Dr. Julia Harder, PharmD CGP
The FDA has expanded the indications for oral lubiprostone (Amitiza®, Sucampo Pharmaceuticals Inc/Takeda Pharmaceuticals USA Inc.) to include opioid-induced constipation in chronic pain patients, at a dose of 24 mcg twice daily. This is the third indication for lubiprostone, which is already approved for the treatment of chronic idiopathic constipation in adults, also at a dose of 24 mcg twice daily, and irritable bowel syndrome (IBS) with constipation in women 18 years of age and older, at a dose of 8 mcg twice daily.
Opioids cause constipation via multiple mechanisms. When opioids bind to peripheral opioid receptors in the gastrointestinal (GI) tract, two main things happen:
Lubiprostone targets the second mechanism. it is a specific activator of CIC-2 chloride channels in the intestinal epithelium, which counteracts the increased electrolyte absorption caused by opioids, and helps increase the amount of fluid that remains in the GI tract. Approval for the new indication was based on results of three phase III, placebo-controlled trials of patients receiving opioids including morphine, oxycodone, and fentanyl for non-cancer pain. At a dose of 24 mcg twice daily, two of the three studies met their primary efficacy endpoint.
According to the manufacturers, the effectiveness of lubiprostone in patients taking methadone has not been established, and it is possible that lubiprostone will be ineffective in patients taking methadone. In the 3 clinical trials that led to the drug’s approval, methadone was not included. In other clinical trials, methadone appeared to prevent beneficial effects of lubiprostone, and laboratory studies have demonstrated that methadone blocks lubiprostone’s stimulation of CIC-2 channels.
How should we use lubiprostone in hospice and palliative care?
|Why should Lubiprostone not be used with patients taking methadone?
Just curious .
-- Marsha Farrell
Posted 5/16/2013 12:21:40 PM
By: Jim Joyner, Pharm.D., C.G.P
The commonly used antibiotic, Azithromycin (Z-Pak, Zithromax), was recently discussed in the medical news due to a report of increased risk for serious cardiac adverse effects associated with its use. This incidence of risk is quite low, but due to the potentially serious nature it has resulted in an advisory memorandum by the FDA. Specifically, there is a small risk of prolongation of the QT interval on the ECG which may progress to a serious cardiac arrhythmia known as Torsades des Pointes (TdP). TdP can lead to ventricular fibrillation and sudden death. In light of this recent focus on the issue of drug-induced QTc prolongation, this seems like an appropriate time to review and discuss other medications which also have the potential to cause this problem, especially since some of them are encountered frequently in the medication regimens for hospice patients.
There are 34 specific medications available for use in the U.S. which have substantial evidence that supports the conclusion that they may prolong the QT interval and have a risk of TdP when used as directed according to approved labeling.(1) The list encompasses certain drugs from a variety of different pharmacologic classes including:
8 different antiarrhythmic drugs,
2 antinausea drugs,
2 antidepressant drugs,
2 anticancer drugs,
2 non-sedating antihistamines,
2 antimalarial drugs,
1 antiangina drug,
1 cholesterol lowering drug,
1 GI stimulant drug
For a complete listing of all of the medications, and detailed information about drug-induced QT prolongation check out this link:
Five of the drugs on this list are quite commonly used in hospice to provide palliative management of a variety of symptoms. Those drugs include: Chlorpromazine (Thorazine), Citalopram (Celexa), Escitalopram (Lexapro), Haloperidol (Haldol), and Methadone (Dolophine).
The incidence of this adverse cardiac effect has not been established for any of these drugs and the majority of patients take these drugs without any problem of a prolonged QT interval or arrhythmia. It is also possible that some patients may have a prolonged QT interval while taking these drugs and exhibit no negative symptoms or effects. In those cases this event would go unnoticed unless an ECG was done. This adverse effect appears to be dose-related and has been associated with patients receiving higher dosages.
Awareness of the following risk factors for QT prolongation and TdP may help reduce the risks for this adverse effect when considering the use of these drugs(2) :
• Cardiac disease (MI, CHF, cardiomyopathy, congenital long QT syndrome, bradycardia)
• Low potassium or magnesium levels (may occur with diuretic usage)
• High drug doses (i.e.; methadone > 200mg/day)
• Combined use of multiple drugs which can prolong QT
• Clinically significant drug interactions that can result in excessively elevated blood levels of a drug identified as having QT prolongation potential
There are reports of several other drugs, commonly used in hospice ( not on the list above) where substantial evidence supports the conclusion that these drugs may also cause QT prolongation but will only present a risk of causing TdP in certain conditions such as over-dosage, significant drug interaction, or in a patient with pre-existing cardiac disease risk factors.(1,2)
The drugs listed below can prolong QT but do not have the higher level of risk for causing TdP as the list of 34 drugs above: Amitriptyline (Elavil), Diphenhydramine (Benadryl), Doxepin (Sinequan), Fluoxetine,(Prozac) Nortriptyline (Pamelor), Paroxetine (Paxil), Mirtazapine (Remeron), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), and Ziprasidone (Geodon).
In conclusion, the risks and benefits of using these drugs must be assessed on a case by case basis. There is no general guideline, nor consensus about when to stop therapy or decrease a dosage with one of these drugs if one is concerned about prolonged QT or TdP. A reasonable approach to the problem in hospice care would include the following:
• Avoid the use of a drug known to cause TdP in a patient with the risk factors described above, unless there is no reasonable alternative available
• Reduce correctable risk factors if possible (low potassium or magnesium)
• Exercise caution when using multiple drugs known to cause TdP or prolonged QT, and utilize doses at the lower end of the therapeutic range when combining these drugs
• Exercise caution when using high doses of drugs known to cause TdP (methadone in doses > 200mg/day)
• Avoid clinically significant drug interactions which may result in significantly elevated levels of the drugs identified with a potential for prolonged QT and TdP
(1.) Arizona Center for Education and Research on Therapeutics
University of Arizona. www.azcert.org
(2.) Yap, Camm: Heart. 2003 November; 89(11): 1363–1372
The state of Washington will soon issue an unprecedented public health advisory that highlights the risks of methadone. This warning has been approved and adopted by a committee of state-appointed medical experts following an investigative newspaper story in the Seattle Times (see link below) which captured the attention of the state legislature. The Times claims that a review of death certificates in the state over the past 8 years turned up 443 cases in which methadone was listed as the sole drug in fatal overdose cases (about 55 cases per year). In addition the newspaper story states that methadone may have somehow been linked to over 2,100 fatal drug over-doses in that same 8 year period from 2003 to 2011. The Times story indicated that Washington's methadone death rate ranks among the country's highest. The story did not specify how many of these fatal overdose cases were situations where the individual was abusing the drug or if they were all patients with a legitimate prescription for the medication.
The health advisory will stress that methadone can be more unpredictable than other analgesics, including other opioids. It will be sent to pharmacies as well as licensed health care professionals throughout the state.
Methadone is unique in a number of areas when compared to other opioids. The unique differences offer very significant benefits as well as challenges to managing toxicity risk. If Washington’s efforts result in an increased awareness among physicians, nurses, and pharmacists of these issues leading to more appropriate methadone prescribing and follow-up, then this public health advisory can be the start of something quite positive. On the other hand, if the state’s initiative is designed to label methadone as a medication that is too dangerous to use in patients with severe chronic pain, then everyone in the state loses.
Methadone has a bi-phasic nature when it comes to duration of analgesic effect. When methadone is initiated ,the duration of analgesic effect is about 4 to 6 hours at the most. After continuous routine use for about five days, the drug exerts a more long-acting duration of approximately 12 hours in a majority of patients. The reason behind this is the fact that methadone is both highly lipid soluble and has a very large volume of distribution in the body. These characteristics result in the drug accumulating in the body (upon continued use) and forming a kind of depot that creates the long-duration of analgesia, which is not seen during the initial few days of therapy. This is very different from other opioids. This concept must be understood and incorporated into the prescribing and monitoring practices whenever methadone is used.
There is also a wider degree of inter-patient variation in response to methadone than may be seen with some other opioids. Some patients may reach the “depot” stage with only 3 days of methadone dosing , while others may take 7 or 8 days. Attentive monitoring of the patient during this accumulation phase is essential. There will also be varying levels of cross-tolerance exhibited when converting from other opioids to methadone. This level of cross-tolerance will vary depending upon the dose of the opioid that one will be converting from. Generally, the higher the dose of opioid, the less cross-tolerance to methadone will be encountered. The practitioner should generally use lower equivalent dosages of methadone for patients on higher doses of other opioids to avoid inadvertent over dosage. Successful methadone dosing may be challenging, however, methadone has been used extensively with very high success rates in numerous palliative care and hospice settings over the past decade. It may be that practitioners in these settings have more experience and a greater appreciation for the unique pharmacokinetics of the drug than some others practicing in the general community.
The advantages of methadone are widely recognized and include the following:
The risks for methadone toxicity due to unexpected drug accumulation or incorrect conversion doses can be managed effectively when the practitioners understand the unique pharmacodynamics of methadone and follow appropriate prescribing and monitoring practices.
The current issue with methadone toxicity addressed in the Times article and subsequently discussed within the Washington state legislature may boil down to a lack of education regarding this unique drug. Physicians, nurses, and pharmacists all need to have a clear understanding of methadone pharmacokinetics before prescribing, dispensing, or caring for a patient on methadone. This drug offers significant therapeutic benefits and unparalleled value over other long-acting strong opioids. It would be very unfortunate if the actions of Washington state result in the denial of methadone availability for the patients suffering from severe chronic pain. On the other hand, this represents a great opportunity to promote and disseminate appropriate information to a wide range of health-care professionals regarding the effective use of methadone for those with chronic severe pain.
Outcome Resources offers all of our hospice clients education and consultations to assist with the effective and safe use of methadone for their hospice patients. If you are interested in learning more about how we help hospices succeed, Contact Us.
|You didn't state your age, what type of lung cancer you have and what stage it was cugaht .If your pain is at an 8 out of 10, then you need to have a more comprehensive pain management situation:First, is your oncologist (cancer specialist) also trained in palliative care?? You might want him/her to refer you to a chronic pain specialist. There are other methods that can treat pain, like the Duragesic transdermal fentanyl patch,that is placed on the skin (the upper torso) for a period of 72 hours (3 days) and then changed; and they come in strengths from 25 micrograms all the way up to 100 mcg.And are you taking Oxycodone in it's pure state, or are you taking the 5/325 APAP? (the one with the acteaminophen) If you're taking those (Roxicet or Percocet) then you're taking entirely TOO much acetaminophen: That can severely damage your liver which can compromise your condition. You might want to ask the doctor for the pure form of Oxycodone (Oxycontin) or Hydromorphone (Dilaudid) I would ask your doctor to try different methods of pain control, I strongly suggest that you request a referral to a chronic pain management specialist. We have the methods to control intractable pain these days, and we should use it Best to youChristopher K.
Posted 2/15/2013 03:03:22 PM
|The original Times article has caused such anti=methadone/painkiller hysteria in the Port Angeles area that it is criminal. I have been getting methadone from a pain management program for years with no ill effects or problems until this article. I have a brain tumor that is too large to remove and massive ulcers in both legs. I suffered with the pain fotr years till methadone, Now I am being forcible detoxed at 40 mgs. a month per state directives I am told. What are legitamate high pain patients supposed to do? The state is saving me from methadone use but the pain is whats going to kill me. Pls. save me from the state I am 100% disabled and have nowhere to turn it would seem.
-- SCOTT B THOMPSON
Posted 6/2/2012 06:35:34 PM
|Great article. Many practitioners are unaware of the uniqueness of methadone and to appropriate dosing for pain control. Thanks for the information.
-- Linda McMahan
Posted 6/2/2012 06:34:46 PM
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
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