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Methadone: Handle with Care


 

Few topics in hospital-based pain management generate such diverse viewpoints as the use of methadone as an analgesic. Increasingly ordered by hospice physicians and some hospitalists as a tool for managing difficult pain cases, it is also coming under scrutiny for risks related to cardiac complications, respiratory depression, and the challenges of determining appropriate doses.

For some, the risks are grave enough to contraindicate methadone prescription for use in routine hospital practice, unless the hospitalist is well-versed in its use and has access to a pharmacist or other pain expert to review medication orders. Hospitalists should also be aware of the Food and Drug Administration’s strongly worded November 2006 Public Health Advisory, “Methadone Use for Pain Control May Result in Death and Life-Threatening Changes in Breathing and Heart Beat.”1

The FDA stopped short of recommending against the use of methadone as an analgesic, but it admonished physicians to use caution when prescribing it for patients unused to the drug—particularly during drug initiation, conversion from another opioid, or titration upward. Patients should be cautioned to take the drug exactly as prescribed. The advisory also recommended a new maximum initial dose of 30 mg per day (typically prescribed 10 mg tid), when initiating methadone for pain management.

Jean Youngwerth, MD, associate program director of the University of Colorado at Denver and Health Sciences Center, is well aware of the benefits and risks of prescribing methadone in her dual roles as hospitalist and palliative care consultant. “It is a great analgesic, becoming a lot more popular in recent years,” Dr. Youngwerth says. “It’s also ridiculously cheap [often under a dollar a day], which is an important consideration for some of our patients returning home with chronic pain. For other patients, it’s an extra analgesic tool, giving good pain relief, especially for refractory somatic or neuropathic pain.”

But methadone also has downsides. “Its pharmaco-kinetics are so complex and poorly understood that people unfamiliar with prescribing it can get in trouble in a hurry,” Dr. Youngwerth says. “You can kill people with oversedation. I do not prescribe it in my hospitalist practice and I discourage other hospitalists from prescribing it for their patients without consulting a pain or palliative care specialist. You don’t see its maximal effects until at least three to four days out, and that’s usually too long for the hospitalist. When I start palliative care patients on methadone, I normally keep them in the hospital for three or four days so that I can monitor the effects.”

Dr. Youngwerth believes her experience in pain management justifies prescribing methadone for palliative care patients. Even so, she always calls one of the local physician pain experts she works with or a hospital pharmacist to make sure she is ordering it safely and correctly. “I don’t think doctors should be scared off by all the bad publicity about methadone, but they need to realize these are valid concerns,” she says. “People run into problems when they assume that it is just another opioid.”

Hospitalists must recognize the stark realities of using the drug.

“Methadone is the easiest opioid to kill someone with,” says Gail Gazelle, MD, palliative care physician with MD Can Help and Harvard Medical School in Boston. “At the same time, its unique properties can give analgesic effects you can get from no other drug.”

For hospitalists, these issues are complicated by their short involvement with hospitalized patients, who are quickly prepped for discharge back to various community settings and living situations.

Dr. Gazelle wonders, “Is a short hospital stay the right place to initiate methadone treatment, given all of the complications?” If the answer is yes, communicating with the attending and agreeing on a plan for its continued use after discharge from the hospital are essential.

Although narcotic abuse is notoriously difficult to manage, with high relapse rates in every setting, methadone maintenance therapy (MMT) has been shown to reduce overall rates of abuse of other drugs, overdose and death, criminal activity, needle sharing, and commercial sex work. Methadone maintenance is a long-term strategy. The drug is provided as a substitute, not a cure, for narcotic abuse. Patients may continue to receive their daily maintenance dose for years. One-year retention rates in several large studies of MMT have ranged from 25% to 60%, while rates of relapse after leaving MMT are high. Stopping methadone use poses the same challenges as quitting any narcotic and should only be done under a doctor’s care.

Methadone is also used to treat heroin withdrawal, an issue for some hospitalized patients. Prescribing methadone for maintenance therapy is limited to federally licensed methadone treatment programs.

A MYSTERIOUS OPIOID

Methadone is a potent synthetic opioid developed in Germany in the late 1930s. It mirrors analgesic effects—and unwanted side effects, such as constipation and respiratory depression—of commonly used opioids such as morphine. But it also has some unique, not fully understood pharmaco-kinetic qualities.

Research at the level of basic science—based on its binding properties to NMDA (n-methyl, d-asparte) receptors in the central nervous system—suggests tantalizing potential for managing hard-to-treat neuropathic pain syndromes. Some experts say, however, that the potential is still largely theoretical and evidence is not yet sufficient to conclusively demonstrate this benefit.2-4

Dosing and equianalgesic conversions are complicated by the fact that methadone’s relative potency, compared with morphine, increases as the volume of analgesic increases. Several studies have recommended a morphine/ methadone ratio of 10:1 for patients taking less than 1,000 mg of oral morphine per day and 15:1 for patients taking more than 1,000 mg of oral morphine.5,6 More recent conversion charts from the End-of-Life/Palliative Education Resource Center at the Medical College of Wisconsin and manufacturer Roxane Laboratories suggest an even greater conversion range: 3:1 or 5:1 for oral morphine doses under 100 mg per day but 20:1 for morphine doses more than 1,000 mg.7

Methadone is more familiar and better tested in the context of treating narcotic withdrawal and dependence. Methadone maintenance therapy (MMT), introduced in 1964, is provided to an estimated 210,000 people with the disease of opioid substance abuse.8 A single daily maintenance dose, administered at one of the country’s 785 federally certified methadone treatment centers, reduces the addict’s appetite for heroin and prevents symptoms of withdrawal, but without heroin’s “high.” The White House Office of National Drug Control Policy calls methadone “a rigorously well-tested medication that is safe and efficacious for the treatment of narcotic withdrawal and dependence.”9 —LB

Complications

There are several critical facets of this drug hospitalists must be aware of:

Unpredictable half-life: Meth­a­­done, relative to other opioids, has high lipid solubility, slow metabolism, and a typical half-life ranging from 15 to 60 hours—although it can be longer. Methadone’s analgesic effect is shorter-lived, so analgesic doses should be given two, three, or four times daily. But the longer half-life means it can take three days or more after the initial dose before the drug’s full effect—on respiration for example—is known. That is why therapeutic doses can build to toxic levels. There is also wide variation in its effects among patients. Guidelines suggest titrating methadone upward for increased analgesic effect should not be attempted until at least three days after the first dose.

Respiratory depression: This is an issue when the drug is initiated in an opioid-naïve patient or is too rapidly titrated. Deaths from methadone have been seen at doses once considered safe. Physicians are cautioned to start patients on low doses while using other, short-acting opioids for breakthrough pain and frequently assessing for signs of overdose or respiratory depression, such as difficulty in breathing, shallow breathing, extreme sleepiness, or inability to think, talk, or walk normally.

Effect on heart arrhythmias: Methadone can prolong the QTc interval in heart function, leading to a potentially serious cardiac abnormality known as torsade de pointes. The potential for cardiac deaths is another complicating factor that may contraindicate methadone for patients at risk for developing a prolonged QTc interval, including patients with cardiac hypertrophy, hypokalemia, or hypomagnesemia, or a history of cardiac conduction abnormalities or taking medications affecting cardiac conduction. A current EKG may be an appropriate precaution when initiating methadone in elderly patients who have a cardiac history or are receiving methadone in high doses or by intravenous administration.

Drug interactions: The list of drugs that interact with methadone is long, with potential for unwanted side effects and increased or decreased potency. This list includes most anti-retroviral treatments for HIV; sedatives, tranquilizers, barbiturates, seizure medications, muscle relaxants, or any central nervous system depressants; certain steroids and anti-fungals; even over-the-counter cough and cold medications. Also watch for medications that treat irregular heartbeat or prolong the QTc interval. Pharmaceutical company labels for methadone, as well as the FDA advisory, contain a more complete list of drugs that interact with methadone. Always review with patients the other medications they take, including over-the-counter medications and alternative treatments.

Other complications: Metha­done should not be prescribed when opioids in general are contraindicated. It can be a management challenge to convert patients from methadone back to other opioids. Another complication of prescribing methadone is the negative publicity it has received in recent years, combined with the stigma of its associations with drug treatment. Some patients, families, or attending physicians may be leery of using it as a pain reliever. It may not be worth titrating methadone to the correct dose in the hospital if it is going to be discontinued post-discharge.

A series of articles in The Charleston (W.Va.) Gazette starting in June 2006 alerted many to the fact methadone is listed by medical examiners nationwide as a cause of death more often than any other prescription pain reliever.10 Methadone was implicated in nearly 4,000 deaths in 2006, four times as many as in 1999. Most of the deaths were considered accidental, and many involved combinations with other drugs—although some were in patients taking methadone as prescribed.

Hospitalists can expect that the diverse caseloads they see likely will include some patients taking methadone. Some may be getting it as an analgesic prescribed by a community physician, pain clinic, or hospice. Others in MMT and receiving a daily dose to manage their addiction disorder may present at the hospital with a different medical problem and perhaps new pain issues.

The hospitalist should not take it for granted that patients on MMT are not also intoxicated or abusing methadone or other drugs, says Michael Weaver, MD, pain and addiction specialist at Virginia Commonwealth University Medical Center in Richmond. Nor should they assume MMT doses are providing adequate analgesia.

“The bottom line in all of these situations is communication,” Dr. Weaver says. Talk to the medical director of the methadone clinic or the community physician who prescribed methadone as an analgesic. Verify the patient’s status, confirm dosage, and discuss the pain issues that need to be addressed—while recognizing pain relief is an appropriate expectation of any hospitalized patient, regardless of drug history or treatment.

Generally, Dr. Weaver says, the maintenance dose of methadone would continue during the hospital stay, and a different analgesic would be ordered for the pain—although the clinic physician may have other ideas. Changing methadone dose or schedule—or attempting to wean a patient off methadone—is not a decision a hospitalist should make unilaterally.11

Advocates extol methadone’s powerful analgesic qualities, even at low doses and especially for patients with difficult-to-manage cancer or neuropathic pain. But its unpredictability, complications, and potential side effects—including death—point to the need for caution in hospital practice.

Methadone’s Merits

Why would a hospitalist want to prescribe a drug that comes with so many caveats?

Carol Jessop, MD, a hospitalist and palliative care consultant at Alta Bates Summit Medical Center in Berkeley, Calif., uses methadone—often in combination with the anti-depressant desipramine or the anticonvulsant gabapentin—to treat complex regional pain syndromes and neuropathic pain.

Dr. Jessop carefully assesses patients for neuropathic pain, listening for descriptors such as burning, stinging, or numbing. These are the patients for whom she most often receives palliative care consultations, often following years of out-of-control pain or lack of response to high doses of other opioids. “My job is much easier now that I understand the difference between nocioceptive and neuropathic pain,” she notes.

“I think methadone is magic, perhaps due to its effect on the NMDA (n-methyl, d-asparte) receptors,” Dr. Jessop says. “I’m also convinced from my clinical experience that there can be nerve healing going on when these pain syndromes are effectively treated. I had a patient with horrible phantom pain following multiple hip surgeries and amputation of his leg. He was referred by a family practitioner, who said, ‘I cannot get this man’s pain under control.’ ” The patient’s pain is now controlled with methadone, 30 mg three times a day. He rarely needs to take his hydromorphone (Dilaudid) for breakthrough pain, and he is able to use his prosthetic leg—which would have been unthinkable before.

Dr. Jessop believes low doses of methadone—even lower than the conversion charts recommend—can have a big effect. “I don’t have problems with methadone because I’m so careful in prescribing it,” she says. “I also work closely with the attending physician and give patients my cell phone number when they return home. It is important to get the family involved and to be clear about the risks and benefits.”

Brad Stuart, MD, senior medical director of Sutter VNA and Hospice in Northern California, also believes methadone can be a wonderful pain management tool. “There is no substitute, in my estimation, to adding a little methadone to the opioid regimen—even just 5 mg of liquid three times a day—for difficult neuropathic pain cases,” Dr. Stuart says. “It’s true that you don’t want to raise the dose too quickly. But I find that it’s unusual not to see benefit in these kinds of patients. I disagree with those who would advise hospitalists to stay away from methadone for treating refractory neuropathic pain. If you start slow and go slow, the risks are small relative to the gain.”

Eduardo Bruera, MD, a palliative care physician at M.D. Anderson Cancer Center in Houston, is another believer in methadone for difficult pain cases, although he emphasizes that his experience is limited to the pain associated with cancer. Dr. Bruera does not use methadone as a first-line analgesic, but he finds it effective when other opioids have not been. “Patients who continue to have a lot of pain after multiple escalating opioid doses or signs of opioid toxicity may be signaling that the opioid you’re using is not working,” he says. “If we make three or four dose changes without response, it’s time to change the opioid.”

Dr. Bruera acknowledges that persuasive research studies to establish methadone’s purported efficacy in treating neuropathic pain have not been conducted. “Unfortunately, methadone is an orphan drug, so we don’t know who would pay for those studies. Should we consider it as a first-line opioid for cancer pain? Again, that is an unanswered question.”

Dr. Bruera has been involved in a number of the few published studies and reviews of methadone’s analgesic efficacy, and he is engaged in ongoing orphan drug status research.12, 13

Methadone as Analgesic

Stephen Bekanich, MD, hospitalist and palliative care consultant at the University of Utah Medical Center in Salt Lake City, falls in the middle range of opinions on methadone.

“From the hospitalist’s standpoint, there are downsides,” Dr. Bekanich says. “People who don’t understand how to titrate it may change doses on a daily basis or more often, which is dangerous. They may not understand the dosing equivalents or pay enough attention to drug interactions.

“Of all the opioids, careful assessment and follow-up may be the most important with methadone. Always make sure you have concrete post-discharge plans. If I didn’t have a pharmacist to collaborate with, as a hospitalist I’d probably stay away from it. But it’s different when I put on my palliative care hat.”

Rachelle Bernacki, MD, a hospitalist, palliative care physician and geriatrician at the University of California-San Francisco Medical Center, agrees methadone can be a useful analgesic­—particularly when other opioids have failed to relieve the pain. “But I don’t start with it; I may add a small dose of methadone to the existing regimen for complex pain,” she says.

“I caution my residents not to try methadone without consulting with someone familiar with the drug,” explains Dr. Bernacki, who adds that she is fortunate to work with a pharmacist at UCSF who is an expert in pain management and palliative medicine. “Having taught residents, I can confirm that there is a lot of confusion about its use. But I have also used methadone in my outpatient geriatric practice—with fantastic results.”

Paresh Patel, MD, a hospitalist at VCU Medical Center, says he and his colleagues use methadone as a second-line analgesic when pain is not well managed with morphine. He always keeps an eye out for the risks, including potential interactions with psychiatric medications and the need to look at EKGs.

Dr. Patel says conversion from other opioids is one of the biggest challenges in using methadone. He is not satisfied with the various published opioid conversion charts and relies on experience and trial and error. “I always wait 48 hours before titrating up,” he says.

More research is needed in this area, Dr. Patel says, and he is thinking of getting involved in a methadone research project. TH

Larry Beresford is a frequent contributor to The Hospitalist.

References

  1. Food and Drug Administration. FDA Public Health Advisory: Methadone use for pain control may result in death and life-threatening changes in breathing and heart beat. Available at: www.fda.gov/cder/drug/advisory/methadone.htm. Last accessed June 4, 2007.
  2. Moulin DE, Palma D, Watling C, et al. Methadone in the management of intractable neuropathic noncancer pain. Can J Neurol Sci. 2005 Aug: 32(3); 340-343.
  3. Altier N, Dion D, Boulanger A, et al. Management of chronic neuropathic pain with methadone: A review of 13 cases. Clin J Pain. 2005 Jul-Aug;21(4):364-369.
  4. Morley JS, Bridson J, Nash TP, et al. Low-dose methadone has an analgesic effect in neuropathic pain: A double-blind randomized controlled crossover trial. Palliat Med. 2003 Oct;17(7):576-587.
  5. Lawlor PG, Turner KS, Hanson J, et al. Dose ratio between morphine and methadone in patients with cancer pain: A retrospective study. Cancer. 1998 Mar;82(6):1167-1173.
  6. Ripamonti C, De Conno F, Groff L, et al. Equianal-gesic dose/ratio between methadone and other opioid agonists in cancer pain: Comparison of two clinical experiences. Ann Oncol. 1998 Jan;9(1):79-83.
  7. Gazelle G, Fine PG. Fast Fact and Concept #75: Methadone for the treatment of pain. End-of-Life/Palliative Education Resource Center, Medical College of Wisconsin, Milwaukee, www.eperc.mcw.edu/ff_index.htm; and Roxane Laboratories, Inc., label for dolophine hydrochloride CH (methadone hydrochloride tablets).
  8. American Methadone Treatment Association. 1998 Methadone Maintenance Program and Patient Census in the U.S., New York, NY, April 1999.
  9. Office of National Drug Control Policy. Fact sheet. Available at: www.whitehousedrugpolicy.gov. Last accessed June 4, 2007.
  10. Finn S, Tuckwiller T. The Killer Cure. The Charlotte (W. Va.) Gazette. Available at: www.wvgazette.com. Last accessed June 29, 2007.
  11. Weaver MF, Schnoll SH. Opioid treatment of chronic pain in patients with addiction. J Pain Palliat Care Pharmacother. 2002:16(3);5-26.
  12. Bruera E, Sweeney C. Methadone use in cancer patients with pain: A review. J Palliat Med. 2002 Feb;5(1):127-137.
  13. Bruera E, Palmer JL, Bosnjak S, et al. Methadone versus morphine as a first-line strong opioid for cancer pain: A randomized, double-blind study. J Clin Oncol. 2004 Jan 1;22(1):185-192.

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