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The contents of this blog contain topics relevant to end of life care written by our own hospice clinical pharmacists. Continue to check this site regularly for the newest post or subscribe to the RSS feed below.
Michelle Mikus, PharmD

POEMS: Patient Oriented Evidence that Matters

We’ve entered a time where everything can be searched on the internet, and now patients have wanted to be more involved in their medical treatment than ever before. Talking to a patient and their families and caregivers is often quite different than talking to another healthcare professional and begs the question “What is important to both patient and medical provider?” That is where Patient Oriented Evidence that Matters (POEMs) comes into play.

Two practitioners introduced the POEMs concept into medicine: David Slawson and Allen Shaughnessy from the University of Virginia. They actually came up with the concept from a formula: U = R·V / W. The formula seeks to equate the information doctors find to its usefulness. In short, the more relevant (R) and valid (V) the information is and the less work (W) it takes to find correlates with higher usefulness (U). With the internet at everyone’s fingertips, practitioners are suffering from “the information paradox” as Muir Gray from the National Electronic Library of Health states, which is described as so much information that they may not be able to find what they need when they need it. This is where POEMs can be useful.

POEMs must meet three criteria: a) address a question that a doctor encounters, b) measure outcomes that doctors AND their patients care about (symptoms, morbidity, mortality, QOL), and c) have the potential to change the way doctors practice. Conventional journal articles outline in high detail specifics about clinical manifestations, however this is not language that the layperson can understand nor will it ultimately affect them. Often journal articles do not ultimately answer a question. The advantage of POEMs includes communication that is centered on what really matters to the patient in a way that is meaningful to the doctor also. A typical POEM report would pose the patient specific question and then provide a bottom line before going into detail. This summary format makes them quite user friendly.

Evidence-based medicine, by definition, integrates patient values and expectations as a core feature along with both individual clinical expertise and the best external evidence. It is a process that starts with the patient presentation/question and ends with the incorporation of findings into the patient’s care, but in the middle includes literature searches and evaluations. By focusing the search and evaluation steps on POEMs, the patient will remain at the center of the care. In addition, information discovered has the potential to be more relevant and valid while requiring less work.

Sample POEM with hospice focus Olanzapine for intractable nausea and vomiting:

Clinical Question: What can be used to treat intractable nausea that has been refractory to conventional nausea medications?

Bottom Line: Olanzapine (Zyprexa) has been found to very effectively control nausea due to its broad spectrum of activity at a dose of 5mg at bedtime.

Reference: Atkinson SR. Olanzapine for intractable nausea and vomiting in palliative care patients not receiving chemotherapy. J Palliat Med. 2014 May;17(5):503-4

Study Design: Retrospective review

Setting: Palliative care

Synopsis: Multiple studies have shown olanzapine to be effective for chemotherapy induced nausea and vomiting however none had previously studied the drug for non-chemotherapy receiving patients with intractable nausea. This type of nausea reduces the quality of life for patients and often results in multiple trials of different medications—sometimes in combination. Patients averaging 65 years in age that were not receiving chemotherapy were initiated scheduled olanzapine 5mg at bedtime. The need for other anti-emetics and rescue anti-emetics was significantly reduced and there were no extrapyramidal side effects reported. One patient required a reduction in dose to 2.5mg at bedtime due to somnolence. Overall, olanzapine has proven again to be effective in addition to being cost effective and its use in intractable nausea and vomiting will reduce drug interactions and polypharmacy.


References:

1. Shaughnessy AF, Slawson DC, Bennett JH. Becoming an information master: a guidebook to the medical information jungle. J Fam Pract. 1994;39:489-499.

2. Smith, Richard. A POEM a week for the BMJ. BMJ 2002;325:983 3. Smith, Richard. What clinical information do doctors need? BMJ 1996;313:1062-1068.

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Delta Campus Pharmacy Student

Management of Pruritus from a Hepatic Etiology

Pruritus is a common symptom experienced by many patients in palliative and hospice care which can dramatically affect a patient’s comfort and quality of life even though it is not the most prevalent symptom such as pain or dyspnea. While the complete pathology of all causes of pruritus is not yet completely understood, the itching sensation is best relieved by properly treating the underlying etiology if it is known.1

Pruritus has been associated with both malignant disease as well as nonmalignant chronic diseases such as renal, thyroid, and hepatic disease. A Cochrane Review found that about one third of all patients with end stage renal disease not on hemodialysis and 70%-80% of patients receiving hemodialysis experience significant pruritus. The same review found that nearly 100% of patients with biliary cirrhosis had a cholestatic pruritus.1 According to the guidelines from the American Association for the Study of Liver Diseases, cholestatic pruritus is often times the initial symptom in half of the patients with biliary cirrhosis.1,2

There exist many therapies that could be used to treat pruritus in general such as antihistamines like hydroxyzine, opioid receptor antagonists similar to naloxone, direct serotonergic agents such as ondansetron, selective serotonin reuptake inhibitors (SSRI’s) such as paroxetine and sertraline, antiepileptics such as gabapentin, and the antibiotic rifampicin. Most of these agents have different mechanisms against pruritus which may be more or less effective given certain patient factors. The American Association for the Study of Liver Diseases guidelines for primary biliary cirrhosis recommend several agents for the treatment of cholestatic pruritus:1,2

Bile Acid Sequestrants: The first line therapy recommendation is to use a bile acid sequestrant agent. Bile acid sequestrants are approved for the treatment of dyslipidemias by functioning as a resin that traps cholesterol and other acids from bile in the GI tract which can allow passing of these substances out through the GI tract instead of being systemically reabsorbed. It is believed that forcing the elimination of these bile acids will also relieve cholestatic pruritus. The bile acid sequestrant of choice is cholestyramine dosed at 4 grams per dose with a maximum dose of 16 grams daily. [The other currently available bile acid sequestrants, colesevelam, and colestipol, have not been studied and currently contain no recommendations for the treatment of pruritis.2] Complications of bile acid sequestrant therapy include gastrointestinal disturbances (constipation, loose stool, cramping, excessive flatus, etc.) and the prevention of drug absorption in the GI tract since acidic drugs will also be trapped by the resin.1,2 It is recommended to separate the administration of a bile acid sequestrant from other medications by 2-4 hours.

Antidepressants: It is believed that serotoninergic activity contributes to signal transduction of pruritus. Several antidepressants have been tested including paroxetine, doxepin, and sertraline. Sertraline 75 mg to 100 mg is the preferred therapy for cholestatic pruritus according to the guidelines by the American Association for the Study of Liver Disease.2 General pruritus relief has been noticed with paroxetine 5 mg to 10 mg at night for multiple etiologies including hepatic and renal disease.1 Doxepin appears to be effective at doses of 25 mg daily, however tricyclic antidepressants tend to have anticholinergic activity which can cause adverse effects in older patients and should be avoided unless necessary.1,3 Relief of pruritus by antidepressants is usually seen in 24 to 48 hours, much sooner than the antidepressant effects of these agents.1 Ondansetron has been studied as a direct acting serotonergic agent, however it has only shown mild to no benefit in clinical trials.1,2

Rifampicin: Rifampicin is an antibiotic and hepatic enzyme inducer shown in several trials and meta-analyses to relieve hepatic pruritus. Recommended dose is 150-300 mg twice daily depending on serum bilirubin (300 mg for bilirubin less than 3 mg/dL and 150 mg for bilirubin 3 mg/dL or higher). Complications of therapy include drug induced hepatotoxicity or renal impairment and hepatic ennzyme induction which could decrease the efficacy of other medication therapies.1,2 Due to the risks for hepatotoxicity and nephrotoxicity, liver and renal function tests will need to be continually monitored suggesting that therapy with rifampicin should be held in reserve for when benefit outweighs risk in end-of-life care.

Opioid Antagonists: While there is strong evidence for the use of the opioid antagonists naloxone or naltrexone, these therapies are usually inappropriate in hospice care since these agents will counter the analgesic activity of other opioids used in the treatment of chronic pain and could also induce opiate withdrawal.1,2 In addition, naltrexone has a rare potential for causing hepatotoxicity which will require monitoring liver function. The recommended dose of naltrexone is 50 mg by mouth daily, however naltrexone is hepatically eliminated and will accumulate in decompensated and end-stage liver disease requiring that the dose of naltrexone be decreased.2 Due to the monitoring burden and the risk of counteracting chronic opiate activity, it is recommended only to use naltrexone when the patient is not taking opioid analgesics and benefit outweighs risk of decreasing liver function.

Antihistamines: The mechanism of antihistaminergic compounds is reliant on non-specific antipruritic effects with little treatment to the direct etiology of hepatic pruritus.2 Complications that occur are the risk of confusion, sedation, exacerbation of dementias, and increase in fall potential for patients that are still ambulatory from the anticholinergic activity of the antihistamine agents similar to diphenhydramine and hydroxyzine.3 It is recommended to use these only when other systemic therapies have failed or are inappropriate.

Phenobarbital: Phenobarbital was once utilized as a therapy for hepatic pruritus, however its use is limited in modern practice due to risks of severe sedation and hepatic enzyme induction.2,3

There is a large variety of medication therapies that can be used to treat pruritus from a hepatic etiology. Topical therapies such as the counter-irritants capsacin or menthol have some limited efficacy1 but the application area may become so large in advanced disease that their use becomes impractical. While conventional therapies of systemic antihistamines may be moderately effective, they have the potential for undesirable adverse events and may be less effective or efficient than an etiology specific agent. Cholestyramine or sertraline may not be the first agent that comes to mind when a patient complains of an itch, however these less conventional therapies have become a mainstay for the treatment of pruritus in advanced hepatic disease. In addition, the use of these alternate therapies broadens the spectrum of drugs that could be used for multiple pharmacological effects and can afford a patient specific drug selection.


Submitted by: James R. Thomas, PharmD., BS Hospice Clinical Pharmacist and Pharmacy Resident at Delta Care Rx


References:

1. Xander, C., Meerpohl, J. J., Galandi, D., Buroh, S., Schwarzer, G., Antes, G., & Becker, G. (2013). Pharmacological interventions for pruritus in adult palliative care patients. The Cochrane Database of Systematic Reviews, 6(6), CD008320. doi:10.1002/14651858.CD008320.pub2

2. Lindor, K. D., Gershwin, M. E., Poupon, R., Kaplan, M., Bergasa, N. V., & Heathcote, E. J. (2009). Primary biliary cirrhosis. Hepatology. doi:10.1002/hep.22906

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Lori Osso-Connor, PharmD, CGP

Role of Warfarin in Hospice and Palliative Care

Patients who make the hospice choice have opted for comfort measures and are no longer seeking life sustaining treatment. However, as hospice professionals encounter daily, many patients are admitted on medications that are considered treatment and are used for curative measures and not palliative measures.

The risk for thromboembolism in hospice and palliative care patients increases due to advanced age and diagnoses such as cancer or cardiomyopathy. Warfarin (Coumadin®) is indicated as treatment to prevent clotting in atrial fibrillation, thromboembolic disease, and artificial heart valves. It is a medication that poses a clinical challenge on whether to continue or discontinue when the patient becomes hospice appropriate. Warfarin’s mechanism of action is to inhibit Vitamin K epoxide reductase which decreases the Vitamin K in the body and decreases clotting. While warfarin is typically indicated as treatment, it could be argued that it is used in hospice and palliative care to provide comfort by reducing the risk of pain and swelling in the extremities due to DVT, unilateral weakness, or paralysis related to stroke.

However, there are several arguments that can be made to support the discontinuation of warfarin in hospice and palliative care. Some issues to consider include:

• The use of warfarin requires PT/INR lab work to ensure therapeutic efficacy. Studies have shown that hospice and palliative care patients require more frequent INR monitoring. These blood draws may be undesirable to the patient and or caregivers at this point in care. Additionally, poor venous access may make obtaining the blood difficult.

• Warfarin is a medication that has many drug-drug interactions including many antibiotics and drug-dietary interactions which could pose unnecessary complications to the patient. Some examples of drug–drug interactions with warfarin in which the anticoagulant effect is increased include levofloxacin (Levaquin ®), sulfamethoxazole/ trimethoprim (Bactrim ®), prednisone, and NSAIDS. In addition, Vitamin K rich foods may decrease the effects of warfarin. Therefore, it is most important to keep a consistent type diet.

• As intake declines or is erratic, the dietary vitamin K may fluctuate which could increase the risk of a bleed or clot.

• Nausea and vomiting could impact the medication adherence which may alter INR due to drug interactions.

• When a dose is changed, it takes 5-6 days to take full effect. If the PT/INR is not carefully managed, it leads to additional increases or decreases in the dose and a myriad of additional blood draws.

• The risk of an intracranial hemorrhage in a debilitated ambulatory patient who may fall is greater than the benefit in preventing a stroke.3

• The risk of a GI hemorrhage is about 8%.1

• The 1-year risk of stroke in atrial fibrillation is 2% in patients treated with warfarin and 4% in those untreated.1

Do the benefits of continuing outweigh the risks? Some factors to consider when facing this decision include: indication, prognosis, bleeding risk, thrombosis risk, nutritional status, appropriate monitoring, medication adherence, medication changes, and patient/family preferences. It is also important to consider whether a new clot will impair the patient’s function or quality of life. As one can see, the choice to discontinue warfarin is a difficult one and is not always clear cut. The risks verse the benefits in each patient must be assessed in accordance with the family and patient’s goals. This individualized approach will help the hospice care professional determine whether the benefits outweigh the risks to the patient and make an appropriate choice.


References:

1. Allen, Richard. “10 Drugs to Reconsider When a Patient Enrolls in Hospice.” NHPCO Newsline(2014): 5.

2. Hill, Robin, Kerri Martinez, Thomas Delate, and Daniel Witt. “A Descriptive Evaluation of Warfarin Use in Patients Receiving Hospice or Palliative Care Services.” Journal of Thrombosis and Thrombolysis 27.3 (2008): 334-39.

3. Von Gunten, Charles, David Weissman, and Janet Abraham. “Fast Fact #278 Warfarin and Palliative Care.” #278 Warfarin And Palliative Care. Web. 26 Feb. 2015

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Char Cole, PharmD, CGP

Impact of Bariatric Surgery on End of Life Care Symptom Management

Obesity is a growing concern in the United States. There are three major types of bariatric surgery done in the United States to combat the obesity problem.

1. Vertical Banded (Stapled) Gastroplasty

2. Adjustable Gastric Banding

3. Roux-en-Y Gastric Bypass

Weight loss occurs by causing malabsorption or by restricting gastric volume or a combination of both. Banding procedures limit the amount of intake, whereas the Roux-en-Y procedure not only reduces the stomach size, it also changes the site of attachment of the small intestine. The Roux-en-Y procedure bypasses the lower portion of the stomach and a much smaller stomach pouch (15-30 mL capacity) is created, then the small intestine (the entire duodenum and part of the proximal jejunum) is removed from the lower stomach and attached to the newly formed stomach pouch. This procedure reduces the surface area that is available for absorption of nutrients and medications.

Different medications have different requirements for absorption and ultimately effectiveness. Medications in aqueous solution are more rapidly absorbed then those in oily solutions. Medications are soluble at different pH levels. Different medications that are more soluble at acidic pH are absorbed in the stomach, whereas medications that are more soluble at alkaline pH are absorbed in the small intestine. Intestinal enzymes are also necessary for the absorption of some medications. The Roux-en-Y Gastric Bypass can alter medication absorption.

Reducing the amount of time needed for absorption of the medication is essential for safe and effective use of medications. The formulation of the medication can be sufficient to reduce the amount of time needed in the stomach/small intestine for absorption. When possible the use of pills that can be crushed should be considered, as well as liquids, subcutaneous, intravenous, rectal, vaginal, intranasal and transdermal formulation and/or routes of administration should be considered. Avoid or use with caution any medication that has a long stomach absorptive phase.

Oral non-steroidal anti-inflammatory drugs (NSAIDs), salicylates and bisphosphonates should be avoided. These medications can cause or increase the potential of the patient to develop ulcers in the new much smaller stomach and/or reduced small intestines in all types of bariatric surgery. If the use of these medications are essential, then consider alternative routes of administration such as topical or injectable. Delayed release preparations of all medications such as CR, SR, XR, LA, EC, etc. should be avoided in Roux-en-Y Gastric Bypass.

Pain management in end of life care is essential. The use of MS Contin or morphine ER should be avoided in patients that have had a Roux-en-Y Gastric Bypass. Due to the reduced surface area of the gastrointestinal tract, the use of immediate release formulations would be a better alternative to extended release preparations. The use of immediate release formulations or non-extended release formulations may require a more frequent dosing schedule; however the Roux-en-Y bypass patient will be more apt to achieve more consistent pain management.

It is important to inform all healthcare providers of a patient’s bariatric surgical history if it exists as this will alter the medication therapy chosen for the patient. The length of time the patient is status post bariatric surgery has no impact to the medication therapy consideration. Once a patient has had bariatric surgery, medications will always need to be adjusted to take into account the changes made to the gastrointestinal tract through the bariatric surgery and how this will alter the absorption of medications. All medication therapies chosen for a bariatric surgery patient should be evaluated for effectiveness and for the increased potential for side effects if the proper monitoring is not done.


References:

1. Vanhoose K. Medication Absorption after Gastric Bypass. Advance Healthcare Network for NPs and PAs. www.ADVANCEforNPs\&Pas\_PrinterFriendly.htm

2. Rogula T, Schauer P. Medications after Bariatric Surgery. www.Medicationsafterbariatricsurgery.htm

3. Miller AD, Smith KM. Medication and Nutrient Administration Considerations after Bariatric Surgery. AM J Health Syst Pharm.2006;63(19):1852-1857.

4. Lawrecki T. How is drug absorption altered by bariatric surgery? University of Illinois Chicago College of Pharmacy

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Delta Campus Pharmacy Student

Tramadol Induced Hypoglycemia: The Latest Consideration for Tramadol in Pain Therapy

Tramadol, a weak opioid analgesic, is primarily popular for its two separate and distinct mechanisms associated with pain management. As an opioid, it inherently binds to the mu-opioid receptor to induce analgesia. But its additional effect results in inhibition of the serotonin and norepinephrine receptors. The latter is believed to play a role in the treatment of neuropathic pain, as this type of pain is believed to be associated with a malfunction of the peripheral or central nervous system.1 Because of this dual mechanism and a general perception that tramadol is safer than most existing opioids, prescribing has grown significantly in recent years.

Like most other therapeutic alternatives in pain treatment, however, it is not free of potentially life-threatening adverse effects. Tramadol carries a risk for the development of serotonin syndrome, a condition characteristic of hyperthermia, irregular heartbeat, organ failure, and death, due to the potential for accumulation of serotonin in the body, as well as a notable risk of seizures, both possible even at therapeutic doses.2 These risks are greatly increased when co-administered with serotonin modulators, such as selective-serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, and antimigraine medications, among others.3

Additionally, tramadol still maintains a similar profile of abuse potential compared to other opioid analgesics. The reclassification of tramadol to schedule IV under the US Controlled Substances act in August of 2014 echoes the emerging association of abuse witnessed from the increased use in practice.2

As of recent, a group of researchers based in Canada and France have now raised a new concern for the use of tramadol in pain therapy. Tramadol has been identified with an increased chance of hospitalization for hypoglycemic episodes, according to researchers. Tramadol administration resulted in a 52% increase in risk of hospitalization for hypoglycemia. The recent study published in December 2014 by Fournier, et al., investigated the growing trend in tramadol-induced hypoglycemia.

A trial conducted within the United Kingdom Clinical Practice Research Datalink (CPRD) linked to the Hospital Episode Statistics (HES) database with an enlisted cohort of 334,034 patients compared the risk of hypoglycemia in patients treated with tramadol versus codeine for non-cancer pain from 1998 to 2012. Selected patients were at least 18 years of age with at least one year of baseline medical history in the CPRD and HES, which covers 13 million patients and over 680 practices in the United Kingdom. Included patients were limited to those newly initiating single opioid therapy with tramadol or codeine.

Typical pain treatment in this population included headache, neuralgia, abdominal and pelvic pain, musculoskeletal pain, injury and/or trauma, and surgery. Additionally, all cases of pain related to cancer were preclusive to inclusion. Within this cohort, 1,105 patients were hospitalized for hypoglycemia at follow-up intervals during the study period. All hospitalized patients were compared to 11,019 controls based on 10 controls on age, sex, and duration of follow-up. The resulting analysis identified an association between tramadol administration and increased risk of hospitalization for hypoglycemia versus the use of codeine (OR 1.52, 95% CI 1.09-2.10). Additional findings of the study noted a trend towards increased risk of hospitalization within the first 30 days of therapy in tramadol versus codeine use (OR 2.61, 95% CI 1.61-4.23).1 This casual relationship identified in early initiation of therapy warrants increased awareness of patient monitoring to avoid potentially life-threatening episodes of hypoglycemia.

It is evident that these findings create a conversation piece regarding the therapeutic use of tramadol, particularly in the growing prevalence of the need to treat diabetic neuropathy. In addition to the concern for opioid-induced adverse reactions, seizures, and a number of drug interactions, the risk for hypoglycemic episodes suggests much more consideration from the prescriber when selecting analgesic therapy, especially when initiating therapy for the first time. Serotonin syndrome poses an additional concern due to the highly prevalent use of serotonin-regulating medications in the (i.e. duloxetine, TCAs, trazodone, etc.), especially in the hospice setting. This, coupled with the risk for hypoglycemia, may lead to unintended consequences in the already vulnerable hospice population. The use of tramadol in hospice still remains less than what is observed in practice of other populations. Nonetheless, as time passes the hospice industry will likely notice increased use due to the pressure of opioid use reform in the United States.

While the authors advised that further research is needed to determine a stronger link, the sheer prevalence of use in practice warrants extra patient consideration. As stated by Nelson L, and Juurlink D, “If we replace conventional opioids with tramadol, as some guidelines have suggested, we may be left with more unintended consequences of the opioid epidemic to worry about.”2


Submitted by: Christopher Smurthwaite, PharmD Candidate at Duquesne University and Mary Mihalyo, B.S., PharmD, CGP, BCPS, CEO at Delta Care Rx


REFERENCES:

1. Fournier J, Azoulay L, Yin H, Montastruc J, Suissa S. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. Published online 8 December 2014. doi:10.1001/jamainternmed.2014.6512. Accessed 24 January 2015.

2. Nelson LS, Juurlink DN. Tramadol and hypoglycemia: one more thing to worry about. JAMA Intern Med. Published online December 08, 2014. doi:10.1001/jamainternmed.2014.5260. Accessed 24 January 2015.

3. Sindrup SH, Ott M, Finnerup MO, et al. Antidepressents in the treatment of neuropathic pain. Basic & Clinical Pharmacology & Toxicology. Published online 9 August, 2005. Accessed 24 January 2015

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