Welcome to the Delta Care Rx Blog

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.

Delta Care Rx is passionate about educating the next generation of hospice care pharmacists. This article was written by a Duquesne University doctor of pharmacy candidate under the supervisor of a Delta Care Rx clinical pharmacist.

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Lack of E-Prescribing Controlled Substances by Doctors

2016 08 22 14 07 33A recent article in USA Today discussed the fact that although electronic prescribing of prescriptions, specifically controlled substances, would be a great way to cut down on abuse and fraud the majority of the United States is not utilizing this system. Only 7% of doctors are electronically prescribing controlled substances today. Currently only three states actually require that controlled substances be e-prescribed, however, only two of these three actually enforce this law. The three states that require controlled substances to be e-prescribed include Minnesota, New York and Maine.

Minnesota was the first state to require e-prescribing of controlled substances, although they do not allow physicians to be penalized for not doing so. New York requires physicians to check the online database to see if patients are getting controlled substances elsewhere before prescribing. They are then required to e-prescribe these prescriptions or they could face legal action. Maine became the third state to require e-prescribing of controlled substances in April 2016 and starting January 2017 physicians could face fines and/or jail time for not doing so.

Opioid abuse is one of the leading causes of death in the country currently, much of the abuse stemming from prescription painkillers. Physicians e-prescribe non-controlled medications on a regular basis and now that they have the ability to electronically send prescriptions to pharmacies for controlled substances they should be utilizing this software. Eliminating paper prescriptions can ensure that the patient is not altering the prescription in anyway, it would lessen the chance of patients ‘doctor-shopping’ to get multiple prescriptions, and it could prevent the chance of physician prescription pads being stolen which we see in the news all too often. Some people are afraid that although e-prescribing may make it harder for drug users to get their hands on controlled substances it could lead to these individuals turning to heroin to get their fix instead. Either way you look at the issue it is amazing that so few physicians are taking advantage of this new technology simply as an easier way to keep records if nothing else.

Hospices utilizing e-prescribe technology automatically meet federal and state regulations regarding how prescriptions are issued for controlled substances. Delta Care Rx is the only hospice pharmacy benefit manager in the United States that has developed their own proprietary e-prescribing platform for hospice clients. Currently, more than 250 clinicians use the Delta Care Rx e-prescribing tool. The number of hospice clinicians utilizing the Delta Care Rx e-prescribing technology is expected to quadruple by 2017 says Drew Mihalyo, PharmD who is the President and COO of Delta Care Rx.


Submitted by: Stephanie Stuparitz, PharmD Candidate 2017, Duquesne University


Reference:
O’Donnell J. Most doctors don’t use e-prescribing for opioids. USA Today. May 19, 2016: 3A.

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Anticoagulation Bridging Chart

There are several patient specific factors that need to be taken into account when selecting an oral anticoagulant. At times, a patient may no longer be appropriate for their current anticoagulant and need to be converted to another agent. The below chart is to serve as a guide when making clinical decisions on how to convert a patient from one anticoagulant to another agent and/or safe practices for discontinuing an anticoagulant.

Drug

Bridging Required

Indication/Dosing D/C Plan for Standard Bleeding Risk Procedure D/C Plan for High Bleeding Risk Procedure
Dabigitran (Pradaxa®)

DVT and pulmonary embolism: YES

Administer 150 mg twice daily after 5 to 10 days of parenteral anticoagulation

Dabigitran to warfarin: YES

Dabigitran contributes to INR elevation; warfarin’s effect on the INR will be better reflected only after dabigitran has been stopped for ≥2 days.

Start time must be adjusted based on CrCl:

CrCl >50 mL/minute: Initiate warfarin 3 days before discontinuation of dabigitran

CrCl 31 to 50 mL/minute: Initiate warfarin 2 days before discontinuation of dabigitran

CrCl 15 to 30 mL/minute: Initiate warfarin 1 day before discontinuation of dabigitran

CrCl  There are no recommendations provided in the U.S. manufacturer’s labeling.

Warfarin to dabigitranNO

Discontinue warfarin and start dabigitran when INR is less than 2

Atrial Fibrillation: CrCl >30, 150mg BIDif CrCl 15-30 then 75mg BID, CrCl

DVT/PE: CrCl >30 150mg BID, if CrCl

CrCl ≥ 50 Stop dabigitran 2 days before procedure

CrCl 30-50 stop dabigitran 3 days before procedure

CrCl ≥ 50 Stop dabigitran 3 days before procedure

CrCl 30-50 stop dabigitran 4-5 days before procedure

Rivaroxaban

(Xarelto®)

Rivaroxaban to warfarin: YES

Typically in general practice, clinicians stop rivaroxaban and start both a parenteral anticoagulant and warfarin at the time the next rivaroxaban dose should have been taken

Warfarin to rivaroxabanNO

Discontinue warfarin and start rivaroxaban as soon as the INR is below 3 to avoid insufficient anticoagulation

Non-valvular Atrial Fibrillation: CrCl >50, 20mg QD w/ evening mealif CrCl 15-50 then 15mg QD

DVT/PE

Treatment: 15mg BID w/ food for first 21 days then 20mg QD w/ food for remaining treatment

Risk Reduction: 20mg QD w/ food

Prophylaxis after surgery:

-Hip replacement: 10mg QD for 35 days

-Knee replacement: 10mg QD for 12 days

CrCl ≥ 50 Stop rivaroxaban 2 days before procedure

CrCl 30-50 stop  rivaroxaban 2 days before procedure

CrCl 15-30 stop  rivaroxaban 3 days before procedure

CrCl ≥ 50 Stop rivaroxaban 3 days before procedure

CrCl 30-50 stop  rivaroxaban 3 days before procedure

CrCl 15-30 stop  rivaroxaban 4 days before procedure

Apixaban (Eliquis®) 

Apixaban to warfarinYES

Discontinue apixaban, and begin both a parenteral anticoagulant and warfarin at the time when the next dose of apixaban should have been taken. Then stop parenteral anticoagulant once INR reaches goal range

Warfarin to apixabanNO

Apixaban should be started when INR is < 2

Atrial Fibrillation: 5mg BID

Any two of the following:  ≥ 80 y/o,  Scr ≥ 1.5 mg/dl or ≤ 60 kg: 2.5 mg BID

ESRD on hemodialysis: 5mg BID

On hemodialysis + ≥ 80 y/o or ≤ 60 kg: 2.5mg BID

CrCl <25: Not recommended

Hip replacement: 2.5mg BID 12-24 hrs after surgery for 35 days

Knee replacement: 2.5mg BID 12-24 hrs after surgery for 12 days

DVT/PE

Treatment: 10mg BID for 7 days then 5mg BID for 6 months

Risk reduction: 2.5mg BID for at least 6 months after DVT/PE

CrCl ≥ 50 Stop apixaban 2 days before procedure

CrCl 30-50 stop apixaban 3 days before procedure

CrCl ≥ 50 Stop apixaban 3 days before procedure

CrCl 30-50 stop apixaban 4 days before procedure

Edoxaban (Savaysa™)

DVT and pulmonary embolism: YES

Oral: 60 mg once daily after 5 to 10 days of initial therapy with a parenteral anticoagulant

Edoxaban to warfarin: YES

Oral: For patients taking edoxaban 60mg once daily, reduce dose to 30mg once daily and begin warfarin concomitantly. For patients taking edoxaban 30mg once daily reduce the dose to 15mg once daily and begin warfarin concomitantly. Measure INR at least weekly and discontinue edoxaban once INR ≥2 and continue warfarin therapy

LMWH and other oral anticoagulants other than warfarin to edoxaban: YES

Start edoxaban at the time of the next scheduled dose, when transitioning from unfractionated heparin, discontinue the infusion and start edoxaban four hours later

Warfarin to edoxaban: NO

Discontinue warfarin and start edoxaban when the INR is ≤ 2.5

Atrial fibrillation: CrCl >50 and CrCl  >95 AVOID USE

DVT/PE

Treatment: CrCl>50 60mg QD after 5 to 10 days of initial therapy with a parenteral anticoagulant, CrCl 15-50  30mg QD,  CrCl

Discontinue at least 24 hours before surgery or invasive procedure Discontinue at least 24 hours before surgery or invasive procedure

Submitted by: Alisha Ensell, PharmD Candidate 2016 and Shelby Scott, PharmD Candidate 2016


References:
1. Metzger A, Nagaraj T. New Oral Anticoagulants: Clinical Parameters and Uses in Practice. Consult Pharm. 2015;30(6):329-45.
2. Lexicomp Online. Lexicomp Web site. http://www.crlonline.com.authenticate.library.duq.edu/lco/action/home

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Tube Feeding Considerations in End of Life Care

Enteral feeding tubes may be helpful for nutrition support in patients that cannot eat but have a working gastrointestinal tract. Administering medication in these tubes is useful for patients that cannot take it another route, but issues can arise. This article discusses some factors that can affect medications given this route and ways to avoid common issues related to administration down a feeding tube.

The placement site of the tube can alter the medication efficacy. Most oral medications are absorbed in the small intestine. Some medications, for example antacids, sucralfate, and bismuth, act locally in the stomach and would provide minimal benefit if administered in a tube that bypasses the stomach. In addition, if medications that rely on extensive first-pass metabolism, such as opioids, beta-blockers, or tricyclic antidepressants, are administered in a tube that ends in the jejunum, they will have increased absorption and greater efficacy possibly leading to more adverse effects. First-pass metabolism is a result of the drug entering the liver after absorption in the gut resulting in much of the drug being metabolized before reaching the systemic circulation. This is taken into consideration when dosing this type of medication and if it is bypassed, by administering into the jejunum, it leads to a higher concentration of drug than intended

The tube size also plays an important part in deciding medication administration. Small bore tubes are more comfortable for the patient but are more likely to clog, especially with medication administration. Only liquid medications should be used in a Dobhoff tube to prevent clogging. Large bore tubes are less likely to clog, but it is important to know that if the tube is being used for suctioning, medications should not be given down that tube because they might be removed before absorption.

Medications should not be administered or mixed with tube feedings because they can interact and lead to negative effects. Phenytoin is the most well-known medication in this situation, decreasing blood levels of the drug up to 75% when administered with tube feeds. It is recommended to hold feedings 2 hours before and after each dose if possible. Warfarin efficacy is reduced when administered through a feeding tube and INR should be monitored more closely. Other medications can form precipitates with tube feedings, such as iron supplements and sucralfate. Liquid medications prepared as syrups can be acidic and denature proteins in the feeding, causing clumps and leading to clogs.

Liquid dosage forms are the preferred form for enteral administration of medications. Suspensions and elixirs are preferred over syrups because they are less likely to clog. Many liquid preparations contain large amounts of sorbitol which can cause GI upset or diarrhea. There are also liquid medications with high osmolality, above 1000 mOsm/kg, which will draw water into the GI tract and lead to cramping, diarrhea, or vomiting. A few examples of medications with high osmolality include acetaminophen elixir, cimetidine solution, metoclopramide hydrochloride syrup, and lithium citrate syrup.

Medications that should not be crushed include tablets that are controlled-release, enteric-coated, teratogenic, or irritants. Disrupting the controlled-release mechanism can cause toxic blood levels of the drug and enteric-coated drugs do not crush well and when mixed with water will bond together creating a clog. If the medication is teratogenic it should not be crushed for the safety of the staff. Capsules with microencapsulated pellets, such as Depakote Sprinkle and Effexor XR, can be opened and the pellets can be administered in large bore feeding tubes.

The tube should be flushed with a small amount of water both before and after medication administration. Flushing helps prevent clogs and interactions between different medications or tube feeds. Also, if medications are scheduled to be administered at the same time, they should not be given down the tube at the same time but rather administered separately while flushing the tube in between each medication. This is important because medications can precipitate or interact if given together increasing the risk of clogs or decreasing efficacy. Also, it is recommended to hold feeding for 30 minutes before and after the medication is administered if it requires administering on an empty stomach and the tube ends in the stomach. No holding is required if the tube ends in the intestine rather than the stomach.

If clogging does occur it is recommended to intervene as soon as possible by flushing with warm water. It is not recommended to try flushing with acidic liquids, such as soda or cranberry juice, because it has not shown to be more effective than water and might compound the issue by precipitating proteins from the feedings. Instead, an alkalized enzyme solution should be used. It is prepared by crushing one sodium bicarbonate 324mg tablet and one pancrelipase tablet mixed together with 5mL of water.

Overall, medication use in feeding tubes can be complicated with many different factors involved. Problems such as clogged feeding tubes and disruption of medication efficacy negatively affect both the patient and the staff. It is important to recognize why these problems can occur and to follow proper administration guidelines to prevent them in the future.


Submitted by: Alexander Fringes, PharmD Candidate 2016


References:
1. PL Detail-Document. A Stepwise Approach: Selecting Meds for Feeding Tube Administration. Pharmacist’s Letter/Prescriber’s Letter. June 2014. 
2. Williams NT. Medication administration through enteral feeding tubes. Am J Health-Syst Pharm. 2008; 65(24): 2347-57. doi: 10.2146/ajhp080155.
3. Beckwith CM, Feddema SS, Barton RG, Graves C. A Guide to Drug Therapy in Patients with Enteral Feeding Tubes: Dosage Form Selection and Administration Methods. Hosp Pharm. 2004; 39(3): 225-37.
4. Emami S, Hamishehkar H, Mahmoodpoor A, Mashayekhi S, Asgharian P. Errors of oral medication administration in a patient with enteral feeding tube. J Res Pharm Pract. 2012; 1(1):37-40. doi:10.4103/2279-042X.99677.

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Use of Nebulized Morphine for the Management of Dyspnea

Dyspnea, or shortness of breath, is a very common complaint in hospice and palliative care. Up to 70% of end stage cancer or COPD patients experience dyspnea.1 Opioids, such as morphine, have been used to relieve the uncomfortable sensation associated with dyspnea. Oral and parenteral morphine are the most well studied routes of administration for this indication. Unfortunately, systemic absorption of opioids can cause adverse events that may be considered unbearable in the hospice population such as nausea, vomiting, drowsiness, constipation, and respiratory depression. Oral administration of morphine takes 15-30 minutes to take effect and lasts about four hours.2,3 While parenteral administration of morphine takes 6-10 minutes to take effect and also last about four hours. Inhaled opioids have a faster onset of action than the oral route and considered less invasive than the parenteral route.2

The use of nebulized opioids can be considered an appealing option compared to the oral and parenteral routes of administration. However, nebulized opioids are not routinely recommended. This is because there is conflicting data as to their benefit. There are no large-scale studies testing the efficacy of nebulized opioids, and smaller studies show conflicting evidence. Some studies show that nebulized opioids are less effective compared to oral or parenteral administration while others show that nebulized morphine is equally efficacious to subcutaneous morphine.1,4 Some patients are noted to prefer nebulized morphine over other routes of administration.4

A systematic review of 18 clinical trials that evaluated all routes of opioids in the management of dyspnea found a statistically significant benefit with the oral and parenteral routes of administration but found the nebulized route of administration to be no more effective than nebulized saline. However, the authors of this review did note that there might have been insufficient data with the nebulized route of administration to make this claim.8 Another review of 9 clinical trials looking at efficacy of nebulized morphine in the management of dyspnea found that 3 of the trials had positive results, but the rest failed to show improvement after treatment. The authors note that the small number of subjects, variety of disease states, and different outcome measures limited the interpretation of the results.9 Based upon these varying results, the use of nebulized opioids for the management of dyspnea are not routinely recommended. If you are going to consider a trial of a nebulized opioid, then it is recommended to use an injectable vial and not the oral morphine concentrate. A review of the literature will find no place where the oral concentrate has been evaluated and one article that directly states that the oral elixir should not be used.10 There is some belief that the sugar-free formulation of the oral morphine solution can be used via nebulizer, however, there is not literature to support this. It is of note that all current oral morphine solutions are sugar free and that the sugar containing oral morphine solutions are no longer on the market.7 There is some concern if the injectable vial needs to be preservative free for use via nebulizer. This concern comes from the fact the preservatives can induce bronchospasm in some patients. This is a rare but sometimes serious side effect. The preservatives of most concern are sulfites and edetate disodium (EDTA), found in both oral and parenteral preparations of morphine.5,6 It is not necessary to use preservative-free morphine, but caution should be used in patients susceptible to bronchospasms. If you are not using a preservative free product, then it is recommended to monitor your patient during the first administration of the nebulized opioid for this side effect. Typical starting dose for nebulized morphine is 2.5-10 mg; this can be titrated up to 30 mg per dose. Alternatives to morphine include hydromorphone 0.25- mg or fentanyl 25 mcg.1 Doses can be repeated every 4 hours as needed.3 Morphine for injection should be diluted to 2 mL volume with normal saline solution, if needed.1


Submitted by: Shawn Millsop, PharmD Candidate 2016 at Duquesne University School of Pharmacy and Lorin Yolch, PharmD, CGP, FASCP, Director of Professional Education at Delta Care Rx


References

1 Ferraresi V. Inhaled opioids for the treatment of dyspnea. Am J Health-Syst Pharm. 2005; 62: 319-320.

2 Bausewein C, Simon ST. Inhaled nebulized and intranasal opioids for the relief of breathlessness. Curr Opin Support Palliat Care. 2014; 8: 208-212.

3 Sarhill N, Walsh D, Khawarm E, Tropiano P, Stahley MK. Nebulized hydromorphone for dyspnea in hospice care of advanced cancer. Am J Hosp Palliat Care. December 2000; 17(6): 389-391.

4 Bruera E, Sala R, Spruyt, et al. Nebulized Versus Subcutaneous Morphine for Patients with Cancer Dyspnea: A Preliminary Study. J Pain Symptom Manage. June 2005: 29(6): 613-618.

5 Excipients in the label and package leaflet of medicinal products for human use. European Commission. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003412.pdf Published July 2003. Accessed June 2, 2015.

6 Beasley R, Fishwick D, Miles JF, Hendeles L. Preservatives in nebulizer solutions: risk without benefit. Pharmacotherapy. January-February 1998; 18(1): 130-139.

7 Gold Standard, Inc. Morphine. Clinical Pharmacology [database online]. Available at: http://www.clinicalpharmacology.com. Accessed June 25, 2015.

8 Jennings AL, Davies AN, Higgins JP, Gibbs JSR, Boardley KE. A Sytematic Review of the use of Opioids in the management of dyspnoea. Thorax. 2002;57:939-44.

 9 Brown SJ, Eichner SF, Jones JR. Nebulized Morphine for Relief of Dyspnea Due to Chronic Lung Disease. The Annals of Pharmacotherapy. June 2005;29:1088-92.

10 Ahmedzai S, Davis C. Nebulised drugs in palliative care. Thorax. 1997;52(Suppl 2):S75-77.

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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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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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Delta Campus Pharmacy Student

Comparison of Insulin Therapies

BACKGROUND: Insulin is a common therapy in the treatment of diabetes mellitus type 1 and 2. With the advent of intermediate-acting and long-acting insulin products, basal insulin therapy has become a common practice usually utilized to reduce the number of injections needed to administer or in combination with a short-acting insulin product in the basal–bolus insulin regimens.

The original insulins created to have longer durations of action were the NPH insulins which utilized a crystalline complex between the insulin and protamine.2 In more recent years, newer basal insulins such as Levemir and Lantus have come onto the market which do not rely on the use of protamine-insulin complexes and also claim to last longer (possibly up to single dose a day administration) with no peak activity. The lack of peak activity promises to reduce hypoglycemia risk and to provide a more basal-like dosing.1,3 The original insulins used as bolus insulin therapy were isolated from either animal or human sources. Today, the standard of isolated insulin therapies is regular human insulin. Like the long acting insulin products, recent years have seen the emergence of rapid acting insulin analogues. These rapid insulins promise to have higher efficacy and safety due to rapid onset (for meal time administration) and shorter duration of action.1,4,5

While the newer insulin products claim to have benefits of duration of action and less risk of hypoglycemia, they come at a higher cost than the regular human insulin and NPH insulin products. The average patient admitted to hospice care usually does not have insulin therapy related to the terminal diagnosis — with some obvious exceptions such as pancreatic cancer. The following is an analysis of the benefits and claimed convenience of the newer designer insulin analogues and how they could be substituted with regular human insulin and NPH insulin.

COMPARATIVE ANALYSIS: All three insulins (glarginine, detemir, and NPH) appear to have an onset of 1 to 2 hours. Peak efficacy of Levemir is at a narrow range of 6 to 8 hours (in graphic data in package insert; the analysis section states that there is “no pronounced peak”) versus a more unpredictable reported peak between 3 and 12 hours of Humulin N. Lantus appears to have the most data to support the assertion that there is no pronounced peak of activity with full onset occurring around 4-5 hours after administration and remaining constant throughout the duration of the trials. Duration of action appears to be similar between NPH and Levemir treatments which officially list their durations of action in package inserts as “up to 24 hours.”2,3 Lantus claims to have a constant level up to 24 hours as well, however all data collection ended at 24 hours demonstrating that it could have a greater than 24 hours duration.15

The variable ranges of duration of action and time to peak pharmacodynamic response could be affected by multiple factors such as patient metabolism, site of administration, administration technique, storage conditions of the product, etc. It appears that the NPH insulin (Humulin N) would be more prone to administration technique errors due to the necessity to remember to resuspend the crystalline suspension dosage form by rolling the vials prior to administration. While Lantus has no particularly documented half-life, Levemir has a similar but slightly greater half-life than NPH which could be the result of its being albumin bound which protects some of the insulin from clearance.6,7 There does not appear to be data readily available on the effects of insulin detemir in patients with hypoalbuminemia which is a common condition as a patient's nutritional status declines in end-of life care.

For hypoglycemia risk, the current American Diabetes Association guidelines state that NPH insulin has a higher risk of hypoglycemia over the newer basal insulins Levemir and Lantus. However, in comparative trials, only one case of severe hypoglycemia will be prevented for every thirty-seven patients treated with Levemir than if all thirty-seven patients were to receive NPH. In the case of non-severe hypoglycemia, the risk was similar between Levemir and NPH.3 In trials of Lantus vs NPH both combined with regular human insulin as a bolus, Lantus would need to be used in 97 patients than if they were treated with NPH in order to prevent only one case of severe hypoglycemia.15

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RESULTS: Given the similar onset, peak, and duration, Humulin N properly dosed twice daily could be used as a treatment alternative to Levemir or Lantus as a basal insulin alternative. While the newer insulins have a significantly less pronounced peak than NPH insulin,2,3,15 Humulin N has a long enough duration of action to be utilized as a longer acting insulin replacement therapy. It appears that hypoglycemia risk is similar between all three insulin therapies. However, it should be noted that Levemir and Lantus have been shown to have a more predictable pharmacodynamic profile over NPH insulin — not more effective6 — and that NPH insulin has the potential for hypersensitivity to the protamine. Regardless, all three insulin therapies can be considered equiefficacious (not equipotent) and can be utilized as basal insulin supplementation.

CONCLUSIONS: The choice between any of the available insulin products appears to be mostly based on clinical safety instead of clinical efficacy. The data suggests that any basal-bolus regimen can be considered equiefficacious if properly managed. The selection on which agents to use for outpatient therapy may need to take into account some of those minute differences in safety or dosing depending on individual patient factors. While true, once a day dosing of Lantus or Levemir may seem appealing since it reduces the number of invasive injections during palliative care, the need for basal insulin therapy decreases as nutritional intake declines. In addition, the existence of mixed human insulin products (Novolin 70/30 and Humulin 70/30) may increase convenience since they can provide both bolus coverage and basal insulin in only one or two administrations a day and can be more easily adjusted for changes in intake than the pure basal therapies. Utilization of the older human insulin products can be beneficial from a cost-effectiveness potential especially in the hospice industry since regular human and NPH insulin are available as a lower cost alternative. The cost-effectiveness of human insulin products can be significant since most hospices will not usually have sufficient insulin utilization for purchasing power as some larger health care institutions.


References:

1. American Diabetes Association. Standards of medical care in diabetes–2014. Diabetes Care. 2014;37 Suppl 1:S14-80.

2. Eli Lilly . Humulin N [package insert] 2013.

3. Novo Nordisk. Levemir [package insert] 2013.

4. Novo Nordisk. Novolog [package insert] 2014.

5. Sanofi-Aventis. Apidra [package insert] 2014.

6. Heise T, Nosek L, Rønn BB, et al. Lower within-subject variability of insulin detemir in comparison to nph insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53:1614-20.

7. Brunner GA, Sendhofer G, Wutte A, et al. Pharmacokinetic and pharmacodynamic properties of long-acting insulin analogue nn304 in comparison to nph insulin in humans. Exp Clin Endocrinol Diabetes. 2000;108:100-5.

8. American Diabetes Association . Insulin administration. Diabetes Care. 2004;27 Suppl 1:S106-9.

9. Goldman-Levine JD, Lee KW. Insulin detemir–a new basal insulin analog. Ann Pharmacother. 2005;39:502-7.

10. Eli Lilly . Humulin R [package insert] 2013.

11. Novo Nordisk. Novolin R [package insert] 2013.

12. Ratner R, Wynne A, Nakhle S, Brusco O, Vlajnic A, Rendell M. Influence of preprandial vs. postprandial insulin glulisine on weight and glycaemic control in patients initiating basalbolus regimen for type 2 diabetes: a multicenter, randomized, parallel, open-label study (nct00135096). Diabetes Obes Metab. 2011;13:1142-8.

13. Meyer C, Boron A, Plummer E, Voltchenok M, Vedda R. Glulisine versus human regular insulin in combination with glargine in noncritically ill hospitalized patients with type 2 diabetes: a randomized double-blind study. Diabetes Care. 2010;33:2496-501.

14. Umpierrez GE, Hor T, Smiley D, et al. Comparison of inpatient insulin regimens with detemir plus aspart versus neutral protamine hagedorn plus regular in medical patients with type 2 diabetes. J Clin Endocrinol Metab. 2009;94:564-9.

15. Sanofi . Lantus [package insert] 2013.

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