Obesity and Analgesic Response to Morphine in the ED
Obesity and Analgesic Response to Morphine in the ED
The key finding of this study was that the analgesic response to a fixed dose of morphine did not change as a function of BMI. Therefore, even morbidly obese patients had a similar response to non-obese patients. Opioids such as morphine may be dosed based on the weight and size of patients, especially for acute pain. This results in heavier patients receiving larger doses in settings such as the ED. However, in obese patients, this could lead to very large doses of morphine, potentially leading to toxicity. In a previous study, 50 patients with acute pain received 4 mg of intravenous morphine with a similar outcome measurement of analgesic response. Patient weight did not influence the degree of analgesic response. Our findings are consistent with that study, showing that obesity status did not influence response even at the upper extreme of BMI. There were 100 morbidly obese patients in our study, which is one of the largest cohorts of this BMI group that has been studied evaluating the use of morphine for acute pain.
There are several factors that can influence the pharmacokinetics and pharmacodynamics of morphine. When given as a single intravenous bolus, the serum concentration of morphine is primarily determined by the volume of distribution. The apparent volume of distribution ranges from 1.0 to 4.7 l/kg. Therefore, there is close to a fivefold difference in this parameter between patients leading to great variations in serum concentrations when patients are given the same weight-adjusted dose (mg/kg). In obesity, changes in body composition such as increased adipose tissue and extracellular fluid further affect drug distribution. However, the effect of obesity and morbid obesity on the distribution of morphine and the resulting serum concentrations has not been studied. In addition, the analgesic effect of morphine is not predicted by serum concentrations. This may be because of factors such as previous opioid use, genetics, psychological characteristics and demographics. Many of these factors are not routinely measured or cannot be measured in the clinical setting, especially when patients present emergently for the treatment of acute pain. Therefore, given this variability in the pharmacokinetics and pharmacodynamics of morphine, it is not surprising that BMI did not predict analgesic response in our study. Even at very high BMI when an association may be more easily seen, this study did not find an association.
Given the variability in analgesic response it is preferable to use fixed doses (eg, 4 mg) in a rapid titration strategy. Using this method clinicians do not need to consider specific variables such as weight even in obese and morbidly obese patients. This also obviates the need to predict responses to single doses of morphine. However, there remain barriers to rapid titration such as nursing time required, leading to delays in drug re-dosing or pain reassessments. In a multicentre study in 20 US and Canadian hospitals less than 50% of patents had any pain reassessments in the ED. One potential solution could be the use of patient-controlled analgesia in this setting. A recent randomised-controlled study in the ED showed that patients who received patient-controlled analgesia had more rapid and greater pain relief than patients who received conventional care. Nonetheless, our results indicate that using fixed doses regardless of patient weight is an appropriate strategy even in the heaviest of patients. Doses can then be titrated to effect based on patient response.
As this was a retrospective study, we were unable to standardise when the post-dose pain score was recorded. Therefore, the time of the first recorded pain score within 2 h of the morphine dose was used to determine analgesic response. As the elimination half-life is 1.5–2 h, this was a reasonable time window to record peak response. This methodology is consistent with previous studies. Pain response could be affected by the source of pain. However, we controlled for this variable in the multivariate analysis. Most patients in our study had abdominal or musculoskeletal pain. Also, an interesting finding was that Hispanic race was associated with better analgesic response in the multivariate analysis. This was an unexpected finding that needs further investigation. Several patients in the dataset were excluded because of missing documentation. This could have skewed the study population. To account for this, we included patients consecutively to minimise the potential for selection bias. However, as this was a consecutive population it took longer to obtain patients in the obese and morbidly obese groups, which could also be a source of selection bias. In addition, the study was limited to a single site and should be extrapolated with caution to other centres. The data abstractor was not blinded to the study hypothesis. Therefore the potential for information bias cannot be excluded.
Discussion
The key finding of this study was that the analgesic response to a fixed dose of morphine did not change as a function of BMI. Therefore, even morbidly obese patients had a similar response to non-obese patients. Opioids such as morphine may be dosed based on the weight and size of patients, especially for acute pain. This results in heavier patients receiving larger doses in settings such as the ED. However, in obese patients, this could lead to very large doses of morphine, potentially leading to toxicity. In a previous study, 50 patients with acute pain received 4 mg of intravenous morphine with a similar outcome measurement of analgesic response. Patient weight did not influence the degree of analgesic response. Our findings are consistent with that study, showing that obesity status did not influence response even at the upper extreme of BMI. There were 100 morbidly obese patients in our study, which is one of the largest cohorts of this BMI group that has been studied evaluating the use of morphine for acute pain.
There are several factors that can influence the pharmacokinetics and pharmacodynamics of morphine. When given as a single intravenous bolus, the serum concentration of morphine is primarily determined by the volume of distribution. The apparent volume of distribution ranges from 1.0 to 4.7 l/kg. Therefore, there is close to a fivefold difference in this parameter between patients leading to great variations in serum concentrations when patients are given the same weight-adjusted dose (mg/kg). In obesity, changes in body composition such as increased adipose tissue and extracellular fluid further affect drug distribution. However, the effect of obesity and morbid obesity on the distribution of morphine and the resulting serum concentrations has not been studied. In addition, the analgesic effect of morphine is not predicted by serum concentrations. This may be because of factors such as previous opioid use, genetics, psychological characteristics and demographics. Many of these factors are not routinely measured or cannot be measured in the clinical setting, especially when patients present emergently for the treatment of acute pain. Therefore, given this variability in the pharmacokinetics and pharmacodynamics of morphine, it is not surprising that BMI did not predict analgesic response in our study. Even at very high BMI when an association may be more easily seen, this study did not find an association.
Given the variability in analgesic response it is preferable to use fixed doses (eg, 4 mg) in a rapid titration strategy. Using this method clinicians do not need to consider specific variables such as weight even in obese and morbidly obese patients. This also obviates the need to predict responses to single doses of morphine. However, there remain barriers to rapid titration such as nursing time required, leading to delays in drug re-dosing or pain reassessments. In a multicentre study in 20 US and Canadian hospitals less than 50% of patents had any pain reassessments in the ED. One potential solution could be the use of patient-controlled analgesia in this setting. A recent randomised-controlled study in the ED showed that patients who received patient-controlled analgesia had more rapid and greater pain relief than patients who received conventional care. Nonetheless, our results indicate that using fixed doses regardless of patient weight is an appropriate strategy even in the heaviest of patients. Doses can then be titrated to effect based on patient response.
Limitations
As this was a retrospective study, we were unable to standardise when the post-dose pain score was recorded. Therefore, the time of the first recorded pain score within 2 h of the morphine dose was used to determine analgesic response. As the elimination half-life is 1.5–2 h, this was a reasonable time window to record peak response. This methodology is consistent with previous studies. Pain response could be affected by the source of pain. However, we controlled for this variable in the multivariate analysis. Most patients in our study had abdominal or musculoskeletal pain. Also, an interesting finding was that Hispanic race was associated with better analgesic response in the multivariate analysis. This was an unexpected finding that needs further investigation. Several patients in the dataset were excluded because of missing documentation. This could have skewed the study population. To account for this, we included patients consecutively to minimise the potential for selection bias. However, as this was a consecutive population it took longer to obtain patients in the obese and morbidly obese groups, which could also be a source of selection bias. In addition, the study was limited to a single site and should be extrapolated with caution to other centres. The data abstractor was not blinded to the study hypothesis. Therefore the potential for information bias cannot be excluded.
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