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!
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 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.
These guidelines were adapted from the following reference: Using oral corticosteroids: a toolbox. Pharmacist's Letter/Prescriber's Letter 2010; 26(5):260507.
|Nearly all of whatever you say is spsuripingly precise and that makes me wonder why I hadn't looked at this with this light before. This particular piece really did turn the light on for me as far as this specific subject matter goes. Nonetheless at this time there is actually one particular issue I am not too comfy with so whilst I attempt to reconcile that with the actual core idea of the position, permit me see exactly what the rest of the visitors have to point out.Very well done.
Posted 8/7/2012 08:19:28 PM
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.
|Jim is so knowelgeable and helpful. It has been my expierence that he truly makes a difference in every pt he consults on.
-- Karen Parks
Posted 6/2/2012 05:07:29 PM
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:
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).
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.
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.
Clinically Significant Drug Interactions
|Increased Methadone||Ciprofloxacin(Cipro), Diazepam(Valium), Fluconazole(Diflucan), ethanol(acute use)|
|Decreased Methadone Effects (reduced effects)||Phenytoin(Dilantin), Phenobarbital, Rifampin, Nelfinavir(Viracept), Ritonavir(Novir)|
Possible Methadone Drug Interactions
|(Clinical effects not documented in literature)|
|Increased Methadone blood levels||Cimetidine(Tagamet), Fluoxetine(Prozac), Paroxetine(Paxil), grapefruit juice|
|Decreased Methadone blood levels||Carbamazepine(Tegretol)|
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.
|You need to be straight with him. Ask him what is more iratmopnt the drugs or ur family? If he can not confidently say ur family end it with him. You and ur kids do not deserve that. It is best for them to be as far away from him as possible. If he can honestly say the family (try to ask him when hes straight) then tell him he needs to get help or he is going to lose the best thing he could ever have. Don't use it as a threat just be honest with him. The treatments won't help him unless he lets them help him. Try to be understanding to what he is going through be supportive but at the same time be strong and firm and smart. Do what is best for you and your children. Most addicts are abusers. Theres a very good chance that he will become violent. Do you really want your children growing up around that?! They are so young, so impressionable. If they see him acting this way they will grow up to think it is ok. If he begins being violent or abusive in any manner and you tolerate it they will think that all women should accept being treated like that. My father was an alcoholic/drug addict, and he could get violent. I am his only child. When she saw what hed become she got rid of him. I saw him once when I was 6 for a visitation and I remember everything was fine then towards the end he became very irrate and i remember him and my mom arguing. And she put me in the car and he grabbed me out he was all sweaty and I was terrified and screaming my mom got me off of him and i remember him putting his sweaty face close to mine and saying something to me i couldnt understand. at the time i didnt no what was going on, but now it makes me so angry to no that he came to see me high!!! and the argument was he watned to stop the visit and go get high then come back to finish the visit he reallly needed it. It makes me sick. I love my mother everyday for getting rid of him and doing everything in her power to keep him away from me (not that it was really hard half the time he forgot i existed) I saw him about 7 yrs ago i was 14 he didnt recognize me i didnt recognize him. My sis told me who it was and when it was brought to my attention i saw he looked just like me .or i looked like him whatever.the point is dont make your children live through that hell.
Posted 2/15/2013 02:53:52 AM
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:
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
|Dr. Klassen, Thanks for your post. The paradoxical reaction to opioids that you describe could be due to active metabolites that are associated with certain opioids, specifically morphine and hydromorphone (not sure which opioids you received). These active metabolites can be associated with neurotoxicity,similar to the symptoms you described including lack of analgesia and in many cases hyperalgesia and allodynia. The impact of the active metabolites are often not significant at low doses, but at higher doses or in the presence of renal impairment the effects can be pronounced. If this situation is not recognized, it often results in the opioid dose being aggressively increased, which actually worsens the adverse response. Opioid rotation to methadone or even fentanyl may be beneficial since neither of these opioids have active metabolites.
-- Jim Joyner, PharmD, CGP
Posted 5/31/2012 01:21:37 PM
|We frequently see these issues in our nursing home where we do a lot of palliative care.
I recently personally had a terrible paradoxical response to opioids post operatively. Zero relief from high does of opioids but ++dysphoria/anxiety. I have none of the recognized risk factors. Found your blog while looking for answers.
What I found here will be useful for staff education when I get back to work but I will continue to puzzle on my own experience. Any thoughts welcome.
-- Steve Klassen, M.D
Posted 5/31/2012 01:20:46 PM
|Frances, I'm glad you enjoyed the article. I hope you'll share our blog with others in the hospice community. Outcome Resources is dedicated to providing hospices with valuable support & information. Thanks for reading!
-- Penelope Gatlin
Posted 5/31/2012 01:20:19 PM
|Thanks. Wonderful article. At hospice of Western Kentucky we see a lot of these reactions.
Posted @ Tuesday, December 15, 2009 2:52 PM by Frances Meserve
Posted 5/31/2012 01:19:23 PM
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