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11 Articles in Volume 7, Issue #4
Cervical-Medullary Meningioma
CES in the Treatment of Depression
Deep Penetration Therapeutic Laser
Fibromyalgia Patient Insights
Invoking the Placebo Effect
Multidimensional Ultrasonography
Paradigm Shift in Cancer Pain Management
Prolotherapy for Low Back Pain
Sedation Levels for Intraspinal Injections
Self-Protection Against “Off-label” Lawsuits
Viewpoint: Methadone Successes and Cautions

Viewpoint: Methadone Successes and Cautions

This is a response to my colleague Forest Tennant on his Viewpoint “Methadone Deaths and Warnings.” Many specialists use methadone as their first line slow release opioid formulation. They prefer methadone because of its long half-life, low cost, low street value (less likely to be diverted). In addition, it has NDMA receptor antagonist activity and affects the catecholamine/serotonin system. My concern is it’s prolonged and unpredictable half-life which may extend beyond the average of 12-16 hours (up to 120 hours). The drug may rise to potentially fatal high plasma levels. The other issue is the interaction with CYP inhibitors and CYP 450 enzyme inducers.

I agree with the consensus document published by the American Society of Anesthesiology, “Slow release formulations (morphine and oxycodone) are preferable to methadone for outpatient pain management because of the risk of respiratory depression due to methadone accumulation—especially when taken more than once a day.”1

I recommend that only experienced specialists use methadone and follow the patient closely. I have asked two clinicians from our Share the Risk Model (San Diego) who have the most experience using methadone to share their views on methadone use.

Viewpoint: Methadone Successes and Cautions

The editorial by Dr. Tennant and review of the pharmacokinetics of methadone by Mercurio and McPherson2 in the prior issue provided an excellent overview of this uniquely important opioid. It is critical for the clinician to thoroughly understand its pharmacologic characteristics to safely use it and it should not be prescribed without extensive training. There is no medication more difficult to use for pain than methadone, and often none as rewarding. Despite its unpredictable and very long half life, it may relieve neuropathic pain, pathological itching, allodynia, tolerance, and pain that is refractory to other opioids—even extreme doses of mu opioids. The difference in efficacy may largely be explained by methadone’s antagonism at the N-methyl-d-aspartate (NMDA) receptor, particularly for hyperalgesia and tolerance, although it modulates the catecholamine and serotonin systems as well. All are known to be important in pain control. It has no metabolites and can be used in renal failure.

Cautions and Pitfalls. As with any opioid, use caution in any patient with history of smoking, co-existing sleep apnea, use of benzodiazepines, or sedatives. The only analgesic that must be avoided with methadone is Ultram as it may cause withdrawal.3

Opioids are antinociceptive and pronociceptive, however ultra-low dose oral naltrexone may potentiate the analgesic effect of opioids and allow significant decrease in dosage, thus lowering the potential for side effects.4,5

Particular difficulties in methadone’s use arise in today’s hospital setting where there is a rush to discharge immediately after surgery or a course of treatment, and the physician does not have the luxury of 3 days to wean a patient from a PCA onto oral medication—let alone 7 days to stabilize on a particular dose of methadone. Further, nurses in community hospitals—unlike nurses in cancer centers—may not be as familiar with severe pain and use of opioids and so greater physician supervision is needed, particularly with prn orders. When using methadone intravenously, it is important to monitor potassium and avoid other drugs that may prolong the QTc interval. Since pain may cause cognitive problems—making it difficult to rely upon patients to understand and follow instructions—close follow up is needed and may be required several times a day and night while titrating opioids.

Though methadone is well absorbed by oral and rectal routes, they may not always be practical. A new route of administration was patented in 2005: oral transmucosal methadone.6 Due to its high lipid solubility, 50-70% of the orally bioavailable methadone is absorbed into the bloodstream within the first 2.5 minutes of delivery to the mucosal tissue. That would be ideal for rapid relief in breakthrough pain, or for those in whom it is not possible to use the intravenous route.

Because HIPAA limits access to patient information and prevents notifying the Medical Board of a doctor’s unsafe practice without the patient’s consent, it may be helpful to use an opioid consent form for full patient authorization—allowing communication with physicians, pharmacists, family, friends, and Medical Board—as a prerequisite for treatment. Treating pain in addicts requires extra caution as discussed in the following commentary by Dr. Rand.

Severe pain can have a demoralizing effect that is disabling and is associated with severe socioeconomic and personal burdens. Opioids cannot treat or disentangle all of these issues. Ongoing patient education and the principle of balance must be continually addressed to avoid side effects and to prevent over-reliance upon the use of medication. We use instruments such as pain logs for assessment of pain, and obtain the help of cognitive behavioral therapy, physiotherapy, nonopioid strategies, and lifestyle changes whenever possible to identify and treat the sources of pain. It takes work, time, and constant review, not just adding a drug. Drugs are not miracle cures for everything.

When using an opioid, methadone may be a first line choice. It may relieve lethargy, cognitive impairment, sleep disorders, and depression seen with pain, with other drugs, and opioids or their metabolites. Due to its broad spectrum of action and lack of metabolites, it may improve pain, ability to concentrate, and function that simply cannot otherwise be achieved. The complexity of prescribing methadone requires extra caution for the expert, but its benefit is underappreciated. When other opioids cause neurotoxicity or fail to relieve pain, methadone may be uniquely effective, even in low doses.

— Nancy Sajben, MD

Viewpoint: Control, Monitoring, and Team Approach in Methadone Treatment

Dr. Tennant asks “So, why is it that turning methadone loose to be prescribed by pain practitioners results in a disturbing rate of poisonings?” Methadone has a narrow margin of safety and requires a high level of knowledge about methadone and opiates. The perception that methadone is safe is based on it’s use in the methadone maintenance clinics (MMCs) for addicts which, due to their high level of control and daily monitoring, boast a high margin of safety and a low death rate.

Pain clinics, on the other hand, are expert at maintaining and observing narcotics for pain maintenance, but many do not have concomitant knowledge compatible with recognizing and treating addictive behaviors. Further, the clientele of pain clinics—unlike that of MMCs who have a high degree of illicit street knowledge of taking drugs, fluctuating doses, and poly-pharmaceuticals—have limited knowledge and little or no experience at taking extra meds on their own, as they are only following instructions. So, when special circumstances occur, they have less knowledge about drug use and can make a fatal flaw in taking their own meds.

Perhaps, one of the reasons methadone use may be on the rise is that, as a maintenance narcotic, it may be considered comparable to ongoing long-term opiate treatments of chronic, intractable pain patients. This analogy may have lulled physicians into using methadone, feeling that this would be a safer method of treating the long-term opiate-dependent pain patients when, in fact, methadone is quite tricky and has a narrow margin of safety.

Another big difference is that, in MMCs, dosing is done once daily while in the pain population, dosing is qid. In the MMCs, the morning dose equates to the highest blood levels occurring in the morning when the patients are out and about, not at home accumulating qid doses and other meds late at night.

Medications, Interactions, and Side Effects. Dr. Tenant goes on to state, “The addict patient will likely be taking all sorts of other drugs, such as anti-depressants, benzodiazapams, stimulants and, most commonly, alcohol.” In fact, any patient that comes in on multiple other drugs is clearly a high risk client and may not be a good candidate for methadone.

In the March 2007 PPM article “Using Methadone Effectively and Safely as Analgesia,”2 the point is made that methadone blood levels are frequently altered by the very same drugs that many chronic pain patients are placed on. When one looks at the negative effects of opiates on physiological processes, the potential side-effects of opiates include depression, sleep disorder, anxiety, hyper-somnia, and cognitive impairments—in addition to the potential to cause cardiac conduction problems and respiratory depression. One should be cautious in using benzodiazapams and psychiatric medications in conjunction with methadone—whether the patient has pre-existing drug usage or is prescribed these medications after being placed on methadone. For example, to treat symptoms of depression and anxiety that often occur with chronic pain, oftentimes anti-depressants, psychotropics, and benzodiazapams are prescribed to the methadone patient. As a result, the effect of serum methadone levels are altered and potentially lead to toxic problems.

Evaluation and Treatment. A team approach is recommended by Dr. Shurman, including an addiction and psychiatric consultation—as well as a sleep disorder specialist, if needed—when starting patients on methadone. I concur with Dr. Tennant that certainly the treater should have a high degree of knowledge about meds and addiction in treating patients. When patients come to me for treatment, it is not uncommon for me to spend two to three hours for an initial in-take. But, the reality for an office visit is that there is no adequate reimbursement for that level of screening. Therefore, the team approach is necessary for treatment.

When starting down the road of opiates for pain, patients follow multiple paths, many of which were not anticipated at the inception of the treatment plan. On initial evaluation of the patient, I clinically assess for potential existing neuroplastic differences that predispose an individual to the negative side effects of opioids. I then consider urine drug screening, measurements of oxygen saturation, and respiratory activity when evaluating side-effects of opiates such as lethargy, depression, insomnia, hyper-somnia, cognitive impairment, and sleep disorders. One has to be cautious that we don’t attribute all side-effects that occur to the pain itself, and realize that the drugs are frequently the responsible agents causing those symptoms.

I might include urine drug screening to assess for drug abuse or addiction. When I am consulting or treating pain in the addicted population, urine Ethyl Glucuronide(ETG) testing for recent alcohol use is specific and available. Quantitative methadone levels can be assessed. Hepatic disease and issues of delayed clearance from polypharmacuticals or alcohol can be explored. Technology is evolving for methods of measuring conjugated and unconjugated opioids that has the potential to assess opioid accumulation or delayed clearance, as well as assessing for the possibility of diversion of prescibed medication.

— Jerry N. Rand, MD


We all agree that methadone is an excellent drug for pain management but only in experienced hands with close follow up. However, for practitioners inexperienced with methadone, it may be easiest to follow the American Society of Anesthesiology guidelines and use morphine/oxycodone derivatives for outpatient pain management. It is important to note, however, that standard practice includes other opioids with variable duration of action and a better safety profile.

Last updated on: January 5, 2012
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