The Hospice Clinician Blog

Practitioners are often unfamiliar with the term “incomplete cross-tolerance” as it applies to opioids, and are unsure of how to apply the principles of incomplete cross-tolerance when converting from one opioid to another. In hospice care, opioid conversions happen frequently, such as when a patient experiences intolerable side effects, the patient needs an alternative route of administration, or the hospice is looking for a more cost-effective alternative. To prevent overdose when converting from one opioid to another, one must always consider incomplete cross-tolerance when calculating a dose of the new opioid.

Cross-tolerance occurs when a patient exhibits tolerance to a drug they have never had before as a result of being tolerant to a similar drug. We know that this happens with opioids – when a patient becomes tolerant to one opioid, such as morphine, he or she will exhibit some level of tolerance to ALL opioids. But this cross-tolerance is incomplete, meaning that the patient currently taking morphine who is tolerant to morphine will not have the same level of tolerance to other opioids – it will be reduced.

The reason incomplete cross-tolerance occurs is that the different opioids have a slightly different pharmacodynamic profile – in other words, they affect the various subtypes of the mu-opioid receptor is slightly different ways. So when a patient switches from one opioid to another, the new opioid may hit the mu opioid receptor subtypes in a way that they patient has not experienced before, and has not yet developed tolerance to at the same level. The new opioid may exert more powerful effects than the previous opioid because of this reduced tolerance – and this puts the patient at risk of overdose.

What this means practically is that, when you are converting a patient from one opioid to another, and you calculate the dose of the new opioid using equianalgesic ratios, you must then reduce the dose of the new opioid by a certain percentage to account for incomplete cross-tolerance. Some experts recommend always reducing the new opioid dose by 50%, and then titrating from there. Other experts recommend taking into account the patient’s current level of pain control before deciding how much to reduce the new opioid dose. For example, one frequently advocated approach is to reduce the new opioid dose by 50% if the patient’s pain control is currently good, reduce by 25% if pain control is only moderate, and do not reduce at all if pain control is poor.

Keeping these principles in mind, an example calculation may look like this:

Let’s say you have a patient taking OxyContin 80 mg BID and you wish to convert to extended-release morphine. The equianalgesic ratio for oxycodone to morphine is 1 mg of oxycodone = 1.5 mg of morphine. So you’d begin by calculating the new morphine dose using this ratio:
80 mg oxycodone BID = 160 mg oxycodone per day
160 mg of oxycodone x 1.5 = 240 mg of morphine

Now, reduce the morphine dose for incomplete cross-tolerance.

240 mg of morphine reduced by 50% = 120 mg of morphine per day --> new dose of extended-release morphine is 60 mg PO BID
240 mg of morphine reduced by 25% = 180 mg of morphine per day --> new dose of extended-release morphine is 90 mg PO BID
240 mg of morphine reduced by 0% = 240 mg of morphine per day --> new dose of extended-release morphine is 120 mg PO BID

You must make the clinical decision of what dose of morphine to use, based on patient-specific factors such as renal function and potential drug-drug interactions, the patient’s status including current level of pain control, and how aggressive you wish to be. And, even when you have adjusted for incomplete cross-tolerance, you should still monitor the patient closely for signs of overdose, because there is no way to accurately predict exactly how much tolerance will change when switching from one opioid to another.

These principles apply to most of the opioids, including morphine, oxycodone, hydromorphone, hydrocodone, codeine and oxymorphone. They apply to immediate-release and extended-release preparations, and to any route of administration, including oral, rectal and injectable. The calculations described in this post do NOT apply to methadone, transdermal fentanyl patches or transmucosal immediate-release fentanyl products. While incomplete cross-tolerance does occur with these opioids, calculating equianalgesic doses is more complicated and should be done by an experienced pharmacist or clinician.

Outcome Resources' team of clinical pharmacists stand ready to assist our hospice partners in such cases, 24/7/365. If your hospice is not currently partnered with Outcome Resources and you would like to learn more about how we can help your staff to provide the best patient care, Request your Hospice PBM Info Kit Today!

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Using oral corticosteroids is more art than science. There are no strict rules about when steroids need to be tapered or how to do so, and every practitioner does it a little differently. However, the following guidelines may help you decide when, and how, to taper oral corticosteroids in your hospice patients.

When to Consider Tapering:

• There is concern that discontinuing the steroid will precipitate a disease flare, such as with autoimmune diseases
• The patient is very frail or has severe hematologic, inflammatory, or other immune disease (i.e., preexisting immune system compromise)
• The patient was taking systemic steroids prior to the disease flare (e.g. a COPD patient on routine prednisone who requires a short steroid burst during a COPD exacerbation)

When to Consider Not Tapering:

• Steroid course less than 2-3 weeks (and no factors described above are present)

• Treating asthma or COPD flare, and the patient was not on oral steroids prior to the disease flare
• Treating an allergic reaction which has resolved
• The oral steroid is causing an severe adverse reaction (must weigh risk of continuation versus risk of abrupt discontinuation)

When in doubt, it’s best to go ahead and taper. Just keep in mind that, by tapering, you may be exposing the patient to more doses of steroid than they need. Oral steroids can cause adverse effects in our elderly patients, so we shouldn’t just “play it safe” and taper everyone.

How to Taper:

• Taper by 5% to 20% every 1 to 2 weeks, depending on underlying illness
• Increase dose and slow taper if patient complains of flu-like symptoms or disease flare

These guidelines were adapted from the following reference: Using oral corticosteroids: a toolbox. Pharmacist's Letter/Prescriber's Letter 2010; 26(5):260507.

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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.

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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.

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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.

(1) J Oncol Pharm Practice 2004;10: 177-82 (2) Immunol Allergy Clin North Am 1991;111: 635-44 (3) Anesthesiology 1989; 71: 489-94 (4) Applied Therapeutics: The Clinical Use of Drugs 8th ed. 2005

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