The Hospice Clinician Blog

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:

1. Gastrointestinal motility is slowed. This is why we recommend stimulant laxatives, such as senna or bisacodyl, to help accelerate GI motility.
2. Electrolyte and water absorption is increased. Osmotic laxatives, like milk of magnesia, polyethylene glycol or sorbitol, that help draw fluids back into the intestinal lumen, counteract this effect and can also be helpful in the treatment of opioid-induced constipation.

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?

• Stimulant laxatives should remain the first-line therapy for patients with opioid-induced constipation.
• Osmotic laxatives such as milk of magnesia, polyethylene glycol and sorbitol are great add-ons when stimulant laxatives aren’t enough. Osmotic laxatives should generally by tried before moving to lubiprostone. They are less expensive (the average cost of a 15-day supply of Amitiza® is $150), and efficacy is better established (only 2 of 3 trials of lubiprostone demonstrated efficacy).
• Lubiprostone should not be used in patients taking methadone.
• The manufacturers recommend lower doses in patients with moderate to severe hepatic impairment. For patients with moderately impaired hepatic function (Child-Pugh Class B), the recommended starting dose is 16 mcg twice daily. For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg twice daily. If this dose is tolerated but the patient has not adequately responded, doses can then be escalated to full dosing with appropriate patient monitoring.

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, 
  6 antibiotics, 
  5 antipsychotics, 
  2 antinausea drugs,
  2 antidepressant drugs,
  2 anticancer drugs,
  2 non-sedating antihistamines, 
  2 antimalarial drugs,
  1 opioid,
  1 antiangina drug, 
  1 cholesterol lowering drug,
  1 anesthetic,
  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:
www.azert.org/medical-pros/drug-lists.htm

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

Reference:
(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

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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:

• Effective where other opioids fail, such as in neuropathic pain
• Available in a variety of dosage-forms  that allow for administration to patients with swallowing difficulties (tablets that may be crushed, oral concentrate solution 10mg/ml)
• Methadone is absorbed well by the sublingual route (for patients that can’t swallow at all)
• The solution form is long-acting just like the tablets
• Very low cost.     Methadone is about  1/20 to 1/40  the cost of other long-acting opioids

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.  

See the Original Article on Methadone in The Seattle Times

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.

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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.

Photo Credit

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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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