# Add a benzo to morphine for better analgesia?



## KellyBracket (Feb 8, 2014)

One of the surprising results I found when I interviewed medics about prehospital analgesia was the belief that it would be helpful to add a benzo to whatever opiod you are giving. (link to study at *http://www.ncbi.nlm.nih.gov/pubmed/22971168*

The medics offered various reasons, mostly having to do with either *treating anxiety*, or trying to *reduce the dose of opiod*. The funny thing is, this approach is not taught in the ED, unless we are explicitly trying to sedate the patient, e.g. for a procedure. I have no idea where people learned this belief.

Nonetheless, some interesting new research was recently published on the effectiveness of this approach, and I was preparing a blog about it. I wanted to see if people felt strongly about this issue, and, if they believe it, where they learned it.

Thanks!


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## zzyzx (Feb 12, 2014)

That study used only 15 paramedics. What the heck? 

Personally I've never considered mixing a benzo and an opiate. Seems like a bad idea to me, just like mixing either with alcohol.


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## abckidsmom (Feb 12, 2014)

There have been times when it seemed to me that moving the patient to the ambulance or just simply driving them over rough roads was as painful as a procedure.  

I have been sorely tempted many many times, but it was eliminated from our scope of practice last year. No mixing of benzos and opioids, period. 

I have experience with conscious sedation from my time in as a nurse, and I always looked at the combination of drugs as such.


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## KellyBracket (Feb 12, 2014)

zzyzx said:


> That study used only 15 paramedics. What the heck?
> ...



Yup, only 15 medics, but it was enough.

We used a *qualitative* methodology, not quantitative, for various reasons. Generally, such studies use much fewer subjects. For more explanation, I've clipped out the relevant bit from the methods section. If you want a reprint, I'm happy to share!



> Many aspects of emergency medical care are best studied using conventional quantitative methods. Efforts to validate the accuracy of a test, or the efficacy of a therapy, require quantitative methods that emphasize reproducibility, randomization, and statistical evaluation of hypotheses. Some phenomena in medicine, however, are not, at least initially, amenable to this approach. Such phenomena may involve a domain in which there is little initial data to guide construction of a suitable trial. Other areas may involve investigations into complex social and organizational issues, where quantitative data may provide statistical accuracy at the cost of ignoring important information that is not well captured numerically.
> 
> Perhaps the most important use of qualitative methods in research is employing them when it is uncertain what a proper research hypothesis should be. Quantitative research, by design, requires a hypothesis to be specified at the outset, so that the result may be deduced. Qualitative research usually involves observing and probing a population, organization, or system, and finding what results are produced through inductive study.
> 
> Qualitative methodologies were used in this study because they can provide a theoretical underpinning for subsequent survey construction, quantitative studies, and behavioral interventions. In particular, qualitative methodologies have been employed to study barriers to implementing or changing medical practice. These particular qualitative data-collection techniques were selected because there has been little formal research on this topic and we wanted to elicit highly valid responses from our group of content experts.


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## KellyBracket (Feb 12, 2014)

The recent study that prompted my original question looked at combining midazolam and morphine, and was pretty well done. I reviewed it at *my FB page*, but I've copied the text below.




> Many paramedics believe that they could control pain better, and reduce morphine dosing, if they were allowed to add midazolam or Ativan. Different reasons are offered for this approach, such as the role of anxiety, the spasming of muscles in trauma, or the difficulty in controlling pain quickly. A recent study demonstrates that this “mixed-therapy” approach is UNNECESSARY, and tends to produce MORE SEDATION, and DOESN'T REDUCE THE DOSE of morphine.
> 
> *"Does midazolam enhance pain control in prehospital management of traumatic severe pain?"*
> http://www.sciencedirect.com/science/article/pii/S0735675714000801
> ...


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## Tigger (Feb 12, 2014)

We give the combo all the time, however there is no requirement to lower the dose of the opiate (MS or fentanyl.) Anecdotally it's been very effective for injuries that result in large muscle spasms. Vertebral and hip fractures are when that combo (usually diazepam) is commonly used, and many patients report that "it's that muscle relaxer drug" that helped the most. We have pretty aggressive dosing for opiates as well, so I don't think these patients were under-dosed either. 

When I fractured several vertebra in a ski crash, the 200 of fentanyl I received in the ED didn't do a lot for me, but the initial 10 diazepam did a lot (the subsequent 20 didn't hurt either). Spasms can be incredibly painful.


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## Carlos Danger (Feb 12, 2014)

I've never read or been taught that benzos _technically_ potentiate opioid analgesia, as far as enhancing their effects on mu receptors or beneficially affecting serotonin kinetics, but the protocols at my last program (where we flew a lot of burn patients) did list bezos as an optional adjunct for the management of severe pain, and it's a pretty commonly used technique in certain anesthesia settings for short term relief of severe pain until something more definitive like a nerve block or general anesthesia can be accomplished. Clinically, my experience is that adding versed to fentanyl generally makes for a markedly more comfortable patient, if their pain was not effectively resolved after a couple healthy doses of fentanyl.



KellyBracket said:


> The recent study that prompted my original question looked at combining midazolam and morphine, and was pretty well done. I reviewed it at *my FB page*, but I've copied the text below. Many paramedics believe that they could control pain better, and reduce morphine dosing, if they were allowed to add midazolam or Ativan. Different reasons are offered for this approach, such as the role of anxiety, the spasming of muscles in trauma, or the difficulty in controlling pain quickly. A recent study demonstrates that this “mixed-therapy” approach is UNNECESSARY, and tends to produce MORE SEDATION, and DOESN'T REDUCE THE DOSE of morphine.
> 
> "Does midazolam enhance pain control in prehospital management of traumatic severe pain?"
> http://www.sciencedirect.com/science...35675714000801
> ...



I can't access this study through my institution; looks like it won't be available until 2/4.

The big things that jump out at me from this abstract are:


The versed or placebo was given prior to the opioid? That is the opposite of how I've used versed as an adjunct. I usually add it after a dose or two of fentanyl, if it appears that it would be beneficial.


The 3-minute dosing interval for morphine. Morphine is a slow drug and peak analgesic effects don't occur for at least 5 minutes; probably more like 15-20 in most cases, maybe even 30, especially when smaller doses are administered. What this means is that if you follow a 3-minute dosing interval it is very likely that you will end up administering a much larger total dose of morphine than you would have if you'd allowed each dose to take full effect before judging whether more is needed. What follows, of course, is a greater chance of seeing the untoward effects of morphine, including respiratory depression, the incidence of which peaks after the analgesic effects do. (FWIW, this is why I think morphine is an all-around pretty lousy opioid for EMS use....but of course that's a whole other discussion.)
I suppose none of that really matters here if the RCT was well designed and conclusively shows that since both groups received the same amount of morphine, _all the versed did_ was increase sedation and resp depression. 

However, I just can't help but think that the use of morphine with such a short dosing interval resulted in a higher than necessary total dose of opioid, which somehow confounded the results. 

I'd be very interested in seeing this study repeated using fentanyl with a 5-minute dosing interval, and giving versed after the second dose of fentanyl, if certain criteria are met. 

I look forward to reading the full text of the article.


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## mycrofft (Feb 12, 2014)

We used to have order to give valium post-op and have an order of demerol (meperidine) as needed for pain. Keeping a patient from getting "wound up" will help prevent the cycle of pain=> anxiety=> pain etcetera .
HOWEVER, postop is not like prehospital in a couple manners. A paradoxic reaction to benzos (disinhibition leading to agitation, hallucination, "partying" behaviors, even aggression, instead of relaxation) can be worked with better when the IV is patent and the pt is in a more controlled environment, and postop is somewhat less of a situation (although not totally free of) presenting unanticipated interactions with other substances on board the pt which th MD's are not aware of like alcohol, methamphetamines, etc.


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## Handsome Robb (Feb 12, 2014)

We can do midaz/fent and midaz/MS on standing orders.

The only time I use the combination is to untangle someone from a bad spot (ie grandma with the femoral head fracture wedged between the toilet and bathtub) or for patients with an injury that is creating or secondary to a muscle spasm (back pain is the most common, then femur fxs).

Midazolam causes relaxation of skeletal muscles. In chronic back pain patients who are suffering back spasms I can give them narcs and hope it works or I can treat the underlying problem that's causing the pain, the spasms, as well as treating their pain. 

Need to pull traction? Perfect mix. Analgesia, sedation and muscle relaxation makes it better for everyone involved. 

According to QA/CQI I'm one of the few that uses it consistently. 

Just my take on it.


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## Carlos Danger (Feb 13, 2014)

Robb said:


> We can do midaz/fent and midaz/MS on standing orders.
> 
> The only time I use the combination is to untangle someone from a bad spot (ie grandma with the femoral head fracture wedged between the toilet and bathtub) or for patients with an injury that is creating or secondary to a muscle spasm (back pain is the most common, then femur fxs).



The times that I've seen it really seem to work wonders is on burn transports. Many times I saw patients still uncomfortable on large doses of opioids chill out dramatically with a dose of lorazepam or midazolam. 

In the burn units they often use dexmedetomidine or ketamine rather than more opioids for debridements or dressing changes or even as infusions to keep opioid requirements down. This is both because of the undesirable side effects of large doses of opioids, but also largely because tolerance to opioids can develop rather quickly when you stack opioids on top of opioids, especially with the potent fentanyl analogues like remi and alfenta that would otherwise be ideal for short, very painful procedures.


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## paradoxicalmotion (Feb 13, 2014)

Out of curiosity, has anyone seen research similar to the French study looking at Ketamine in addition to morphine/fentanyl/pick-your-favorite-narc?


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## mycrofft (Feb 13, 2014)

Listened on the radio as a man screamed from one end of Lincoln, NE, to the other, being zapped with more and more valium. He was horribly burned (died later after air transport, THAT must have been real dream flight) and with the drugs available in 1981 I think they were concerned with the likelihood an effective dose of meperidine or the other fashionable analgesics would likely kill him in the ambulance or the airplane.

"Snowing" people with benzos is still practiced and it has some potential liabilities...like ODing on benzos, benzos stacking up until the liver starts working again then slamming into play, paradoxic effecst, and (especially in emergencies) unknown drugs or alcohol on board.


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## KellyBracket (Feb 13, 2014)

To a large degree, I think we're talking apples and oranges here. Adding benzos to opiods is a great mix, if you are lookng to go down the procedural sedation route. If that's what your protocols call for, great. But in terms of just augmenting analgesia, without affecting LOC, you may be on shakier ground. Certainly in any US ED, that won't fly.



Tigger said:


> ... Anecdotally it's been very effective for injuries that result in large muscle spasms. ... 200 of fentanyl I received in the ED didn't do a lot for me, but the initial 10 diazepam did a lot (the subsequent 20 didn't hurt either). Spasms can be incredibly painful.



Depending on your weight, 200mcg of fent is a good start, but I wouldn't call it extraordinary. The concept of "muscle relaxant" has been called into question by many people smarter than I. Yes, propofol is also a good "relaxant," but at the effective dose it has some other effects on respiration. And that's what the current study suggests - you get respiratory depression before any effects on pain.



Halothane said:


> ...Clinically, my experience is that adding versed to fentanyl generally makes for a markedly more comfortable patient, if their pain was not effectively resolved after a couple healthy doses of fentanyl.
> 
> 
> The versed or placebo was given prior to the opioid?
> The 3-minute dosing interval for morphine.... What follows, of course, is a greater chance of seeing the untoward effects of morphine, including respiratory depression, the incidence of which peaks after the analgesic effects do.


I'm sure your experience shows that versed makes patients more comfortable, the question is, if this practice is adopted on a large scale, will we see higher rates of apnea, hypoxia, excessive somnolence? 

As for the study, the Versed was given immediately after the morphine. 
As for the interval, my apologies - it was 3 mg every* 5 *minutes, not 3. I think this is a fairly conventional understanding of the onset time (e.g. uptodat lists 5-10 minutes), and the low dose, and short time interval, is unlikely to produce significant OD, I think.



mycrofft said:


> We used to have order to give valium post-op and have an order of demerol (meperidine) as needed for pain. Keeping a patient from getting "wound up" will help prevent the cycle of pain=> anxiety=> pain etcetera .


What's Demerol? 
We found in our own study that paramedics are very concerned with the "wound up" issue, while in-hospital folks tend to just use more opiods. Again, and interesting difference in perspectives



Robb said:


> ....
> 
> Need to pull traction? Perfect mix. Analgesia, sedation and muscle relaxation makes it better for everyone involved.



Sounds like procedural sedation, which may be very appropriate. But your protocols ought to be clear on that point, and call for increased monitoring requirements. 



Halothane said:


> The times that I've seen it really seem to work wonders is on burn transports. Many times I saw patients still uncomfortable on *large doses of opioids* chill out dramatically with a dose of lorazepam or midazolam.


I think part of the issue is what we call "large doses of opiods." Some RNs or medics consider 10 mg of morphine to be the big guns, and any unresolved pain indicates the need for extraordinary measures.

In the end, I think that adding benzos is great, but that isn't analgesia, it is sedation, and the rates of side effects in this study seem to demonstrate that point.

Anyone how wants the pdf of the new paper, PM me. Or message me through my facebook page for mill hill ave command. 

Okay, now I have to drive through the snow to get to work. Great discussion!


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## NomadicMedic (Feb 13, 2014)

It was common practice at my last service to potentiate morphine with promethazine. You got a little sedation, pain management and it was perfect for moving little old ladies with hip fractures. 

I certainly don't think we should be sedating patients to the point of "procedural sedation levels" however, a touch of anxiolytic certainly would make the entire experience a bit more pleasant, no? I find most of the discomfort from patients is worry about the car they just crashed, worry about the chest pain they're experiencing, worry about whatever… dosing them with 200mcg of Fent may not be the best solution. Sure, they're experiencing pain, but they're also extremely anxious.

There needs to be a better solution, don't you think?


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## Merck (Feb 13, 2014)

I would hardly call a total of 10mg of MS extreme.  But I do have to agree with the addition of a sedative to common analgesia when the occasion demands it.  Someone mentioned burns and this is certainly a good case, as is other areas where the pain is extreme or manipulation will cause pain to break through any analgesia already give.  Sure there's some crossover to procedural sedation and I think that is totally appropriate, so long as the downsides are recognized and the crew is prepared for the result (mainly hypoventilation).  To this end EtCO2 and SpO2 monitoring are probably ideal, as well as good old-fashioned patient assessment.

Pain in itself isn't always a problem but the perception of pain is.  This is why procedural stuff is so effective.  In essence - pain not remembered didn't occur.


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## mycrofft (Feb 13, 2014)

Merck said:


> I would hardly call a total of 10mg of MS extreme.  But I do have to agree with the addition of a sedative to common analgesia when the occasion demands it.  Someone mentioned burns and this is certainly a good case, as is other areas where the pain is extreme or manipulation will cause pain to break through any analgesia already give.  Sure there's some crossover to procedural sedation and I think that is totally appropriate, so long as the downsides are recognized and the crew is prepared for the result (mainly hypoventilation).  To this end EtCO2 and SpO2 monitoring are probably ideal, as well as good old-fashioned patient assessment.
> 
> Pain in itself isn't always a problem but the perception of pain is.  This is why procedural stuff is so effective.  In essence - pain not remembered didn't occur.


That's why they used to slam women in childbirth with scopolamine, and predatory dates use rohypnol. 

And don't forget pain is a symptom. One of my clinical instructors used to relate how an elderly post-CVA pt was unable to speak but obviously in pain, so they kept giving him pain meds until they figured out his external catheter (back then they used to tape them on) had twisted about 200 degrees from the original position….

10mg morphine is not excessive_ if the pt isn't circulating other meds and alcohol_.  That's why before I'd ask for a name (but after asking what's wrong), I'd ask if they were taking other meds, drugs, or alcohol. Then ask again later.


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## Merck (Feb 13, 2014)

Obviously one had to take into account other factors and medications when determining analgesia requirements, anticipated effectiveness and risk. With regard to the remembers pain I was reflecting on a recent clinical rounds I attended where an anesthesiologist mentioned that the perception of pain is the pain, the physical change (such as tachycardia in one who is sedated) is a somatic response. I suppose it's a little philosophical and certainly forms no basis for knocking people unconscious but there's a reason why procedural sedation is what it is.


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## Handsome Robb (Feb 13, 2014)

KellyBracket said:


> Sounds like procedural sedation, which may be very appropriate. But your protocols ought to be clear on that point, and call for increased monitoring requirements.




We call it concurrent sedation and analgesia and there are pretty strict requirements as to how we do it. But it isn't limited to procedures. I can give the combo all the way to the hospital at 5 minute intervals for the midaz and fent then MS is 15 minutes. 

We're just now getting side stream capnography and they haven't added it into the protocol but I pointed out that it should probably be mandatory in that protocol. I'd rather look at their true ventilators status than try to keep one eye on their respirations all the damn time. 

I think in certain situations like those that have been listed it is a great way to use benzodiazepines and opioids concurrently however I don't really see it becoming a norm for standard analgesia.


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## mycrofft (Feb 13, 2014)

Merck said:


> Obviously one had to take into account other factors and medications when determining analgesia requirements, anticipated effectiveness and risk. With regard to the remembers pain I was reflecting on a recent clinical rounds I attended where an anesthesiologist mentioned that the perception of pain is the pain, the physical change (such as tachycardia in one who is sedated) is a somatic response. I suppose it's a little philosophical and certainly forms no basis for knocking people unconscious but there's a reason why procedural sedation is what it is.



Having had two elective cardioversions and a high colonoscopy in the last five years, I'm very happy with not remembering them.

But the propofol seems to leave me behind the IQ curve for a week or so afterwards. General using valium as a premed…not so much.

Starting to sound like people comparing brands of beer or something??:huh:


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## Handsome Robb (Feb 14, 2014)

Mycrofft, somewhat personal so you don't have to answer if you don't want but were both your cardioversions done with propofol?

We are only allowed to sedate for cardioversion, I've brought it up a few times about concurrent pain and sedation during cardioversion.


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## mycrofft (Feb 14, 2014)

Robb said:


> Mycrofft, somewhat personal so you don't have to answer if you don't want but were both your cardioversions done with propofol?
> 
> We are only allowed to sedate for cardioversion, I've brought it up a few times about concurrent pain and sedation during cardioversion.



Yeah, I believe they were done with propofol. (Which my auto speller keeps changing to "proposal"). I was _out_ and woke up in a recovery section. The colonoscopy was also done with it and they had trouble waking me up.

When we did colonoscopies (few) at the doc in a box I worked at in 1986-87, we used I.V. valium and hydrazine with ok effect; sedated and didn't _care_ when they experienced discomfort…sort of like Demerol used to be  ("Go on, cut off my other leg, what's for supper?").


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## Carlos Danger (Feb 14, 2014)

mycrofft said:


> Yeah, I believe they were done with propofol. (Which my auto speller keeps changing to "proposal"). I was _out_ and woke up in a recovery section. The colonoscopy was also done with it and *they had trouble waking me up*.



That is quite unusual. The primary reason propofol has become so popular for those procedures is precisely because people wake up so quickly and completely, and usually feel perfectly normal afterwards. In contrast to sedation techniques using opioids and benzos, where some people say they don't feel right for a whole day or two.


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## mycrofft (Feb 14, 2014)

Well, maybe they slipped me a mickey?





"Easily woken" can be like "Minor office procedure"; try it yourself once. Sternal bruising is not a sign for me that it was easy.

*BUT we digress….*


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## Carlos Danger (Feb 14, 2014)

Dr. Walsh was kind enough to send me the paper, and since I have today off, I was able to read it this morning.

I think there are some problems with the protocol used in the study:


Morphine vs. fentanyl is a matter of personal preference in most cases, but fentanyl is objectively faster in onset, time to peak effect, and offset, which I think makes it a fair claim to say it is a better choice anytime you are trying to "titrate" your doses so that you get a satisfactory effect with the smallest dose possible. Also, being devoid of histamine release makes fentanyl a "cleaner" drug, which becomes important, I think, when you are trying to discern the effects of several drugs given at once. Anecdotally I think these properties make fentanyl just "work" better adjunctively with benzos.


I hate to belabor the point about the time-to-peak effect, but it is of critical importance in this setting. Onset time for morphine is anywhere from 2-10 minutes depending where you look, but _time to peak effect_ is much more important when you are repeating doses, and it is up to 30 minutes according to some references. 5 minutes is simply not enough time between doses of morphine to reliably assess how well your previous dose(s) worked, and therefore how much more you should give. This doesn't matter as much with the smallish doses that are often used in EMS and in some ED's, but if you are giving more substantial doses, then it could definitely become an issue as your first 1 or 2 doses are just taking full effect as you are pushing your 3rd or 4th dose. I don't question the statistical analysis which showed no difference in opioid requirements between the versed and placebo groups, but I can't help but think that the fairly rapid administration of substantial repeat doses of morphine blurred the picture to a degree.


Unless I am misunderstanding the paper, the versed or placebo was given prior to the morphine ("only one dose at baseline"). Whether it was given first or second doesn't really matter though, the important thing is that it was given automatically without any assessment as to whether it was indicated....certainly not everyone in pain needs or is a good candidate for the adjunctive use of a benzo. If we go around giving a drug to everyone we encounter without assessing whether it is indicated or even whether the patient will tolerate it, we shan't be surprised to see a large number of untoward effects associated with the drug. 


The dose of versed they used (0.04mg/kg) is a fairly hefty dose. That's 3.2 mg in an 80kg patient, which is not a lot of versed if given alone, but in combination with a good dose of morphine (8 mg for that same 80kg patient....followed at least once by another 3mg dose, and then possible by more 3mg doses), it is far more than I would give without closely assessing the need. The total morphine dose for the versed group was 14mg, which again, is quite a bit to give over a short period of time in addition to versed....it's really not surprising that they had more problems with sedation and resp depression in that group. 

I think the only thing we can reliably take from this study is that we should not give versed with opioids without first assessing the need, and that the versed/morphine combo is not a great one. If the study was repeated with fentanyl and the versed was only given if an adjunct was needed after the opioid, then I think we might see quite different results. 

Once the patient is comfortable, then longer-acting opioids such as dilaudid or morphine work well to maintain the state of comfort. But knocking out that initial anxious "wound up" state that some are in is much easier to do with a faster opioid, and sometimes with some benzo added.


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## mycrofft (Feb 14, 2014)

Great reply.

As an aside to the entire thread, with how long a treatment-plus-transport time would this be useful? How would receiving such a patient affect handoff to the ED? Or to a home hospice caregiver, etc? (Yes, people go home in extreme pain, too).


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## EMTelite (Feb 14, 2014)

I have seen posts on tbis before but I have also done some research your benzo wil offer an anesthetic property which seems to lead to the belief it potentiates the effect of your analgesic. An anti inflammatory will do more to potentiate the effects of your analgesic 

Just my opinion


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## ChrisV (Mar 3, 2014)

Never tried this approach as protocol didn't allow it.  Frankly it seems like an excellent idea.  Had a patient with a compound fracture, that I was blessed to witness said fracturing event, have an allergy to morphine (Fentynal was backordered) which was the only pharmaceutical available at the time.  A healthy dose of Versed and quality splinting was enough to eliminate the pain until arrival at definitive care.  Furthermore, the patient didn't remember the painful splinting and transferring.  The combination of the benzo and the opiod seems like a fantastic idea.  Thanks for the link to the study.


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## the_negro_puppy (Mar 4, 2014)

Our protocols allow Intensive Care Medics to use Midazolam for severe pain (burns, bad fractures) after Morphine (0.1 / 0.2mg/kg) have been given. I have seen this done once with a fractured femur, I believe 2 x 1mg IV dosages were given after approx 15mg of Morphine. 

However Ketamine is given far more often if extra analgesia is required.


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## FiremanMike (Mar 5, 2014)

At the FD we were just given the ability to use versed for severe pain after exhausting our fent.  Where I do CCT we generally alternate 2.5 of versed and 50 of fent every 5 or so, but that's really for sedation and not pain.


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## KellyBracket (Mar 5, 2014)

FiremanMike said:


> At the FD we were just given the ability to use versed for severe pain after exhausting our fent.  Where I do CCT we generally alternate 2.5 of versed and 50 of fent every 5 or so, *but that's really for sedation and not pain.*



Important distinction!


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## Handsome Robb (Mar 7, 2014)

FiremanMike said:


> At the FD we were just given the ability to use versed for severe pain after exhausting our fent.  Where I do CCT we generally alternate 2.5 of versed and 50 of fent every 5 or so, but that's really for sedation and not pain.




Sounds like post intubation sedation maintenance blouses. Glad to know that there's agencies out there doing it right though! Cause we sure don't


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