provided superior pain-relief. Their final conclusions were are follows:

“Due to the absence of fatal complications such as respiratory failure and the lack of need for monitoring, injection of ketamine with haloperidol can be used as one of the safest and most appropriate sedatives in the ED,” the study authors noted.

“Most appropriate Sedatives in the ED“. Not most appropriate pain-relievers.

I’ll take fentanyl any day.

Author: PsychosomaticAddict

Chronic Pain Patient Advocate. Pain Coach. Patient. Living with High Impact Chronic Pain and advocating for proper pain treatment, including opioids where appropriate. Busting the myths. Exposing the actual science.