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14 Articles in Volume 12, Issue #2
Chronic Pain in the Elderly: Special Challenges
Chronic Pain School
Diagnosis and Management Of Myofascial Pain Syndrome
ECG Screening Prior to Initiating Methadone: Is it Really Necessary?
HCG and Testosterone
How to Manage Unmotivated Pain Patients
March 2012 Pain Research Updates
Methadone for Pain Management
PPM Editorial Board Discusses Methadone Prescription Safety Measures
PPM Launches Online Opioid Calculator
Spontaneous Low Back Pain, Radiculopathy, And Weakness in a 28-Year-Old
Tapering a Patient Off Opioids
The Comorbidity of Chronic Pain and Mental Health Disorders: How to Manage Both
What Are Best Safety Practices For Use of Methadone In the Treatment Of Pain?

What Are Best Safety Practices For Use of Methadone In the Treatment Of Pain?

Questions and Answers with Lynn R. Webster, MD, and Mary Lynn McPherson, PharmD
Practical Pain Management wanted to address the major safety concerns for prescribing physicians and patients regarding methadone use in pain management. To explore this topic, we spoke to Lynn R. Webster, MD, FACPM, FASAM, co-founder and Chief Medical Director of Lifetree Clinical Research, Salt Lake City, Utah, and President Elect for the American Academy of Pain Medicine; and Mary Lynn McPherson, PharmD, BCPS, CPE, Professor and Vice Chair in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy in Baltimore, Maryland. In PPM’s exclusive Q&A, Dr. Webster discusses the misconceptions regarding methadone and ways to safely administer this agent in patients with pain, while Dr. McPherson explains why methadone poses safety risks and how to safely convert patients to methadone from other opioids.

PPM: Dr. Webster, you recently participated in an expert panel, which found that methadone represented less than 5% of the total number of opioid prescriptions each year between 2002 and 2008, yet was implicated in approximately one third of opioid-related deaths.1 Can you please comment on the significance of these findings?

Dr. Webster: These findings are enormously significant. No one can deny that harm from methadone is disproportional to other opioids. This doesn’t mean methadone can’t be used safely, but unfortunately many prescribers do not understand the risk of methadone and contribute to many of the deaths.

PPM: What is the major safety concern regarding the use of methadone in the treatment of pain?

Dr. Webster: The major safety concern is overdose death, caused by respiratory depression and cardiac arrest. All other risks are reversible or manageable. Most overdoses occur when initiating methadone therapy at too high of a dose, rotating from another opioid to methadone, or titrating up the methadone dose too rapidly.

PPM: What are the major patient- and prescriber-related risk factors in patients taking methadone for pain management?

Dr. Webster: Respiratory depression usually occurs with high doses of methadone and when this agent is used in combination with other central nervous system depressants, most commonly benzodiazepines. Actually, much of the research on respiratory depression and opioids originated with methadone and benzodiazepines. All benzodiazepines should be avoided if possible when using methadone, particularly at bedtime. If a benzodiazepine is needed, then a polysomnography should be performed to assess for the safety of the combination.

However, respiratory depression can be the cause of death when initiating methadone therapy at a low dose as well. Sometimes patients will take more medication than instructed because the analgesic effect of methadone is usually 4 to 6 hours, but the respiratory depressant effect of this agent can be up to 100 hours and is cumulative over 1 to 2 weeks.

Other risk factors for respiratory depression include lack of knowledge on methadone prescribing among physicians and unanticipated medical or mental health comborbidities among patients, including sleep-disordered breathing, depression, anxiety, and substance abuse disorders.

PPM: Can you please comment on the importance of electrocardiogram (ECG) monitoring in patients taking methadone?

Dr. Webster: Methadone can prolong the QT interval but not usually at lower doses. However, there could be an additive—if not synergistic—effect with other medications that can prolong the QT interval. Some people are genetically vulnerable to a prolonged QT interval and this can only be assessed with an ECG. Many individuals participate in my clinical trials and it is not uncommon for me to see a QTc >500 milliseconds, which is a level I would be concerned about.

Of course, the occurrence of torsades de pointes is most often seen at higher doses, so dose is a risk factor. As a result, it is advisable to order an ECG to measure the QT interval before initiating methadone therapy and to repeat the ECG as the dose is increased. I usually recommend performing an ECG before starting methadone and at 50 mg, 100 mg, and every 20 mg increase thereafter. However, there is no consensus on when ECGs should be obtained.2

PPM: How can pain practitioners help mitigate the risk for cardiac and respiratory adverse events in patients taking methadone for pain management?

Dr. Webster: Do not use conversion tables to determine an equianalgesic dose of methadone. These tables are flawed and can be fatal to use. There is little to no cross-tolerance between methadone and other opioids. Avoid initiating methadone therapy at a dose of more than 15 mg per day if possible. Do not dose escalate more often than weekly and use an immediate-release opioid to help with pain while titrating methadone to an effective dose over a month or more.

PPM: What misconceptions about methadone should prescribers be aware of?

Dr. Webster: The major misconception is that equianalgesic tables can be used to determine equianalgesic doses of methadone and any other opioid. It is almost always unsafe to start methadone on a dose above 20 mg per day, regardless of the amount of an opioid the patient has been on. In other words, there is little to no cross-tolerance, and when a patient is started on methadone, it should be prescribed as if the patient is opioid naïve.

PPM: How can clinicians best educate themselves and their patients on the proper use of methadone in the treatment of pain? Are there any prescribing guidelines or educational programs that you would refer them to?

Dr. Webster: Use the recommendations outlined in my review article published in the Journal of Opioid Management3 as well as the eight prescribing guidelines described at YourLifeSource.org.4 Other guidelines are available on the American Pain Foundation’s PainSAFE Website.5

In addition, I recommend using the following six simple steps for educating patients about the risks associated with prescription opioids6:

  1. Never take a prescription painkiller unless it is prescribed to you. Everyone responds differently to pain medications. What is safe for one person may not be safe for another.
  2. Do not take pain medicine with alcohol. Never mix the two; it is a dangerous combination that can be deadly. Alcohol increases the toxicity of pain medication.
  3. Do not take more doses than prescribed. Even after the effects of a pain medicine seem to have worn off, it is still depressing the respiratory system. Some medications like methadone may relieve pain for a few hours but will have a prolonged respiratory depressant effect. The body must develop a tolerance to the respiratory depressant effects before the dose can be increased.
  4. Use of other sedative or anti-anxiety medications can be dangerous. Combining pain medicines with other sedative drugs, such as diazepam (eg, Valium), can increase the toxicity of the pain medication. Only take other medications if directed by the prescribing doctor.
  5. Avoid using narcotic medications to facilitate sleep. Narcotic medications can suppress respiration during sleep. Speak to your physician about safe methods to manage pain during sleep.
  6. Lock up prescription painkillers. If consumed by children or other family members, or stolen and sold on the street, prescription pain medicine can kill.

PPM: What would you say to clinicians regarding the risks versus the benefits of methadone for the treatment of chronic pain?

Dr. Webster: If the clinician understands the risks, methadone is a reasonable option for many patients. Methadone is inexpensive, and in some instances, because of cost or formularies, it is the only option for a strong analgesic. However, it is very dangerous if used like other opioids. I would suggest that prescribers only use methadone if they understand the risks.

A Pharmacist’s Perspective on Methadone

PPM: Dr. McPherson, what are the pharmacokinetic issues behind the risk for QTc prolongation/torsades de pointes and respiratory depression in patients taking methadone for pain management?

Dr. McPherson: There are many risk factors for QTc prolongation that predispose patients to the arrhythmia torsades des pointes, including older age, female gender, history of structural heart disease, personal or family history of prolonged QT interval, human immunodeficiency virus (HIV), low potassium level, history of drug-induced torsades des pointes, and use of drugs known to prolong the QT interval (antidepressants, antipsychotic agents, antiretrovirals, antibiotics, potassium- or magnesium-lowering agents, and alcohol or cocaine use).

Specific to the pharmacokinetics of methadone, concurrent use of medications that inhibit the cytochrome P450 3A4 (CYP3A4) enzyme may result in an increased methadone serum concentration, which increases the risk of QTc prolongation. Medications that inhibit the CYP3A4 enzyme include the HIV antivirals (eg, indinavir [Crixivan], nelfinavir [Viracept], ritonavir [Norvir]) and anti-infective agents (eg, clarithromycin [Biaxin], itraconazole [Sporanox], ketoconazole [Feoris, others]), among other agents. Patients should be counseled to contact their healthcare provider if they experience dizziness, palpitations, or syncope when taking methadone.

All µ-receptor opioid agonists including methadone may cause potentially fatal respiratory depression. With methadone, this risk is due to the discrepancy in time to steady-state serum concentration (and cardiac and respiratory adverse effects) and duration of analgesia. Methadone has a very long serum half-life, taking 4 to 7 or more days to achieve steady-state serum concentration, but the duration of analgesia is considerably shorter. Therefore, the peak respiratory depressant effect of methadone typically occurs later and persists longer than the peak analgesic effect, especially when starting methadone therapy. Thus, care must be taken to consider the time to steady-state serum concentration when adjusting the dose of methadone (I usually wait 5 to 7 days, if possible), and there are many differences in conversions to methadone as described below.

PPM: How do you convert patients to methadone from another opioid?

Dr. McPherson: There are many advocated mathematical methods used to switch to methadone. It is critically important that practitioners understand the potency of methadone relative to other opioids. It is very clear that conversion from other opioids is not linear; the higher the dose of the previous opioid the patient was on, the more “potent” the methadone dose is. Regardless of the method of conversion chosen, practitioners should be conservative, starting with a low dose and providing adequate rescue analgesia, and then increasing the dose with caution (no sooner than 4 to 7 days). In my practice, I use a modified Morley-Makin model for methadone conversions: For patients younger than 65 years of age and receiving less than 1,000 mg oral morphine equivalent per day, I use a 10:1 (oral morphine:oral methadone) ratio. For patients over 65 years of age or patients taking between 1,000 and 2,000 mg oral morphine equivalent per day, regardless of age, I use a 20:1 (oral morphine:oral methadone) ratio. For patients receiving greater than 2,000 mg oral morphine equivalent per day, I use an even more conservative ratio (eg, 30:1 or 40:1).

PPM: How do you counsel patients regarding the safe use of methadone?

Dr. McPherson: I tell patients to report any dizziness, palpitations, or syncope to their healthcare provider. Also, I get the family and caregiver involved and ask them to report if the patient seems to be increasingly drowsy or seems to have slowed respiration or periods of apnea, more rapid respirations or shallow breathing, slurred speech, loud snoring, or smaller than usual pupils. I counsel patients to take methadone as directed and to not take extra doses.

Last updated on: March 19, 2012
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