Intravenous morphine at 0.1 mg/kg is not effective for controlling severe acute pain in the majority of patients

The EMS Garage also covers pain management on the 5/08/10 podcast. Pain Management: EMS Garage Episode 85. Go listen to that, as well. Chris Montera, Dr. Keith Wesley, Will Dunn, Kyle David Bates, Kelly Grayson, and I discussed several aspects of prehospital pain management.

I have been meaning to cover the research on prehospital pain management for a long time. I did write about one excellent study of fentanyl.^[1] Currently, the big obstacle is that there is now so much research to cover. Back in the 1990s, when I would try to persuade doctors that prehospital pain management was safe, there was very little to show to support that statement. A common medical command order was for 0 mg morphine, but we could repeat that as often as we liked. Some times we would get orders for 2 mg morphine and sometimes have the possibility of repeating that dose one time.

From the title of this, you can see that the authors take a dim view of that kind of dosing. Intravenous morphine at 0.1 mg/kg is not effective for controlling severe acute pain in the majority of patients.^[2] This study was just on adults, so we should consider the size of an adult. I consider ballpark figures for a small adult to be 50 kg (110 pounds), a medium sized adult to be about 80 kg (176 pounds), and a large adult to be about 110 kg (231 pounds), although there does not seem to be any shortage of people significantly larger than that.

Using these very rough estimates, 0.1 mg/kg would be 5 mg morphine for a small adult with severe pain. The title of the article states that this dose would be inadequate for most patients with severe pain. If the common doses of morphine that used to be given were 0 mg, 2 mg, and 4 mg, were we doing anything more than relying on the placebo effect for the majority of pain relief?

If 5 mg is inadequate for a small patient with severe pain, 8 mg is inadequate for a medium patient, 11 mg is inadequate for a large patient, and there are plenty of much larger patients, what good was a typical dose of 2 mg morphine, assuming that the doctor would be generous enough to even give orders for this dose? Another reason for putting off writing about this has been my attempt to avoid making this just a rant about neglect of patients with severe pain.

Let's assume that you are not a misanthrope. You are not the kind of person to hurt strangers, just because you can get away with it. You might even occasionally apply the Golden Rule of Do to others as you want them to do to you. What would you want done to you?

0 mg morphine? This can be roughly translated to non-medical terminology as, What are you crying about? I am the one who has to listen to your crying!

2 mg morphine? Even for the small adult, this does not come close to the 0.1 mg/kg that the authors state is inadequate.

2 mg morphine with a repeat dose of 2 mg morphine? At least we are moving away from a complete placebo dose in the small patient, but in the medium sized patient, this is not much different from the single dose of 2 mg for the small patient. For the large patient, this is still just a placebo. For the extra-large patient this is just a very bad joke.

After all of that, what does the actual study state?

A standard means of taking into account the heterogeneity of analgesic response in treatment is titration of dosage, with small increases of dose over short periods of time. Some emergency medicine texts recommend a range of doses (eg, 0.05 to 0.15 mg/kg)⁶; others provide a single dose (eg, 10 mg)⁷ or a single weight-based dose (0.1 mg/kg)⁸ with the proviso that the dose should be titrated to desired analgesic effect. There is little evidence about whether these recommendations are routinely followed in ED care.

Although titration is a goal for optimal management of acute pain, a first step is to assess the recommended starting dose. Given the various recommendations for intravenous morphine, ranging from 0.05 mg/kg to 10mg, we chose to assess the analgesic response to the recommended weight-based dose of 0.1 mg/kg. The purpose of this investigation was to quantify the proportion of patients in acute pain who had less than a 50% reduction in pain intensity 30 minutes after intravenous administration of 0.1 mg/kg of morphine.^[1]

Arguments can be made that this endpoint is as valid as reduction of pain to less than 3 out of 10. Farther down, I will compare the results if 3 out of 10 had been used.

patients were eligible if they were between 21 and 65 years of age, spoke English or Spanish, or had acute pain with onset within the past 7 days. Exclusion criteria included previous use of methadone, use of other opioids or tramadol within the past 7 days, previous adverse reaction to morphine, chronic pain syndrome, altered mental status, pregnancy, use of monoamine oxidase inhibitors in the past 30 days, systolic blood pressure less than 100 mmHg, or inability to provide informed consent.^[1]

All reasonable exclusions.

Patients were asked by the research associates to rate their pain intensity at baseline and 30 minutes post baseline. Peak analgesia from intravenous morphine is achieved within 5 minutes of administration in most patients.^9,10 Clinically, 30 minutes seemed to be a reasonable time within which adequate analgesia should be achieved in patients with severe pain. Further, it is unlikely that an analgesic effect would be missed with this interval because the elimination half-life of morphine is 2 to 4 hours.^9,10[1]

I confess. I only checked the abstracts for footnote 9^[3] and footnote 10^[4] cited for morphine reaching peak effect within 5 minutes. I do not feel that 5 minutes is accurate for peak effect. For peak serum levels, 5 minutes may be correct. When acute pain patients start discussing their serum morphine levels with me, then I will wonder about this, but not before then. I will address the onset of effect of morphine and the peak effect in covering other acute pain research that more directly addresses this.

I feel that an assessment of pain at 30 minutes will not miss a significant amount of the pain relief that morphine will provide.


On the side, I have provided parts of the chart from the study that shows the change in pain levels at 30 minutes. this is the caption - Figure.

Distribution of 30-minute pain score by baseline pain score.*

*Shaded area indicates number and percentage of patients whose pain scores decreased <50%.^[1]

In other words, if a patient's rating of their pain started at 10 out of 10, the shaded area extends down to the top of 5 out of 10. If a patient's rating of their pain started at 8 out of 10, the shaded area extends down to the top of 4 out of 10. You can see how many patients remained in the less than 50% relief by the shading.



Pain is generally rated on an 11 point scale from 0 being no pain. Some people like to start at one, feeling it is more important to have the scale only have ten points, but end at ten. So 1 is nothing for them. I feel much more comfortable explaining to patients that nothing means nothing. Actually, I find that I do not have to explain the concept of zero. For somebody experiencing severe pain, I expect that zero is their desired level of pain. 10 is the worst pain imaginable. On the podcast, Dr. Wesley has a very creative way of describing the worst pain imaginable.

For the patients starting with the pain level of 10 out of 10, 68.1% did not have relief of at least 50%. That number really does not tell us a lot, but it is less than one third, so that means a lot of patients with very little relief. We are not describing complete relief of pain, but only a reduction of 50%. Less than 1/3 having a 50% reduction in pain level is pathetic.

15.9% had no relief at all. None.


15.8% had a decrease in pain to 3 out of 10 or less. The difference is just due to rounding. Both percentages represent 13 out of 82 patients. I added up the fractions, so that the numbers on the chart match my numbers. For patients with an initial pain level of 10 out of 10, a decrease of 50% is expected to be much more likely, because the target also includes patients with a decrease in pain to 4 out of 10 and patients with a decrease in pain to 5 out of 10.

For these patients, it would not have mattered if we had started at 0 mg morphine, 2 mg morphine, 4 mg morphine, or the larger dose of 0.1 mg/kg. There was no improvement. I know what you're thinking. At least the pain did not get worse.

How would we know? Maybe their pain did get worse, but they didn't have any higher number to use to tell us. Maybe they just initially rated their pain higher than they should have. It happens. This is one of the problems of the pain rating scale - subjectivity.



We also have too many people who feel quite comfortable under-treating the pain of other people. I do not think they should be making pain management decisions. Well, maybe they would be more appropriate making pain management decisions if they were intentionally torturing people.

If a lack of compassion/lack of empathy is a problem for healthcare providers, perhaps this is one criterion that we can use to identify those who might be better off being seamlessly integrated into the exciting field of fast food service. These paramedics, viewing patient care with a Quantity is Job One approach, will not be missed by patients. A lot of people have been saying that we should find a way to eliminate those without empathy from the classrooms. They feel that it is easier to teach people to be paramedics, than it is to teach empathy. I am not convinced, but this is certainly worth considering.



Now, let's look at the patients who were slightly better off. They only rated their pain as a 9 out of 10, initially. How did they do?

74.9% had less than a 50% relief of pain. One problem here is that half of 9 is 4 1/2. There is no 4 1/2 out of 10 on the list. Patients who started with a pain level of 9 out of 10 needed to lower it to 4 out of 10 for the purposes of it being considered a 50% decrease in pain for this study.

How would things have been different, if we split the 3 patients in half? Don't worry, when we get to the overall numbers, we end up with an even number. No procrustean methodology is intended. These 3 patients make up 25% of the patients who initially rated their pain 9 out of 10. If we split that in half, we would have 62.4% with a 50% reduction in pain. If we considered all of the 4 out of 10 patients to have had a 50% reduction in pain, then the split is 50% of the 9 out of 10 patients with a 50% reduction in pain.

The 8 out of 10 patients had 16.7% with no change in pain. A 50% reduction in pain was reported by half of the 8 out of 10 patients.

The 7 out of 10 patients had the most interesting changes. None of the patients had the same pain level as initially. 40% of the 5 patients with 7 out of 10 pain (2 patients) had an increase in level of pain. This is the kind of thing that is supposed to be impossible. Apparently, impossible is a bit over-rated.

How could a patient receive such a large dose, at least compared with what has been considered the normal dosing, and not only not improve, but have an increase in pain? Not just one patient, but 2 patients.

There is always the possibility of drug diversion, but during a study, with more people paying attention to what is going on, that is even less likely than under normal circumstances.

The 7 out of 10 patients had the worst improvement of all. Some had their pain increase, but none of them had a more than 50% improvement in their pain. Zero.

If you were to use the same approach as with the 9 out of 10 patients and count a change to 4 out of 10 as a 50% improvement, since there is no 3 1/2 out of 10, you would still have 80% with less than 50% improvement.

Finally, there are the 6 out of 10 patients. Both improved to 4 out of 10, which means none of them had more than 50% improvement in their pain.

Overall, more than 2/3 of severe pain patients had a less than 50% improvement in pain. Even if you added in the patients who improved to 5 out of 10 from 9 out of 10 and the patient who improved to 4 out of 10 from 7 out of 10, you only end up with 63.9% improving by less than 50%. Just under 2/3.

The primary measure of adequate analgesic response to morphine is percentage of reduction in pain intensity dichotomized into less than 50% versus greater than 50%. Although there are other measures, we chose a 50% or greater reduction in pain because this threshold has been used frequently in pain meta-analyses and has the appeal of quantitative simplicity and easy clinical interpretation. Patients’ age, sex, and pain location were obtained from the medical record or the patient. Ethnicity was self-reported. Additional administration of analgesics was ascertained from the records and consultation with the ED staff. Patients in this study were placed near the physicians’ and nurses’ station, directly in the line of sight of the staff and thus were under constant supervision. The research associates monitored the patients carefully as well. Vital signs were routinely measured by the nursing staff at 0, 15, and 30 minutes. For the purposes of the study, the research associates monitored the oxygen saturation, blood pressure, pulse rate, and respiratory rate at 0 and 30 minutes. Patients were reassessed by the clinical staff if systolic blood pressure was less than 100 mm Hg, pulse rate was less than 60 beats/min, or respiratory rate was less than 12 breaths/min to determine whether an opioid antagonist was needed. If oxygen saturation dropped by more than 5%, the patient was reassessed, and oxygen was administered at a fraction of inspired oxygen that returned the oxygen saturation to its baseline level. Patients whose presenting oxygen saturation was 95% or less were given oxygen on presentation.^[1]

How many patients ran into problems from this larger than normal dose of morphine?

One patient was reassessed by the medical staff because the respiratory rate was 12 breaths/min, 1 patient’s oxygen saturation dropped more than 5%, 2 patients had a systolic blood pressure less than 100 mg Hg, and 8 patients had a pulse rate less than 60 beats/min (range 52 to 60 beats/min). None of the patients required administration of an opioid antagonist at any time during the 30-minute study period or for 2 hours thereafter.^[1]

Not any problems that required any kind of intervention that could not be handled by a basic EMT, never mind a medic with all sorts of advanced implements of destruction. Essentially, with 10 minutes of training and authorization to add oxygen, people from registration and housekeeping could have manged these patients safely.

The protocol specified a dose of 0.1 mg/kg morphine to be given intravenously during 1 to 2 minutes. Because of rounding up or down, some patients received weight-based doses that varied slightly from the specified dose. Before data analysis, we decided to accept weight-based doses ranging from 0.09 to 0.11 mg/kg as meeting the protocol criterion for a 0.1 mg/kg standardized dose.^[1]

Earlier, I mentioned that a decrease in pain to a level of 3 out of 10 is commonly used. In this study of severe acute pain, there was a less than 50% decrease in the pain level for 67% of patients.

What if the goal had been a reduction of pain to 3 out of 10, rather than the easier to reach reduction of 50%?

82% of patients did not reach the 3 out of 10 pain level.

An 82% failure rate when the goal is a pain level of 3 out of 10, or better.

A 67% failure rate when the goal is a 50% decrease in pain, or better.


People continue to tell me that this is not a problem. However, these people are not the patients with severe pain. These people are the administrators, the medical directors, the nurses, and other paramedics. In other words, the people denying the problem are the ones supposed to be making sure that this problem does not happen.

Things are improving, but it would be difficult for things not to improve. A lot of this improvement is due to research. This dismal starting point I attribute to the paranoia of the What if . . . ? crowd. They would rather restrict something they do not understand, than learn how to use it properly. They are very dangerous. Fortunately, abundant research is pointing out the ridiculous nature of their restrictions on pain management.

LIMITATIONS
Our sample is almost entirely composed of poor, inner-city Hispanic and black patients. Given the many cultural influences perception and expression of pain, it is quite possible that prevalence of poor response to morphine in other settings and other populations may differ from what we have reported. Because a convenience sample was recruited when trained research associates were present, the findings might have differed if consecutive patients had been enrolled. The patients in this study had heterogeneous locations of pain, having in common only high pain intensity and need for opioid analgesics. However, this reflects the true variety of clinical emergency practice. Some of the pain, though severe, was episodic and fluctuating. Thus, assessment of it at 30 minutes using a single numeric rating scale reading may not provide an accurate overall reflection of the degree of pain relief experienced during the preceding half hour. There is no a priori reason, however, to postulate that this methodology of sampling produces bias because pain that is changing over time seems about as likely to worsen as it does to improve throughout a constant interval.^[1]

Pain of 3 out of 10 is often used, because this is a decrease to mild pain, rather than severe or moderate pain. There is much more that can be said about the ways of measuring pain, but I am not going to do that, today.

This study assessed an initial dose of morphine that is consistent with starting doses recommended in standard texts.^6-8[1]

This dose clearly provides inadequate analgesia, and it may well be higher than what is routinely administered in many EDs.^[1]

To summarize. 0.1 mg/kg should only be viewed as a starting dose.

Some of you may be wondering why I am using a study of morphine administered by doctors in an ED as a surrogate for morphine/fentanyl administered by paramedics before arriving at the hospital. The paramedic is as close to the patient as you are to the computer screen. How does a competent paramedic miss significant changes in patient presentation under those circumstances? There are incompetent paramedics. They should be remediated, but if they are not capable of providing competent care, they need to explore areas of employment where their lack of competence is less dangerous. There is no obligation by any employer to endanger patients by protecting the jobs of less than competent paramedics.

In the hospital, the doctors and nurses are assessing and treating other patients, documenting patient care, restocking, dealing with other patients, et cetera. If anyone believes that there is closer observation in the ED, than in a competently staffed ambulance, please provide some evidence to support this extraordinary claim.

Patients in this study were placed near the physicians’ and nurses’ station, directly in the line of sight of the staff and thus were under constant supervision.^[1]

That may seem reasonable to someone who has never set foot in the Montefiore Medical Center's ED. This is not meant as a sleight to anyone working there. There are times when all sorts of craziness is going on and the claim that, without some staff member directly assigned to their care, any patients thus were under constant supervision, is not believable. In EMS, we almost always have more providers than patients. In the ED, the reverse is true. This is unavoidable.

The quote actually states, Patients in this study were placed near the physicians’ and nurses’ station, directly in the line of sight of the staff. That leads up to a conclusion that is inappropriately drawn from the first part of the sentence. The conclusion should be that because patients were directly in the line of sight of the staff, if the staff actually did look up and did focus their eyes on the patients directly in their line of sight and did decide to assess the appearance of those patients, then the patients could be said to be thus under occasional intermittent supervision at a distance. To claim that these patients thus were under constant supervision, is an unreasonably optimistic exaggeration.


Footnotes:


^ ¹ Public Perception of Pain Management
Rogue Medic
Article



^ ² Intravenous morphine at 0.1 mg/kg is not effective for controlling severe acute pain in the majority of patients.
Bijur PE, Kenny MK, Gallagher EJ.
Ann Emerg Med. 2005 Oct;46(4):362-7.
PMID: 16187470 [PubMed - indexed for MEDLINE]



^ ³ The diposi tion of morphine in surgical patients.
Berkowitz BA, Ngai SH, Yang JC, Hempstead J, Spector S.
Clin Pharmacol Ther. 1975 Jun;17(6):629-35.
PMID: 1139854 [PubMed - indexed for MEDLINE]

The disposition of serum morphine following administration of 10 mg/70 kg was determined by a sensitive and specific radioimmunoassay in 31 anethetized surgical patients ranging in age from 23 to 75 yr. Following iv injection, 93 per cent of the morphine disappeared from the serum within 5 min. The early serum levels of the drug (2 min) correlated directly with the patients' ages (r equal to 0.63, p smaller than 0.01). Patient 23 to 50 yr of age averaged 0.29 mug/ml, whereas patients 51 to 75 ur of age averaged 70 percent higher, 0.49 mug/ml. The serum half-life between 10 and 240 min was independent of age and averaged about 2 hr after either iv or im administration. Following im admininstration, morphine was rapidly absorbed, with peak levels occurring within 10 to 20 min. The decline in morphine serum levels paralleled the decline in morphine analgesia and was coincident with the apperance of morphine glucuronide in the serum. These studies demonstrate the applicability and specificity of the radioimmunoassay for morphine and suggest that serum levels of morphine may be a useful and objective indicator of its pharmacologic activity.

^ ⁴ Kinetics of intravenous and intramuscular morphine.
Stanski DR, Greenblatt DJ, Lowenstein E.
Clin Pharmacol Ther. 1978 Jul;24(1):52-9.
PMID: 657720 [PubMed - indexed for MEDLINE]

The disposition of parenteral morphine was assessed in two pharmacokinetic studies. In Study 1, 10 mg of morphine sulfate was administered by intravenous (IV) infusion, intramuscular (IM) injection, or both, to 8 healthy young adult male volunteers. Plasma morphine concentrations were determined by radioimmunoassay in multiple blood samples drawn after each dose. Mean (+/-SE) kinetic parameters following IV morphine were: volume of distribution (Vd), 3.2 (+/- 0.3) L/kg; elimination half-life (t1/2beta), 2.9 (+/- 0.5) hr; clearance, 14.7 (+/- 0.9) ml/min/kg; extraction ratio, 0.70 (+/- 0.04). After IM morphine, peak plasma levels ranged from 51 to 62 ng/ml and were reached within 20 min of injection. The absorption half-life averaged 7.7 (+/- 1.6) min. Systemic availability was 100% complete. In study 2, 4 elderly male patients (61 to 80 yr of age) received 45 to 80 mg of morphine sulfate IV prior to operative repair of an abdominal aortic aneurysm. Morphine pharmacokinetics were determined as described above. Kinetic variables were Vd, 4.7 (+/- 0.2) L/kg; t1/2beta, 4.5 (+/- 0.3) hr; clearance, 12.4 (+/- 1.2) ml/min/kg; extraction ratio, 0.59 (+/- 0.05). Both studies demonstrate that morphine distribution is rapid and extensive and its t1/2beta relatively short. IM morphine is rapidly and completely absorbed.

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