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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.
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


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.


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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Holly Lassila, DrPH, MSEd, MPH, RPh

Health Literacy: Do Patients Really Understand What We Are Communicating?

The definitions of literacy range from the Merriam Webster definition of the “ability to read and write” to the National Literacy Act of 1991 definition of “an individual’s ability to read, write and speak English and compute and solve problems at levels of proficiency necessary to function on the job and in society, to achieve one’s goals, and to develop one’s knowledge and potential.” Functional health literacy can be distinguished from literacy as the “ability to read and comprehend prescription bottles, appointment slips, and the other essential health-related materials required to successfully function as a patient.”3

Poor health literacy affects people of all ages, races, incomes and education levels and affects 36% of U.S. adults.4 According to Doak et al, the average American reads at an 8th or 9th grade level; however, most health care materials are written on a 10th grade level.5 Poor health literacy is of great concern within a public health context as demonstrated by the inclusion of “increasing health literacy skills” as one of the objectives in the Healthy People 2020 goals.

Basic health literacy is fundamental to the success of each interaction between health care professionals and patients. Low health literacy may result in poor self-care management, increased disability and morbidity, and adverse health outcomes such as ED visits and hospitalizations.4

Health care professionals working in hospice are often educating not only the patient but the caregivers and other support systems for the patient. Being aware of available tools can aid in supporting patients and families. Health communication materials which may be helpful include:

1. SIMPLY PUT: A guide for creating easy-to-understand materials. This is a publication developed by the Centers for Disease Control and Prevention which highlights many best practices regarding assessing and creating written information for the public on almost any scientific subject. [http://www.cdc.gov/healthliteracy/pdf/Simply_Put.pdf]

2. ASK ME 3: This is an educational program designed by the National Patient Safety Foundation to improve communication between patients and health care providers and encourage patients and caregivers to become active members of their health care team. [https://npsf.siteym.com/?page=askme3]

3. SCRIPT YOUR FUTURE: This is a campaign designed to help patients become adherent with taking their prescribed medication regimens. Some of the tools included allow the health care provider and patient to personalize health literacy interventions regarding medication adherence and education. [http://www.scriptyourfuture.org/]

Communicating with patients is a large component of clinical practice. Being well versed in cultural competence, understanding socioeconomic factors, a patients/caregivers education level, and patient’s priorities or motivations can be powerful tools in the promotion of health literacy and clear communication.


1. Merriam Webster: An Encyclopedia Britannica Company. Available at: http://www.merriam-webster.com/dictionary/literate. Accessed December 15, 2014.

2. National Literacy Act of 1991. Available at: https://www.govtrack.us/congress/bills/102/hr751. Accessed December 15, 2014.

3. Ad Hoc Committee on Health Literacy for the Council on Scientific Affairs, American Medical Association. Health Literacy: Report of the Council on Scientific Affairs. JAMA. 1999; 281(6):552-557.

4. U.S. Department of Health and Human Services. Office of Disease Prevention and Health Promotion. Healthy People 2020. Washington, DC. Available at http://www.healthypeople.gov/2020/topicsobjectives2020/default.aspx. Accessed December 15, 2014.. 5. Doak CC, Doak LG, Root JH. The literacy problem in teaching patients with low literacy skills. 2nd ed. Philadelphia, PA: JB Lippincott Co; 1996.

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Michelle Mikus, PharmD

Death with Dignity: An Overview & Legislative Update

Death with Dignity has become a household phrase since People magazine published young Brittany Maynard’s story concerning the issue. As a result of her emotional experience and story, Death with Dignity and “right to die” proponents all over the country have been refueled to get bills passed and laws put in place giving certain terminally ill patients the choice to end their own lives. Working in their favor are five states that already allow patients the right to die: Oregon (law passed in 1994), Washington (2008), Montana (2009), Vermont (2013), and New Mexico (2014). It should be noted that in both Montana and New Mexico a court case must be involved before being deemed lawful. Because of this, there is not much utilization.

In the three states that have laws allowing physician assisted suicide, certain criteria must be met in order to receive a prescription for the necessary medications:

1. Patient must be a resident of Oregon, Washington, or Vermont.

2. Patient must be 18 or more years old.

3. Patient must be capable of making health care decisions for themselves.

4. Patient must be diagnosed with a terminal illness that will result in death within six months.

5. Two physicians must evaluate that all above criteria is met.

In addition to all criteria being met, there are waiting periods before some of the steps can be accomplished. This includes the longest waiting period of 15 days between the first and second oral requests to the physician. In addition, there is a 48-hour waiting period before the prescribed medications can be picked up at a pharmacy.

In December of 2014, Medscape published an ethics report focused on “Life, Death, and Pain” that was given to 21,531 physicians in both the US and Europe. The very first question was “Should physician-assisted suicide be allowed?” The results in favor of allowing this were 54%, which is an 8% increase since the 2010 survey asking the same question (statistics from the US physicians only). Not far off from these physician results are results from a recent Gallup poll, in which 58% of Americans answered in favor of physician assisted suicide and 7 out of 10 were in favor of euthanasia for terminally ill patients.

Many states have legislation in the works to allow Death with Dignity acts similar to Oregon’s. States include: Connecticut, Hawaii, Kansas, New Jersey, and Pennsylvania. In 2012 Massachusetts voters blocked a right to die act with 51% against the act and 49% in favor. In early 2014, the New Hampshire House of Representatives rejected a bill that would allow such a law. Legislators in Colorado plan to introduce a bill in the 2015 session that would make physician assisted suicide legal.

There are many arguments both for and against laws allowing physician assisted suicide. However, regardless of opinions, it cannot be ignored that it is a hot topic and there will continue to be legislation throughout this coming year regarding the subject. Join us for a Brainy Brunch in December of 2015 to take a closer look at physician assisted suicide and the most recent news surrounding the topic.


1. Death with Dignity Across the U.S. Updated November 13, 2014. http://www.deathwithdignity.org/advocates/national. Accessed December 20, 2014.

2. Eckholm E. New Mexico Judge Affirms Right to ‘Aid in Dying.’ The New York Times. January 13, 2014. http://www.nytimes.com/2014/01/14/us/newmexico-judge-afirms-- right-to-aid-in-dying.html?module=Search&mabReward=relbias%3Ar&_r=0. Accessed December 20, 2014.

3. Kane, L. Medscape Ethics Report 2014, Part 1: Life, Death, and Pain. December 16, 2014. http://www.medscape.com/features/slideshow/public/ethics2014-part1. Accessed December 20, 2014. 

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