Among the most difficult of long-acting opioids to prescribe and manage is the synthetic opioid methadone. The Centers for Disease Control and Prevention reported in its July 2012 issue of “Vital Signs” that methadone was involved in nearly one-third of deaths from prescription drug overdoses. (See the sidebar “Additional reading.”)
With growing concern about the safety of methadone, the American Pain Society published a new clinical practice guideline in the April Journal of Pain to improve physician education about methadone safety.
Because it is very difficult and dangerous to use, methadone should not be prescribed by a novice or by a practitioner who is not familiar with it, experts agreed.
“One important thing to keep in mind is that methadone should only be chosen for treatment of chronic pain after a trial of other safer opioids,” said George D. Comerci Jr., MD, FACP, a professor of medicine and co-director of the University of New Mexico's ECHO(r) Chronic Pain and Headache Telemedicine Clinic in Albuquerque.
And even then, Dr. Comerci said, methadone is probably most appropriately used in neuropathic pain conditions due to its unique property of blocking the opioid mu receptor and the NMDA receptor, which is often activated in chronic neuropathic pain. Methadone should not be used to treat pain conditions such as fibromyalgia, chronic migraine, or chronic tension headache, and other pain conditions best treated with adjuvant medications.
Why methadone is different
Methadone has appealing characteristics when compared with other long-acting opioids, according to Daniel P. Alford, MD, FACP, an associate professor of medicine at Boston University School of Medicine (BUSM) and director of the Clinical Addiction Research & Education Unit at Boston Medical Center.
“First, methadone is an incredibly cheap drug. Compared with other long-acting opioids, methadone costs pennies,” said Dr. Alford, who also directs the BUSM Safe and Competent Opioid Prescribing Education (SCOPE of Pain) program. “Another point of appeal is that methadone is available in small doses.”
Methadone tablets are available in doses as low as 5 mg. This means that physicians have more flexibility, and in some cases, Dr. Alford said, patients are advised to take only a half-tablet dose of 2.5 mg. Other extended-release opioids start at higher doses that require the patient to already have tolerance to opioid adverse effects such as sedation and respiratory depression.
Another apparent advantage of methadone, however, can make it difficult to manage, according to Roger Chou, MD, MPH, FACP, lead author of the American Pain Society guideline and professor of medicine and medical informatics and clinical epidemiology at Oregon Health & Science University in Portland. Compared with other long-acting opioids with a half-life of 2 to 3 hours, methadone has a half-life that ranges from 15 to 60 hours in most patients and is usually around 30 hours.
“It typically takes 3.5 to 4 half-lives for drug levels to become steady, so with methadone the levels will continue to go up for 4 to 5 days before they steady out,” Dr. Chou said. “This long half-life is one of the reasons we think methadone has been associated with so many overdose deaths, with patients either increasing the dose on their own or a doctor increasing the dose without a long enough interval to let drug levels even out.”
Methadone can also result in prolonged QTc intervals and put patients at risk for fatal arrhythmias, added Dr. Alford.
Testing and counseling
Because methadone can be more challenging, a disciplined approach is required to screen patients before its use.
Before prescribing any opioid, physicians should perform a detailed assessment of the patient that includes a thorough exploration of the pain condition; a complete medical history; a physical examination; a psychosocial evaluation, including a detailed drug and alcohol history; and a family health history. In addition, the patient should be screened for other medical conditions, such as liver disease or severe chronic obstructive pulmonary disease, which may contraindicate opioid therapy.
“I always advise developing a treatment plan for the patient that includes goals and objectives of pain management,” Dr. Comerci said. “I want to help the patient define what he or she hopes to achieve with this medication, such as controlling their pain enough to go out dancing with their spouse or partner, or throwing the ball around with their child.”
This type of defined goal will help physicians assess later if the pain management is working and, if it's not, support a decision to stop the use of methadone.
Physicians should also discuss the risks and benefits of methadone treatment. Risks of treatment with any long-acting opioid are varied and numerous and can include depression, gastrointestinal side effects like constipation, and endocrine issues like low testosterone. Dr. Chou said a baseline echocardiogram is also recommended to screen for people who may already have prolonged QTc interval or those who present with risk factors.
Juliet K. Mavromatis, MD, FACP, an internist practicing in Atlanta, said she also always informs patients that they may become physically dependent or addicted to a long-acting opioid.
“Patients need to know that up front, and they also need to know that their body can become tolerant and that the medication may lose any efficacy over time,” Dr. Mavromatis said.
Treatment and monitoring
As a starting dose, Dr. Comerci said that he prescribes methadone every 8 hours at a dose of 2.5 to 5 mg and will not increase the dose for 7 to 10 days. Some patients metabolize methadone very slowly, and more frequent dosing can result in severe toxicity.
With any long-acting opioid, careful monitoring and follow-up are recommended. Dr. Alford said he applies the concept of “universal precaution.” Because physicians cannot know with 100% certainty that a patient will not misuse long-acting opioids, it is important to apply the principles of risk assessment and monitoring to all patients, he said.
Primary care physicians should monitor patients taking methadone with frequent face-to-face visits (at least monthly early on and at least every 3 months later on), pill counts, and urine drug tests, Dr. Alford said. Physicians should also ask their patients at each visit how methadone is improving their chronic pain and function.
Dr. Alford uses a simple assessment called PEG (pain, enjoyment, general activity). This assessment asks patients to pick a number on a scale from 0 to 10 that best describes their average pain in the past week, and if their pain has interfered with their enjoyment of life and their general activity.
“These 3 questions can quickly address 3 important domains—pain, function and quality of life,” Dr. Alford said. “It does not prove or disprove whether a patient's pain is real or not, but it does allow for a pseudo-objective way to see if opioid therapy is helping.”
During follow-up visits or phone calls, physicians should be screening for aberrant drug-related behaviors that suggest the patient has lost control of the medication, such as running out of his or her prescription early, losing prescriptions, or consistently escalating the dose.
“I also look for patients who have a compulsive use or preoccupation with the medication,” Dr. Alford said. “This is when a patient is so focused on the opioid that they are no longer focused on their pain relief.”
All of the experts interviewed also mentioned the importance of physicians checking any prescription drug monitoring program websites that may be available in their state of practice.
“On Georgia's monitoring website you can search for a patient who is using a scheduled substance and verify that the patient is not getting other controlled substances from other physicians,” Dr. Mavromatis said. A list of prescription drug monitoring programs by state is available online from the Prescription Drug Monitoring Program Training and Technical Assistance Center, a partnership of the Department of Justice Assistance and Brandeis University's Heller School for Social Policy and Management.
Dr. Alford stressed that clinicians are not Drug Enforcement Administration proxies and that even patients who are exhibiting aberrant drug-related behaviors may also truly be experiencing chronic pain. However, if there is a pattern of aberrant behaviors that raises concerns for patient safety, then it is critical to discontinue the opioid regardless of apparent benefits. Ultimately, he said, primary care physicians need to feel comfortable that, when they write a prescription for a drug like methadone, the patient is going to take it exactly as prescribed.
Dr. Comerci recommended referral to a pain management clinic for patients with particularly complex or unusual pain syndromes, such as those associated with multiple sclerosis or complex neuropathies, substance abuse issues, and complex psychiatric disorders, or whenever the physician feels like he or she is outside his or her comfort zone.
However, he also acknowledged that pain management clinics are not available everywhere. In that situation, he said that physicians inexperienced with methadone should reach out to colleagues or local hospitals to try to locate a physician who is more familiar with treating complex pain management cases.
“If a practitioner is not familiar with the use of methadone and wants to use it for a pain condition, we strongly advise that the clinician seek help from someone who knows how to use methadone,” Dr. Comerci said.