Is JIF peanut butter better, worse, or not really any different than Skippy? Although there are passionate advocates for each (and don’t get me started on creamy or crunchy), in reality they are both pretty much the same. The same can be said for many commercially available products we routinely use in our clinical practices including many pharmaceuticals like morphine and hydromorphone. Indeed, I think we can all agree that morphine and hydromorphone are excellent opioid analgesics, but is one really better (fewer side effects, faster onset time, less respiratory depression) than the other? Many anesthesiologists have strong preference for one or the other, but these opinions are frequently based on what they were taught in residency, personal experience, and anecdote (what I would call “bubbemeises” or old wive’s tales). Although morphine is a bit cheaper than hydromorphone, both are relatively inexpensive (pennies/dose) (see PS at the conclusion).
Despite decades of use, rigorous comparisons between these 2 opioids have never been made. In today’s meticulously conducted human (adult) volunteer study, the authors, Meissner et al.1 from Leiden University, the Netherlands, suggest hydromorphone may have a significantly better clinical profile. For many of you who may not be familiar with the type of research in today’s PAAD, the Leiden group is unquestionably the world leaders in opioid pharmacokinetic and pharmacodynamic research and their science is brilliant and always worth reading carefully. Myron Yaster MD
Original article
Meissner K, Dahan A, Olofsen E, Göpfert C, Blood J, Wieditz J, Kharasch ED. Morphine and Hydromorphone Effects, Side Effects, and Variability: A Crossover Study in Human Volunteers. Anesthesiology. 2023 Jul 1;139(1):16-34. PMID: 37014986.
When choosing a perioperative mu agonist opioid, morphine, hydromorphone, fentanyl, methadone, or oxycodone, physicians make their decisions based on onset and offset times, efficacy, side effect profiles, availability, and cost. Other important factors which may be even more important are familiarity and experience with the drug. Ideally, one would choose an opioid that has the most efficacy and least side effects, particularly respiratory depression. Meissner et al.1 hypothesized that “that IV morphine and hydromorphone differ significantly in drug effects and side effects and their interindividual variabilities. The premise was that this could affect drug safety, and that, based on the identification of these factors, opioid selection can be made more rationally. The specific aims of the study were to define the onset, time course, and interindividual variability of morphine and hydromorphone analgesia, miosis, and respiratory depression, and to define the concentration–response relationships for these effects and their variability.”
How did they conduct this research? After a single opioid dose was administered to adult volunteers, timed (arterial) plasma concentrations were drawn and analyzed and correlated to analgesic responses to thermal stimuli, miosis, and respiratory effects. Equianalgesic doses of morphine and hydromorphone (0.05 mg/kg v 0.2 mg/kg respectively) were administered intravenously as a 2 hour infusion Although the commonly accepted equi-potency ratio is M:H 5:1, the authors administered doses reflecting a ratio of M:H of 4:1.2 “At each time point during the 12 h experiment, the following measurements were taken in order: (1) respiratory rate, peripheral oxygen saturation measured by pulse oximetry, and end- expired carbon dioxide concentration; (2) dark-adapted pupil diameter (in triplicate) using an infrared pupillometer (Neuroptics, USA), and (3) antinociception (response to heat pain). After 2 weeks, the volunteers returned to the lab where they were crossed over to the other treatment and restudied.
The method of measuring pain response to heat is reproducible and fascinating. I (MY) learned this technique of maximally tolerated responses to increasing temperature from Dr. Tom Henthorn who learned how to do it while a visiting professor in Leiden. It is both quantifiable and reproducible. “Two analgesia measurement models were implemented sequentially using a Peltier-type thermal stimulator and thermode applied to the forearm (Pathway, Medoc Advanced Medical Systems, Israel). The first was the “method of limits” (a continuous increase from 32°C at 0.8°C/sec until the maximally tolerable temperature was reached, at which point the subject pressed a button and the thermode cooled; the temperature cutoff was 52°C). Measurements were performed in triplicate, with the thermode moved between measurements. The mean of three temperatures was recorded as the result. The “ramp and hold method” was the single application of six different specific temperatures (41°, 43°, 44.8°, 46.5°, 48.2°, and 50°C, each applied once in random order), with the probe moved to different spots on the forearm after each measurement. Subjects were asked to rate the pain at each temperature on a 0 to 100 verbal analog scale.”1
Meissner et al. found “that the relationship between analgesia and respiratory depression differed between the two drugs, with morphine having “less analgesia” for any given degree of respiratory depression as well as a delayed onset and longer duration of respiratory depression. The authors suggest that hydromorphone may, as a result, have advantages in the clinical setting.”1 Further, the “onset, magnitude, and duration of miotic, analgesic, and ventilatory effects of hydromorphone were characterized by temporal coincidence”, that is, they matched. This was not the case with morphine in which the ventilatory effects of morphine were greater than the magnitude of analgesia and was temporally delayed. Thus, ventilatory depression occurred later than the peak of analgesia and lasted longer than analgesia. Miosis and analgesia also did not match temporally, with miosis occurring earlier than analgesia and faded sooner making the use of pupillometry questionable.
All we can say is “WOW”! As the authors conclude: “at the doses studied, hydromorphone compared with morphine had a faster onset of effects and greater analgesia relative to respiratory depression, and morphine respiratory depression was delayed relative to analgesia. These results suggest that hydromorphone may have clinical advantages compared with morphine for treating acute pain in perioperative, emergency department, and other acute care settings.”1
We wonder what opioid do you routinely use in use in your practice and do you or your hospital’s pharmacy make these decisions? Has this article changed your mind? Send your responses to Myron who will post in a Friday reader response.
PS: From pricing information provided by Mark Schreiner MD based on data from drugs.com. Please note that these prices may be higher or lower based on your hospital pharmacy purchasing contracts which are often bundled and not purchased individually.
The price of IV morphine 1 mg/mL = $37.90/900 mL or $0.04/mg. It comes in other concentrations as well. The 10 mg/mL = $33.05/10mL = $3.30/mL or $0.33/mg. The oral formulations come in oral solutions and tablets. The 30 mg tablet = $37.74/100 tablets or $0.38/tablet or $0.01/mg. The oral solution comes as either a concentrate 20 mg/mL or 20 mg/5 mL. The concentrate 20 mg/mL costs $12.79/15mL or $0.85/mL or $0.04/mg. The 20 mg/5mL solution costs $15.22/100 mL or $0.15/mL or $0.04/mg.
IV hydromorphone also comes in multiple formulations. The 2 mg/mL = $29.04/10mL or $2.90/mL or $1.45/mg. The 10 mg/mL formulation = $26.26/10 mL or $2.63/mL or $0.26/mg. The oral 2 mg tablet costs $11.11/10 tablets or $1.11/tablet or $0.56/mg. The oral liquid costs $59.36/150mL or $0.4/mg.
Remember when comparing costs, the equipotent dose of morphine to hydromorphone is 5:1 so you need to divide the morphine dose by 5 to get an equivalent hydromorphone IV dose. Further, morphine has poor bioavailability (30-40%) so to get an equivalent PO to IV morphine dose, the IV dose should be multiplied by 3 times. Hydromorphone has much better bioavailability (70-80%) so the same oral as IV dose can be administered, although some opioid conversion resources recommend an IV:PO ratio of 1:2.5.
Finally, both opioids are extremely inexpensive and although there are slight cost differences they really don’t amount to very much.
References
1. Meissner K, Dahan A, Olofsen E, et al. Morphine and Hydromorphone Effects, Side Effects, and Variability: A Crossover Study in Human Volunteers. Anesthesiology. Jul 1 2023;139(1):16-34.
2. Hong D, Flood P, Diaz G. The side effects of morphine and hydromorphone patient-controlled analgesia. AnesthAnalg. 10/2008 2008;107(4):1384-1389.