The Hospice Clinician Blog

Methadone in Hospice and Palliative Care

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Jim Joyner, Pharm.D, our Director of Clinical Operations, recently presented an informative 90 minute program about Methadone use in hospice at the Minnesota Hospice and Palliative Care Conference on April 12th. The program was titled "Methadone: Is This Old Drug in Your Future?" This well received program was presented again this month in California's beautiful Napa Valley for the San Francisco Bay Area Chapter of the Hospice and Palliative Nurses Association on May 1st. Outcome Resources specializes in assisting hospices with increasing utilization of Methadone as a long-acting opioid. While Methadone has clinically significant advantages in the palliative care setting, it is also cost effective. Our team of PharmDs can assist your hospice with education programs for nurses and prescribing physicians, consultation for specific patients, protocols and guidelines for use. Check back soon for a link to a video of Dr. Joyner's presentation. Also, see the previous articles on our Blog regarding Methadone for more information.

Methadone for Hospice Patients Part 2

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Advantages of Methadone in Hospice

Unlike other opioids, Methadone has significant ability to inhibit the NMDA receptor(n-methyl-d-aspartate receptor) at therapeutic doses (Davis, Walsh (2001) Support Care Cancer; 9:73-76). Activation of the NMDA receptor produces central nervous system sensitization, so this pharmacological effect makes Methadone a much more effective drug for neuropathic pain than other opioids. There is also evidence that inhibitory activity at the NMDA receptor sites reduces the possibility of tolerance to Methadone when compared to that exhibited by other opioids (Hewitt (2000) Clin J Pain; 16:S73-79).

In addition to being a long-acting opioid that may be dosed at 8 to 12 hour intervals, Methadone is available in a variety of dosage forms:

• Tablets: 5mg, 10mg, and 40mg (dispersible tablet)
• Oral solution: 5mg/5ml, 10mg/5ml
• Oral concentrate: 10mg/ml
• Sterile injection: 10mg/ml.

Methadone is well absorbed by the sublingual route which may be of critical importance in patients that are unable to swallow and in whom infusion therapy is not feasible (Coluzzi (1998) J Pain & Symptom Management; 16:184-192). Although oral morphine solution is often administered by the sublingual route, there is evidence to suggest that it is poorly absorbed because of its low lipid solubility (Coluzzi (1998) J Pain & Symptom Management; 16:184-192). Methadone may offer distinct advantages over oral morphine solution when the sublingual route of administration is indicated.

One of the most impressive advantages to this unique opioid is its very low cost compared with other potent opioid drugs. Methadone is about one-tenth of the cost of an equivalent dose of the Fentanyl patch (generic) and one-seventh the cost of Morphine extended release tablets (generic).

Indications for use of methadone for hospice pain management

Methadone is appropriate for treating chronic severe pain, including cancer pain and neuropathic pain. It is an excellent choice when rotating a patient from other opioid therapy which may be either ineffective or causing intolerable side effects. A study of cancer patients who had uncontrolled pain and/or intolerable adverse effects showed 80% of the patients reported improvement in pain control and reduction of adverse effects following rotation to Methadone (Mercadante, et al. (2001) J Clin Oncology; 19:2898-2904). Morphine has been associated with a variety of adverse effects including pseudo-allergy (itching, flushing, sweating) and tremors. Methadone is synthetic and belongs to a distinctly different structural class than Morphine, making it a good alternative to patients exhibiting the pseudo-allergy symptoms.

In patients receiving Morphine who have renal impairment, an active metabolite, Morphine-3-glucuronide can accumulate and is thought to be associated with neurotoxic symptoms (myoclonus, allodynia, and hyperalgesia). (Anderson, et al. (2003) J. Pain & Symptom Management; 25: 74-91). There is also evidence that Morphine-3-glucuronide may actually antagonize the analgesic effect of Morphine itself. (Anderson, et al. (2003) J. Pain & Symptom Management; 25: 74-91). Since Methadone does not have any active metabolites and the dosage does not need to be adjusted for renal impairment, it is ideal for the patient with renal impairment or for a patient on Morphine that is exhibiting neurotoxic side effects.

Drug interactions with Methadone

There are a variety of potential drug interactions with Methadone. Many of the potential interactions cited in the literature have not been associated with documented clinical effects, even though alterations in Methadone plasma concentrations may be statistically significant. This may be due to the pharmacodynamics of the drug, specifically; long half-life, extensive distribution, and extensive tissue binding. These factors may blunt the clinical impact of some potentially interacting drugs that may induce or inhibit inactivation of Methadone in the liver. Refer to the drug interaction table for details. There are various strategies for managing drug interactions, however, if the combination of interacting drugs cannot be avoided a general rule of thumb is to adjust the Methadone dose by 25%; upwards if the interacting drug has been shown to result in decreased Methadone clinical effects or down if the interacting drug has been shown to result in increased Methadone clinical effects. Dosage adjustment may not be necessary for drugs which have the potential for altering enzymatic metabolism of Methadone, yet have not been shown to result in a change in the clinical status of patients. The clinician, however, should be alert to possible changes in the clinical picture when any potentially interacting drug is added or removed.

Conclusion

Methadone is a valuable analgesic with distinct advantages over other opioids that make it a viable option for treatment of chronic severe pain. Clinicians who prescribe Methadone need to be familiar with its unique pharmacokinetics and the dosing ramifications for safe and effective use of the drug.

Outcome Resources is dedicated to supporting hospices in the utilization of methadone and provides consultations and education programs geared toward this and other palliative appropriate medications. Call today to learn more about how we can assist your hospice by providing cutting-edge clinical support services including a direct line to experienced pharmacists.

Methadone for Hospice Patients Part 1

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Introduction

Methadone is a potent synthetic opioid with unique characteristics that offer some distinct advantages over other opioid drugs. It was developed as an analgesic in Germany in the late 1940s. Despite its advantages, the level of Methadone prescribing for chronic pain has remained relatively low until recently. Primary reasons for the lack of widespread use of Methadone for chronic pain include:

• The difficulty of titrating the dosage when initiating Methadone therapy
• The fact that Methadone may carry some negative stigma since it is best known as a treatment of opioid drug addiction
• Complex pharmacokinetics, potential drug interactions, and dynamic opioid conversion ratios

Methadone and Prescriptive Authority

Regulations restrict the prescribing of Methadone for treatment of addiction to FDA approved drug treatment programs. These restrictions do not apply when Methadone is prescribed to treat pain, however, some healthcare professionals have been reluctant to prescribe it due to fear of scrutiny by regulatory agencies (Baumrucker (2000). Amer. J. Hospice & Palliative Care; 17(3): 153-154). Methadone is a schedule II controlled substance that may be prescribed for treatment of pain by any physician with valid Drug Enforcement Agency registration.

Pharmacokinetics of Methadone

Methadone is a fat soluble drug which is widely distributed and bound to various tissues. The extensive distribution and tissue binding is responsible for the long half-life of the drug and extended duration of analgesic effect upon continuous chronic use. (Goodman and Gilman. The Pharmacological Basis of Therapeutics 11th Edition). The Methadone distribution phase is complete in 4 to 6 days at which time a "steady-state" condition is achieved between drug levels in the plasma and drug tissue levels. It is because of this extensive distribution phase that the drug may appear to have a shorter duration of analgesic action initially, then exhibit a longer half-life & extended duration of action once the distribution phase is complete. During the last few days of the distribution phase after Methadone therapy is initiated the clinician should be alert for signs of drug accumulation and possible adverse effects (somnolence, delirium, respiratory depression). Methadone is primarily eliminated by metabolism in the liver to inactive metabolites.(Eap, et al. (2002) Clin. Pharmacokinetics 41: 1153-93).

There is no need for dosage adjustment of Methadone in patients with renal impairment such as those often required with Morphine which has a potentially toxic metabolite that can accumulate and cause toxicity in these patients.

Methadone Dosage for Hospice Patients

For opioid naïve patients, a starting dose of 2.5mg orally every Q8hr has been suggested (The College of Physicians and Surgeons of Ontario (Nov 2000)). In frail, elderly patients the starting dose may need to be reduced to 2.5mg Q12h. The duration of analgesic effect of a single dose may be in the range of 4 to 6 hours for many patients during the initial distribution phase when starting Methadone treatment, therefore, a need for PRN doses should be expected in order to titrate to the therapeutic dose during this period.

Breakthrough pain can be managed by using Methadone doses equal to 25-50% of the total daily routine dose at intervals of every 4 hours as needed during the distribution phase. At the end of the distribution phase on approximately Day 5, the total amount of PRN Methadone required for the previous 24 hours is added to the routine total daily dosage and administered in divided doses at 8 or 12 hour intervals. Alternatively, oral morphine solution may be used on a PRN basis for management of breakthrough pain.

For patients who will be converted from another opioid to Methadone, there are a variety of published methodologies available. Outcome Resources pharmacists use  the following guidelines for conversion which were derived from Ayonrinde and Bridge (Med J Aust 2000) and Ripamonti (Cancer Pain & Palliative Care 1999):

Methadone Conversion Guide for Hospice

• Convert current opioid dose to the total daily dose of oral Morphine
  equivalent (see Opioid Conversion Table below)
• Convert the oral Morphine equivalent to the total daily dose
  of oral Methadone (see Morphine to Methadone ratio Table below)
• Divide total daily Methadone dose into 3 or 2 doses and administer
  at 8 or 12 hour intervals

Morphine to Methadone Ratio Table

Sample Methadone Conversion for hospice: 

We have a patient on Fentanyl patch 300mcg/hr that we want to convert to Methadone. Fentanyl is converted to an oral Morphine equivalent of 600mg/day using the opioid conversion table. The oral morphine equivalent is then converted to oral Methadone 60mg/day using the Morphine to Methadone ratio table. This total daily dose is then given in divided doses at 20mg Q8hr. This may be further converted to a Q12h regimen at 30mg Q12h for many patients allowing for greater convenience and compliance.

All equi-analgesic ratios are approximations and are intended to be used as tools to guide the clinician in the determination of an equivalent dosage. Final decisions regarding the appropriate conversion doses should be tempered by individual patient clinical factors including current level of pain, history of compliance with the previous regimen, renal and/or hepatic function, and potential drug interactions.

TO BE CONTINUED... See Part 2 for Advantages of Methadone, Indications for Use, and Drug Interactions.

Outcome Resources is dedicated to supporting hospices in the utilization of methadone and provides consultations and education programs for hospices geared toward this and other palliative appropriate medications. Call today to learn more or contact us for a Free Hospice Pharmacy Consultation.

Pain Management in Hospice Patients: Reactions to Opioids

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Hospice patients may report allergies to opioids, but often these are pseudoallergies consisting of symptoms of itching, flushing and sweating. Pseudoallergy type reactions are relatively common.

True allergy to opioids is rare. (1) Pseudoallergy is caused by release of histamine from the mast cells in the skin, a non-immunologic event. (2) True allergy is believed to be IgE mediated or T-cell mediated. (3) If the reaction is only flushing, itching, or sweating the opioid can often be continued with the addition of an antihistamine or dose reduction. (4) If the true nature of the reaction to an opioid is not clarified, the hospice patient may be incorrectly "labeled" as allergic to opioids and opioid drugs may be withheld unnecessarily.

If the reaction consists of hives, increased heart rate, severe hypotension, or bronchospasm the patient should be assumed to be exhibiting a true allergic reaction and the clinician will need to decide which, if any, opioid is safe for the hospice patient.

Codeine, Morphine, and Meperidine are associated with the most allergictype reactions. (1) It has been suggested that hospice patients allergic to one opioid are less likely to react to an opioid in a different structural class.

It is reasonable to consider rotating from an opioid from one class to one from another distinct class in some situations. The 3 main structural classes are as follows:

• Morphine group: morphine, codeine hydrocodone, oxycodone, oxymorphone, hydromorphone, levorphanol

• Diphenylheptanes: methadone, propoxyphene

• Phenylpiperidines: fentanyl, meperidine

Some patients may experience localized itching and redness underneath the Fentanyl patch. Patch site rotation is very important to reduce this risk. This reaction can be managed by topical application of a steroid, such as triamcinolone spray prior to application of the patch.

Although many hospice patients may report a history of allergy to opioids, most have only experienced a side effect . Proper selection of an opioid medication based upon past history can result in significantly improved outcomes in pain management for the hospice patient.