Wednesday, April 27, 2011

Transdermal Granisetron for Refractory Nausea and Vomiting

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By Gordon J Wood, MD
Vol 11, No. 1 - January 2011


Ms JB is a 32 year old woman with type 1 diabetes who underwent a living related donor renal transplant and a subsequent pancreas transplant. Unfortunately, both transplants were complicated by rejection and graft failure requiring re-initiation of hemodialysis in 2007. Since that time she has suffered with constant, intractable nausea with multiple episodes of vomiting throughout each day. Her symptoms were initially thought related to diabetic gastroparesis but they did not respond to metoclopramide, erythromycin or pylorus muscle botulinum toxin injections. An electrical gastric stimulator was to be placed but was aborted when a gastric emptying study was normal. Extensive workup, including laboratory studies, endoscopy, CNS imaging and abdominal imaging, was unrevealing. She received little or no benefit from adequate trials of domperidone, prochlorperazine, ondansetron, oral granisetron, promethazine, trimethobenzamide, scopolamine, mirtazapine, dronabinol, pancreatic enzymes and a proton pump inhibitor.

She underwent voluntary admission to a psychiatric hospital for treatment of any possible contributing eating disorder without any improvement. Since 2007, she has had more than 40 admissions to the hospital for nausea and vomiting. A feeding J-tube was placed to maintain adequate nutrition in 2008. She presented to the Palliative Care clinic in 2010 for further management of her nausea and vomiting. After a complete history and physical, the etiology of her symptoms remained somewhat elusive. She had nausea before her transplant and it had resolved when the kidney was working then recurred when it failed so the final conclusion was that her symptoms may be due to a poorly defined metabolic process related to her renal failure. Olanzapine was initiated on the first visit for refractory nausea and vomiting and the patient was referred to psychology and psychiatry to help with coping and to address underlying depression and anxiety. At the subsequent visit she noted some benefit so the olanzapine dose was increased and a granisetron transdermal patch was added. At the next visit her symptoms had improved dramatically with a clear temporal relation to starting the granisetron patch. She was only vomiting once or twice in the morning and was relatively asymptomatic through the day. In her first clinic visit she had vomited multiple times through the visit and appeared miserable.

At this visit she was asymptomatic, neatly dressed, wearing makeup and was thrilled at this new level of symptom control which was allowing her to re-engage her life.

Discussion: There were many factors that likely contributed to the dramatic improvement in Ms JB’s refractory nausea and vomiting. Better psychiatric care through the palliative care psychologist and psychiatrist almost certainly played a role in her overall clinical turn-around. The close attention, serial visits and supportive counseling she received in the Palliative Care clinic could also have been therapeutic. Up-titration of her olanzapine also likely was helpful. Olanzapine is an atypical antipsychotic that works on multiple receptors including dopaminergic, serotonergic, adrenergic, histaminergic and muscarinic receptors. Of particular interest is its antagonism of 5HT2 receptors which are located in the vomiting center and are not well targeted by other traditional antiemetics. Multiple small trials have demonstrated efficacy of olanzapine for chemotherapy-induced nausea and vomiting.1 Many palliative care practitioners are now also starting to use olanzapine for refractory nausea and vomiting in patients with advanced cancer and other life-limiting conditions.2-4

Even with all of these possible contributors to her improvement, there still seemed to be a clear benefit that came with initiation of the granisetron patch. While intravenous and oral granisetron have been available for some time, transdermal granisetron (Sancuso©) is a relatively new addition to the practitioner’s toolbox for difficult to control nausea and vomiting. Transdermal granisetron was approved by the FDA for chemotherapy-induced nausea and vomiting (CINV) in September of 2008 based largely on a trial of 582 patients receiving multi-day moderately or highly emetogenic chemotherapy. Patients received either oral or transdermal granisetron and achieved equally good control of their symptoms with either method (approximately 60% in each group achieving complete symptom control). The most common side effect in both groups was constipation.5 The patch is an 8x6cm clear, plastic-backed patch and is worn for 7 days. Pharmacokinectic studies suggest that the patch delivers a dose equivalent to 2 mg of oral granisetron each day it is worn.6

It is thought to exert its antiemetic effect through antagonism of 5HT3 receptors in the gut and chemoreceptor trigger zone.7 Experience with the patch outside of CINV, however, is limited. This case suggests that transdermal granisetron may have a role in other cases of refractory nausea and vomiting. It is unclear why the transdermal form of the drug worked so much better than the oral version for Ms JB. It could reflect absorption issues, especially if she was unable to keep the pills down. It could also reflect compliance issues and may bring into question the adequacy of her prior trial of oral granisetron. Whatever the mechanism, however, the result was dramatic. Further study of this agent in settings other than CINV is clearly needed. Hopefully these results can be replicated and other patients with difficult-to-control nausea and vomiting can achieve life-changing results similar to those achieved by Ms. JB.

1. Navari RM, Einhorn LH, Loehrer PJ Sr, Passik SD, Vinson J, McClean J, Chowhan N, Hanna NH; Johnson CS (2007). A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Supportive Care in Cancer, 15 (11), 1285-91 PMID: 17375339

2.  Srivastava M, Brito-Dellan N, Davis MP, Leach M, Lagman R (2003). Olanzapine as an antiemetic in refractory nausea and vomiting in advanced cancer. Journal of Pain and Symptom Management, 25 (6), 578-82 PMID: 12782438

3.  Jackson WC, Tavernier L (2003). Olanzapine for intractable nausea in palliative care patients. Journal of Palliative Medicine, 6 (2), 251-5 PMID: 12854942

4.  Passik SD, Lundberg J, Kirsh KL, Theobald D, Donaghy K, Holtsclaw E, Cooper M, & Dugan W (2002). A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. Journal of Pain and Symptom Management, 23 (6), 526-32 PMID: 12067777

5.  Boccia RV, Gordan LN, Clark G, Howell JD, Grunberg SM, on behalf of the Sancuso Study Group (2010). Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study. Supportive Care in Cancer PMID: 20835873

6.  Howell J, Smeets J, Drenth HJ, & Gill D (2009). Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapy-induced nausea and vomiting. Journal of Oncology Pharmacy Practice, 15 (4), 223-31 PMID: 19304880

7. Wood, G., Shega, J., Lynch, B., & Von Roenn, J. (2007). Management of Intractable Nausea and Vomiting in Patients at the End of Life: "I Was Feeling Nauseous All of the Time . . . Nothing Was Working" JAMA: The Journal of the American Medical Association, 298 (10), 1196-1207 DOI: 10.1001/jama.298.10.1196

Wednesday, April 27, 2011 by Christian Sinclair ·

Sunday, March 13, 2011

What to do after the patient is made comfort measures only (CMO)

Pallimed Case Conferences ( is closed to comments and new posts as of April 25, 2013.
This site will stay online as an archived source, but will no longer be updated.
For active posts on these cases and new cases go to 
This case is now posted at Pallimed.

By Robert Arnold, MD
Vol 11, No. 2 - February 2011

Case:  The patient is a 75-year-old man who presented with a severe headache and syncopal episode.  His past medical history is remarkable for diabetes, hypertension, hyperlipidemia and an MI in 2009. His family brought him to his local emergency room where it was noted that he had a blown right pupil, and CT scan revealed a large subarachnoid bleed.  He was intubated and life flighted to the hospital.  There he was seen by neurology and neurosurgery, and it was determined that he was not a surgical candidate.   Over the next three days he had little neurological improvement, and after meeting with the family it was decided that he should be made comfort measures only.  He was extubated and 24 hours had stable vital signs, although he was still comatose.  The neurology and neurosurgery team are unclear about what should happen next or about the topics that need to be discussed with the family.
Discussion:  Deciding to focus only on comfort is a major transition point for patients, families and health care providers.  After making this decision, most families are not sure what comes next.  They look to health care providers to reassure them that they are doing the right thing and to ensure that their loved one does not suffer and that they are prepared for the next few days. The following questions should guide one’s action after a patient is made CMO:
1.   Are the patient’s symptoms adequately treated/prevented?
UPMC Health System has developed a comfort measures only order sheet in order to optimize symptom management in CMO patients. (see order on demand). It reminds clinicians that:
a.    All medications and laboratory tests that do not promote comfort should be discontinued.
b.   Most patients near the end of life are not awake enough to tell us when they have symptoms.  Instead, clinicians should treat nonverbal signs such as  rapid respiratory rate (>24/minute), grimacing, moaning, and restlessness presumptively as signs of discomfort or shortness of breath.
c.    The appropriate medications to treat pain or shortness of breath are opiates.
To promote rapid control of symptoms, prn opiates can be titrated rapidly (every 15-30 minutes for iv dosage and 60 minutes for oral opiates.) An infusion may be started if the patient has active symptoms requiring several boluses.
d.   Terminal delirium is treated using benzodiazepines.
e.    The only evidence-based treatment for secretions, or “the death rattle,” is glycopyrrolate.
2.   Does the family want information about what they are likely to see as their loved one dies?
Most families do not have a great deal of experience with death and dying.  It is appropriate to ask them if they would like to hear what they are likely to see over the next hours/days. This information may decrease their fear of the unknown and reassure them that their loved one is “on the right trajectory” and not suffering.  For example, one can tell families that as patients die it is normal that: 1  
a.    They are less responsive and sleep most of the time. Hearing may persist, however, and thus families should feel free to talk to their loved one.
b.   They eat and drink less.  This is not uncomfortable and good mouth care relieves any thirst the patient may have.
c.    Their urine output will decrease, and their hands and feet may become cool.
d.   Their breathing may become irregular with periods of apnea.
e.    They may begin to “gurgle.” This is not uncomfortable to the patient but can be distressing to families who are worried that their loved one is “drowning.” Drawing an analogy to snoring may be helpful.
Finally, families often want to know how long their loved ones will live.  This is an extraordinarily difficult question because of our limited ability to prognosticate the exact time of death.
(Our ability to predict the time of death is no better than our ability to predict the time of birth–we can set boundaries but not determine exact times). Acknowledge your uncertainty, and then give your best judgment–whether hours to days or days to a week or two. Asking the family if they have any specific concerns is often helpful.
3.   Does the patient or family have religious traditions that the health care team should be aware of?
Ask the family whether there are any spiritual or religious traditions that are important to them or their loved one.  In Western Pennsylvania, the most common tradition one needs to be aware if is Catholic need for Sacraments of the Sick prior to death. The chaplaincy service at many hospitals is available 24/7 to meet with families and provide support.
4.   Is there anyone else who needs to come and say goodbye?
It is useful to ask families whether there is anyone else who would like to say goodbye to their loved one.  In addition, families are often unsure what or how much to tell children about their loved one’s dying or whether to let them see them. Asking about this issue allows the family to express their discomfort and ask questions. This is a complicated topic about which social workers often have particular expertise.2
5.   What dispositional issues should be discussed with the family?
There are three general options for patients who have been made CMO:
a.       The family may wish to stay in the hospital, either with or without hospice.  Given that roughly 70% of patients die within 24 hours of having life sustaining treatments stopped in the ICU, this is a reasonable option for the first day.  Staying in the hospital for longer periods may not be the best option as the staff have competing responsibilities, hospitals are not set up to focus solely on comfort, and many hospitals have a 2-3 day time limit for in-hospital hospice.
b.      For patients who have symptoms and are actively dying, the most appropriate location may be an inpatient hospice unit (either a stand alone unit or located in a long term care facility). These units are staffed by hospice nurses, social workers, and physicians and provide excellent palliative care as well as attention to families’ psychosocial and religious needs. There are a number of these units within Western Pennsylvania.
c.       Taking the patient home with hospice may also be a good option for families, provided they have enough support and are willing to have their loved one at home.  It is important to remember that when a patient is at home, hospices provide roughly 2-4 hours of care a day depending on the patient’s needs.  Thus, the family needs to understand and be willing to provide basic comfort care for their loved one (with direction and guidance from the hospice).
Which options are available and will fit the patient/family needs will vary depending on the patient’s clinical status, the insurance, and family situation.  Care managers and social workers in most units are knowledgeable about these issues and can help guide the family about the appropriate choice given their values.  Given this, it is important to have them meet with the family shortly after the patient is made CMO.  In difficult or complex cases, the palliative care social workers are available for consultation and help.
1.   The palliative care service can provide teams with informational brochures that describe the dying process.
2.   The palliative care service has reading material that they can provide to the primary service to give to families.

Sunday, March 13, 2011 by Christian Sinclair ·

Saturday, March 12, 2011

Pallimed Redesign

Pallimed Case Conferences ( is closed to comments and new posts as of April 25, 2013.
This site will stay online as an archived source, but will no longer be updated.
For active posts on these cases and new cases go to 

The Cases blog will be acting as a redesign test site for all of the Pallimed blogs since it has been dormant for so many months.  No worries fans of great cases, it will soon be back to posting cases every other week.

Expect delays and odd formatting issues Saturday March 12th through the 14th.

Saturday, March 12, 2011 by Christian Sinclair ·