Welcome to the next installment of the Anesthesia Patient Safety podcast hosted by Alli Bechtel. This podcast will be an exciting journey towards improved anesthesia patient safety.
Medication safety is a very important component for safe anesthesia care. It is one of the APSF Patient Safety Priorities that includes drug effects, labeling issues, shortages, technology issues, and processes for avoiding and detecting errors. The focus for our show today is Methadone, a medication that is becoming more common in the perioperative time period and has special considerations for perioperative administration.
We review the article from the February 2018 APSF Newsletter by Murphy and Szokol, “Use of Methadone in the Perioperative Period.” You can find the article here. https://www.apsf.org/article/use-of-methadone-in-the-perioperative-period/
Murphy and Szokol provide some answers to these important questions:
- What is the most effective analgesic dose of methadone?
- What is the most appropriate dose of methadone for patients undergoing various surgical procedures?
- Which patients are at risk for complications related to the administration of methadone?
- Is methadone safe for use in outpatients?
- Does a single dose of methadone cause QT prolongation?
- Can intraoperative methadone reduce the risk of the development of chronic postsurgical pain?
- Is methadone use in the operating room associated with a greater risk of postoperative respiratory depression compared to other opioids?
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© 2021, The Anesthesia Patient Safety Foundation
Hello and welcome back to the Anesthesia Patient Safety Podcast. My name is Alli Bechtel and I am your host. Thank you for joining us for another show. Medication safety is a very important component for safe anesthesia care. You have heard me talk about it before the show, but medication safety is one of the APSF Patient Safety Priorities and this includes drug effects, labeling issues, shortages, technology issues, and processes for avoiding and detecting errors. The focus for our show today is a medication that is becoming more common in the perioperative time period and has special considerations for perioperative administration.
Before we dive into today’s episode, we’d like to recognize Preferred Physicians Medical Risk Retention Group, a major corporate supporter of APSF. Preferred Physicians Medical Risk Retention Group has generously provided unrestricted support as well as research and educational grants to further our vision that “no one shall be harmed by anesthesia care”. Thank you, Preferred Physicians Medical Risk Retention Group – we wouldn’t be able to do all that we do without you!”
And now, the moment you have been waiting for…today we will be reviewing an article from the February 2018 APSF Newsletter by Murphy and Szokol, “Use of Methadone in the Perioperative Period.” To follow along with us, click on the newsletter heading, 4th one down is Newsletter archives, then scroll down to February 2018. Look over to the column on the left and scroll down until you see the article. Are you using methadone as part of your practice?
So, what is the big deal with methadone, what makes this a unique opioid analgesic, and why are we seeing an increasing role for perioperative methadone administration?
Methadone arrived on the scene in 1946 and it has made a big splash in the past 70+ years. At the time of this article in February 2018 there were over 15,000 PubMed citations. This drug is often used as replacement therapy for patients suffering from heroin addiction. Today, though we are going to review the uses of methadone in the perioperative period. Back in 2018 and today, it is important to evaluate alternatives to short acting opioid medications in light of the opioid epidemic in the United states and around the world.
Anesthesia professionals have a strong background in pharmacology and perioperative pain management. In the OR, we often use medications including Fentanyl, Sufentanil, and Remifentanil which are opioid pain medications with short durations of action and then for postoperative pain management we may prescribe hydromorphone or morphine for as needed intermittent injection or on a patient controlled analgesia device. This has been pretty standard treatment for postop surgical patients, but we have recognized that there is a problem with this approach…there can be big changes in the serum opioid concentrations leading to poor pain control or increased side effects including respiratory depression. The phrase for this is the “peaks and valleys” and this is a hallmark of intermittent opioid administration leading to poorly controlled pain after surgery. This can be a big problem as it may be associated with increased morbidity and mortality, lower patient satisfaction, and chronic postoperative pain.
This is where methadone comes in to help with improved perioperative pain management. It is a long-acting opioid that acts as a μ-receptor agonist with an onset time of 6-8 minutes and a half-life of 24-36hrs. The clinical effect resolves following systemic elimination after administration of higher doses. An appropriate dosing strategy for methadone may include the highest dose above the minimal analgesic concentration that does not cause respiratory depression. Studies have shown the methadone administration greater than or equal to 20mg will have a duration of analgesic effect that is close to the half-life of 24-36hrs. You can probably see where the authors are going here because they write that administration of a one-time 20mg methadone dose to an adult surgical patient at the time of induction may provide good pain relief up to POD 2. There is another important consideration for Methadone. It is also an antagonist at the NMDA receptor which may help to prevent hyperalgesia and allodynia following surgery as well as have a role for the treatment of neuropathic pain. But wait, there’s more…Methadone also decreases the reuptake of Serotonin and Norepinephrine in the brain leading to improved mood and this mechanism of action may also have a significant impact on the affective dimensions of pain processing, but you will need to be careful with administration of methadone to patients who are on medications that increase Serotonin levels as there may be an increased risk for Serotonin Syndrome.
And now it is time for a literature review. Let’s head back to the 1980s in Australia where Gourlay and colleagues conducted a study of 23 healthy adult patients for abdominal or orthopedic surgery who received 20mg methadone at the time of anesthesia induction. Nine of the 20 patients did not require any additional pain medications, 6 patients requested non-opioid pain medication postoperatively, and 8 patients required additional opioid administration postop. The investigators found that the duration of analgesia was 18.4 hours. Another trial included 16 adults patients who received 20mg Methadone during induction of anesthesia. In the recovery room, patients received additional methadone doses (1-3 doses for a median total dose of 10mg) if needed for pain control if the patient spontaneously reported significant pain, continued to have an unstimulated respiratory rate greater than 10 breaths per minute, and maintained appropriate level of consciousness. The investigators reported duration of analgesia to be 21 hours with mean pain scores of only 1.5 on a scale from 1-10.
Gourlay and colleagues conducted another study utilizing perioperative methadone administration with 20 adult patients for abdominal surgery who received either 20mg methadone or morphine during induction. In the PACU, patients received either 5mg methadone or 5mg morphine by blinded syringe if needed for pain control. In both groups, patients required additional 8-9mg opioid in the PACU, but the mean duration of analgesia was 21hours for patients in the methadone group and only 6 hours for patients in the morphine group. The good news was that patients in the methadone group had a longer duration of analgesia and there were no reported adverse events in that group as well.
Now, we are going to continue our literature review, but move into the 1990s where studies were done for patients undergoing gynecologic and abdominal surgery as well as pediatric patients undergoing surgery who received methadone for pain management with reduced pain scores and analgesic requirements for the patients who received methadone. These studies had significant limitations though and did not utilize blinding, randomization, or further standardization of the anesthetic technique and the sample sizes were small.
So with that, let’s move up to the year 2011 and take a look at the study by Gottschalk and colleagues that included 30 complex spine patients who were randomized to the methadone group, which included 0.2mg/kg methadone at induction, or the Sufentanil group, which included a bolus at induction followed by an infusion. At 48hours postop, the methadone group had decreased postop opioid requirements and pain scores by 50%. Also, in 2011, a study evaluated methadone pharmacokinetics in 31 adolescent patients for complex spine surgery who received doses of 0.1, 0.2, or 0.3mg/kg methadone up to max dose of 20mg methadone. The results included linear pharmacokinetics for methadone over the dose range.
The next study that we are going to talk about was conducted by the authors of this article! Murphy and colleagues completed a randomized control study of 156 cardiac surgery patients who received either methadone 0.3mg/kg or fentanyl 12 mcg/kg during induction of anesthesia. The results included reduced postop IV morphine requirements in the methadone group by 40% over the 24hours following extubation and decreased pain scores by 30-40% as well as improved patient-perceived quality of pain management for POD 1-3 in the methadone group. The same investigators completed a randomized study of 120 complex spine patients who received either 0.2mg/kg methadone at the beginning of surgery or 2mg hydromorphone at the end of surgery. Patients who received methadone needed less IV and oral opioid medication during the postoperative period and had lower pain scores with improved satisfaction in their pain management during POD 1-3. For better news, the patients who received methadone did not have any adverse reactions in the studies that we talked about today, but keep in mind that these studies were not powered to detect opioid-related respiratory depression.
That was a great literature review of some very interesting studies. Some of the dosing strategies for methadone used in the studies may sound familiar for methadone administration strategies for patients undergoing cardiac, complex spine, and abdominal procedures today. The data suggests that methadone may be safe and effective for perioperative pain management. The authors conclude with several important questions in their 2018 APSF article that still needed to be addressed.
First, “What is the most effective analgesic dose of methadone?” In 2018, there had only been one dose-response study of perioperative methadone administration. The most common doses used were 20mg or 0.2mg/kg. Going forward, it will be interesting to see if higher doses provide better pain control, but it will be important to balance that with the risk for respiratory depression.
Second, “What is the most appropriate dose of methadone for patients undergoing various surgical procedures?” This is an important question because just like for other surgical procedures, the dosing strategy for methadone may be different for various surgical procedures. For example, what is the most appropriate methadone dose for patients undergoing cardiac surgery compared to complex spine surgery? What is the most appropriate dose for patients who are already on chronic opioids prior to surgery and how does this differ for various surgical procedures?
Third, “Which patients are at risk for complications related to the administration of methadone?” This is such an important question as we think about keeping patient safe during anesthesia especially older patients with significant medical comorbidities.
Fourth, “Is methadone safe for outpatients?” In 2018, the authors tell us that studies were currently underway so this will be something that we will need to return to the literature to review going forward.
Fifth, “Does a single dose of methadone cause QT prolongation?” This has long been a boards question about QT prolongation and methadone administration for good reason since patients who take large doses of methadone for a long time are at risk for QT prolongation, torsade de pointes, and death, but the good news is that in the trials of single dose methadone for improved perioperative pain control there were no reported adverse cardiac events. Further investigation is needed in this area though.
The next question is “Can intraoperative methadone reduce the risk of the development of chronic postsurgical pain?” Another great question and another way to help make anesthesia safer for our patients by decreasing the risk for postop chronic pain. The authors tell us that methadone may be helpful for decreasing chronic postsurgical pain by decreasing pain during postop days 1-3 as well as due to its mechanism of action as an NMDA receptor antagonist. Patient with reduced opioids requirements for postoperative pain control following perioperative methadone administration may also have a lower risk for postoperative opioid addiction. It appears that the NMDA receptor blocking is an important piece to this puzzle since this helps to prevent hyperalgesia and allodynia and help prevent tolerance to opioids. Thus, the improved pain control at multiple receptors for longer duration with methadone may be beneficial for preventing chronic postsurgical pain.
One final question that the authors leave us with is “Is methadone use in the operating room associated with greater risk of postoperative respiratory depression compared to other opioids?” Remember the literature review that we did earlier, well, there were no adverse respiratory events following methadone administration in those studies. The bad news is that these were small studies that were not designed to evaluate for postoperative respiratory depression, hypoxemia, or airway obstruction. This is another area where we need more information from future studies. It is important to remember that due to the long half-life of methadone of 24 hours, if there is respiratory depression, patients may require a naloxone infusion since the half-life of naloxone is only 60 minutes.
We made it to the end of the article and our review of perioperative methadone use today, but this is not the end of the story. Methadone may already be playing an important role for perioperative pain management at your institution and we will be on the look-out for additional studies to evaluate the best dose and timing and most appropriate patients for methadone administration as well as evaluation of the safety of perioperative methadone use going forward.
If you have any questions or comments from today’s show, please email us at [email protected].
Visit APSF.org for detailed information and check out the show notes for links to all the topics we discussed today. Plus, you can find us on twitter and Instagram! See the show notes for more details and we can’t wait for you to tag us in a patient safety related tweet or like our next post on Instagram!! Follow along with us for anesthesia patient safety pictures and stories!!
Until next time, stay vigilant so that no one shall be harmed by anesthesia care.
© 2021, The Anesthesia Patient Safety Foundation