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by Drew Rosielle (@drosielle)

A few months ago an interesting olanzapine study was published which I have been meaning to write a post about. It's important because while olanzapine has really established itself in the last decade as a highly effective antiemetic for chemotherapy induced nausea and vomiting, and is now in multiple CINV guidelines (eg Antiemetics: ASCO Guideline), etc, we don't have a lot of data for its efficacy for nausea outside of CINV, and so a well-done RCT is welcome.

The study is a multi-center, US, adult, randomized, placebo-controlled, double-blind trial of olanzapine for nausea in advanced cancer patients who are not receiving chemo. (Small note: the abstract says 'double-line' instead of 'double-blind,' and as someone who does my best to edit typos from my and others' work all the time, it is just interesting and kind of quaint to see such a typo in a JAMA journal. I actually tried to figure out if 'double-line' is some novel trial design I had missed but I'm pretty sure it is not.) While well-done, it is a small study and is described as a pilot study by the investigators.

Patients (n=30, ~45% Black American and the rest mostly white, mean age ~60 years, broad spectrum of solid tumors represented, most were on either/both metoclopramide/ondansetron at baseline) had to have chronic nausea for at least a week rated >3 on a 0-10 scale, not be on chemo for at least 2 weeks (for the most part CINV is defined as chemo on days 0-5 of chemotherapy), and not be on 'antipsychotics' otherwise (to be clear, they allowed use of common neuroleptic antiemetics like prochlorperazine and metoclopramide but presumably these folks weren't on quetiapine, risperidone, etc & if you were wondering none of them were on haloperidol at baseline).

Patients were randomized to placebo or 5mg olanzapine orally, daily, for 7 days. Patients filled out simple, daily, self-reported 0-10 symptom scales looking at nausea, but also appetite, fatigue, sedation, and pain; as well as vomiting episodes and global well-being.

Primary outcome was change in nausea scores from baseline to day 7.

The results were ridiculous, as you can see by the Figures. The authors couldn't say that in print of course, so instead they noted, 'No other drug studied in this situation has been reported to decrease nausea/vomiting more than what was observed in this study.'



Nausea went from a baseline of 9/10 to 1/10 in the olanzapine arm and was unchanged in placebo arm. Emesis episodes went from 2 a day to zero in the active group, 3 to 2 a day in the placebo arm. Self-reported appetite improved from 1/10 to 7/10 for olanzapine, 1/10 to 2/10 for placebo. Given all this it won't be surprising to hear that global well-being improved in the olanzapine group as well, more than placebo.

My biggest challenge with olanzapine is its sedating/fatiguing effects and at least in this group on this relatively low dose of olanzapine, those toxicities weren't evident in their findings, and in fact self-reported fatigue improved in the olanzapine group vs placebo.

They noted that after the 7 days the patients could enter open label observation and all the olanzapine patients chose to stick with it.

So, wow. My guess is most who prescirbe olanzapine regularly aren't surprised that it is effective outside of CINV. Like many other antiemetics, it seems to have broad antiemetic efficacy. The magnitude of the effects though are what's really impressive and while I have zero doubt olanzapine is more effective than placebo for nausea in these patients, I think we'll need larger studies before we can make firmer conclusions about the 'actual' magnitude of benefit. That is, it may see get attenuated with larger trials, but I'd be surprised if it's more than a modest attenuation.

This is not the final word on olanzapine of course, like with everything else in medicine we would greatly benefit from comparative efficacy studies. Given how my clinical practice works, in that I don't prescribe more than one dopamine blocker at a time (eg both olanzapine + prochlorperazine or metoclopramide), comparative studies between those agents would be particularly welcomed (with metoclopramide we have comparative data for CINV with olanzapine, but not elsewhere). Especially given the relative expense, it would be helpful to know whether we should even be using prochlorperazine as a first-line agent anymore.

Basically what I'm saying is olanzapine is arguably in the running to become of our first-line dopamine antagonist antiemetic in palliative care, I think that's a reasonable possibility, and one that could be answered with additional investigation which I hope trickles out in the coming years. Please don't send me angry @'s on Twitter, I'm not saying olanzapine *is* currently first-line, more that at this point I wouldn't be surprised if we landed there in the coming decade.

A global aside about olanzapine. Why is it so good? My theory around olanzapine's efficacy, which I don't think is a profound one, but one I'll state publicly anyway, is that besides stopping a lot of patients from puking, it has significant, welcome, 'additional' effects which make many of our patients globally feel better, effects that many of our other common antiemetics eg ondansetron/prochlorperazine don't really have. By additional effects I'm talking about mood effects, anxiolysis, maybe a little mood elevation, etc. Olanzapine's impacts on those in addition its chemoreceptor trigger zone action is why it helps our patients so profoundly in a way many other of its peers just don't.

A final digression about appetite. This is not proof that olanzapine is an effective treatment for cancer related weight loss/cachexia syndrome. Nothing that I know of has been clearly demonstrated to be effective for that (apart from effectively controlling the underlying cancer). However I've long wondered whether we've missed the boat on drug investigation for cancer cachexia (which is super-complicated, with multiple interacting causes in any patient, and just not something that's amenable to being 'fixed' with a pill, or any other monotherapy like vaporizing high THC cannabis, etc), by ignoring the opportunity to study orexigens as essentially palliative therapies for the 'distress of low appetite'. Eg, I have a lot of patients who take orexigens and 'like them,' say they feel better on them, appreciate the fact that they feel hungrier, participate more in the social aspects of eating, etc, but who's actual weight loss/cachexia is not improved by them. Ie, I think there is a relatively understudied potential for some of these drugs as palliative agents for anorexia, as opposed to disease-modifying agents for cachexia.
For more Pallimed posts about nausea.
For more Pallimed posts by Dr. Rosielle click here.

Drew Rosielle, MD is a palliative care physician at the University of Minnesota Health in Minnesota. He founded Pallimed in 2005. You can occasionally find him on Twitter at @drosielle.

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In general, I am a cynic and a nihilist. That means when reviewing the literature, I find most glasses half empty rather than half full (OK, probably this is true in life, but that is TMI). I am very unlikely to try a new treatment based on one study.

For every rule, however, there is an exception. I am completely enthralled with aromatherapy and thus found an article in the Annals of Emergency Medicine by Beadle on isopropyl alcohol nasal inhalation for nausea in the emergency department. It was a randomized controlled trial which made it swoon-worthy. The only problem was it was a placebo trial and so my friend(s) pooh-poohed the article. I was thrilled to see the follow-up, double-blind RTC article by April: “Aromatherapy Versus Oral Ondansetron for Antiemetic Therapy Among Adult Emergency Department Patients: A Randomized Controlled Trial,” in February 2018, again in the Annals of Emergency Medicine. The fact that it was positive means that anyone who I talk to has to hear about it (as well as how they must watch Nanette and how excited I am about the new season of The Good Place).

The aim of the 2018 study was to compare nasally inhaled isopropyl alcohol versus oral ondansetron (aka Zofran) for the treatment of nausea among emergency medicine patients. They looked at 120 adult patients with nausea or vomiting who did not require an IV. The patients who were randomized into the three groups: (1) isopropyl alcohol plus 4 mg of oral ondansetron; (2) isopropyl alcohol plus oral placebo; (3) inhale saline plus 4 mg of ondansetron. (They did not do a double placebo because there is placebo-controlled data that both drugs work). The isopropyl alcohol was a commercially prepared, medical pad placed 1-2 cm from the patient’s nose and the patient was instructed to nasally breathe to inhale the isopropyl alcohol. Measurements were made at 10, 20, 30, and 60 minutes and then hourly until disposition using a 0-10 cm visual, analog scale.

Mean nausea scores decreased 30 mm in the alcohol and ondansetron group, 32 mg in the alcohol placebo group, and 9 mm in the saline ondansetron group (this was statistically different). Patients in the isopropyl alcohol groups also had better nausea control at the time of discharge and higher satisfaction with no adverse events.

On to the evaluation questions:

Was this study valid?

The assignment of patients to treatment was evenly randomized. All of the patients who entered the study were accounted for at the conclusion and there was complete follow-up. They asked the patients and clinicians if they could tell what group they were in (they could not). The patients seemed to be treated in an identical manner. Rescue antiemetics were less common in the groups who got the isopropyl alcohol versus the ondansetron alone.

Were the results clinically important?

The investigators used 20 mm as a clinically significant result, which seemed to be reasonable. They did not make any adjustment for compounding variables, but I really was not sure what the confounding variables should be; this seemed reasonable.

The problem with the study is the question whether the results will help me care for my patients. My patients are not young, relatively, healthy individuals with viral illnesses who do not need an IV. That is unclear and if I am being my normal, cynical self, I probably should just move on!

On the other hand, given that this trial has absolutely no side effects and I can carry alcohol swabs around in my coat, I stick with my love of this article. I mean seriously, why wouldn’t you try this in the hospital on patients with nausea and vomiting.

So, I am going to urge you to watch Nanette, the Good Place and carry around isopropyl alcohol swabs in your pocket on rounds. Tell me if you think I am wrong!

Robert Arnold, MD is a palliative care doctor at the University of Pittsburgh and a co-founder of VitalTalk (@VitalTalk). He loves both high and low brow comedy (The Good Place and Nanette), pop culture (the National Enquirer and Pop Culture Happy hour) and music of all kinds (not opera tho!) You can find him on Twitter at @rabob. 

More Pallimed posts from Bob Arnold can be found here. More journal article reviews can be found here. More posts on nausea can be found here.

References

Beadle KL, Helbling AR, Love SL, April MD, Hunger CJ. Isopropyl Alcohol Nasal Inhalation for Nausea in the Emergency Department: A Randomized Controlled Trial. Ann of Emergency Med. 206: 68 (1):1-10

Hines S, Steels E, Chang A, et al. Aromatherapy for treatment of postoperative nausea and vomiting. Cochrane Database Syst Rev. 2012;(4):CD007598.

April MD, Oliver JJ, Davis WT, Ong D, Simon EM, Ng PC, Hunter CJ. Aromatherapy Versus Oral Ondansetron for Antiemetic Therapy Among Adult Emergency Department Patients: A Randomized Controlled Trial. Ann of Emergency Med. https://doi.org/10.1016/j.annemergmed.2018.01.016

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Case:
Ms. Turner* is a 29-year-old woman with recently diagnosed ovarian cancer discovered after presenting to the ED with worsening abdominal pain. CT imaging showed a 4.8cm cystic mass extending from her right ovary, and the surgical pathology revealed ovarian adenocarcinoma. Two weeks post-operatively, she was hospitalized for initiation of chemotherapy, and the palliative care service was consulted for symptom management. Despite having received treatment with ondansetron (Zofran®), aprepitant (Emend®), dexamethasone (Decadron®), lorazepam (Ativan®), and haloperidol (Haldol®), she developed significant nausea and vomiting on the first day of chemotherapy infusion with symptoms worsening on her second day of chemotherapy. She described feeling utterly miserable and fearful about her next chemotherapy infusion, and she was continuing to experience nausea and repeated episodes of emesis overnight with minimal oral intake. Ms. Turner also described an underlying history of anxiety disorder predating her cancer diagnosis. At home she typically smoked marijuana on a daily basis to help manage her anxiety symptoms, which she reported did not interfere with her successful function at work and school. On review of systems, she noted abdominal discomfort for which she was taking low dose oxycodone and that she had not moved her bowels for several days.
Discussion:
Nausea and vomiting (NV) are commonly reported side effects with chemotherapy.¹ The primary pathway for NV involves the chemotherapy drugs directly stimulating the chemoreceptor trigger zone (CTZ), in the area postrema at the base of the fourth ventricle. Activated receptors in the CTZ transmit signals to the vomiting center in the brainstem to produce NV. Receptors in the CTZ include serotonergic receptor 5-hydroxytryptamine type 3 (5-HT3), dopaminergic (D2) and neurokinin type 1 (NK-1) receptors. In addition, chemotherapy can damage GI mucosa causing local release of 5-HT3 neurotransmitters by gut enterochromaffin cells, activating peripheral pathways along the vagus and splanchnic nerves and directly triggering the vomiting center. Finally, chemotherapy-associated anxiety may also stimulate the vomiting center through central cortical pathways. Whether transmitted via signals from the CTZ, the cortex, or peripheral inputs, the vomiting center has several different receptors involved in initiating the vomiting reflex: muscarinic acetylcholine (Achm), histamine type 1 (H1), and 5-hydroxytrypamine type 2 (5-HT2).¹

Given the pathways for chemotherapy-induced nausea and vomiting described above, 5-HT3 and NK-1 receptor antagonists such as ondansetron and aprepitant, in combination with dopamine antagonists such as haloperidol, are typically effective for treatment of NV. In some cases, however, patients may develop breakthrough nausea and vomiting despite adequate standard therapy requiring additional or alternative anti-emetic medications. According to guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network, there are several categories of second-line agents that may be useful in refractory cases.^2,3

The cannabinoids dronabinol (Marinol®) and nabilone (Cesamet®) are both FDA approved for refractory chemotherapy-induced nausea and vomiting.⁴ Unlike other anti-emetic medications which block receptor activity for their therapeutic effect, cannabinoid effect is exerted by agonist activity on the cannabinoid receptor in the brain CB1.⁵ Dronabinol is a Schedule 3 synthetic THC (delta-9 tetrahydrocannabinoid). Starting dose is typically 5mg 2 hours prior to chemotherapy and every 4 hours as needed, with a maximum dose of 15mg. Nabilone is a Schedule 2 drug with longer onset and duration of action, and is dosed 1-2 mg twice or three times daily as needed. Studies demonstrate that dronabinol and nabilone are effective for treatment of nausea and vomiting; however, their use is limited by their side effect profile including vertigo, xerostomia, hypotension, dysphoria, and hallucinations.^4,5

Olanzapine (Zyprexa®) is an atypical antipsychotic which antagonizes multiple neurotransmitters including dopamine at D1, D2, D3 and D4 brain receptors; acetylcholine at muscarinic receptors; serotonin at 5-HT2, 5-HT3, and 5-HT6 receptors; catecholamines at alpha-1 adrenergic receptors; and histamine at H1 receptors.⁶ Several studies have demonstrated its utility for treating chemotherapy-induced nausea and vomiting.⁶ No studies have specifically compared it to haloperidol or other atypical anti-psychotics for treatment of nausea, although several authors have argued that it is the multiplicity of olanzapine’s receptor activity which contributes to its effectiveness. The recommended dosing is 5mg orally daily starting 1-2 days before chemotherapy, then 5-10mg daily for days 1-4 of chemotherapy. Side effects include sedation, dry mouth, increased appetite, hyperglycemia and postural hypotension.^2,3

Metoclopramide (Reglan®) has central and peripheral anti-dopaminergic activity, and at high doses also exerts 5-HT3 antagonist effect which is thought to contribute to its anti-emetic effect.1,2 Because of its low therapeutic index, metoclopramide is typically reserved for patients who are intolerant or refractory to first line anti-serotonergic agents. Dosing is 10-40 mg IV 30 minutes prior to chemotherapy, then every 4 to 6 hours as needed.³ An alternate dosing strategy is 1-2 mg/kg 30 minutes before chemotherapy and then repeated 2 hours after chemotherapy for 2 doses, and then every 3 hours for 3 doses. Side effects include dystonia, akathisia, sedation, and esophageal spasm. Pretreatment with diphenhydramine (Benadryl®) will decrease risk of extrapyramidal reactions.²

Benzodiazepines are most useful in cases of anticipatory NV, which is thought to be a conditioned reflex as a result of prior poor control of emesis during chemotherapy treatment.³ The phenomenon involves the development of NV when a sensory stimulus (ie, the sights, sounds, or smells of chemotherapy clinic) becomes paired with the experience of symptomatic chemotherapy treatment. After a conditioning period (ie, repeated chemotherapy infusions in clinic), the sensory stimulus or anxiety from negative anticipation may trigger NV before the patient has even received the chemotherapy infusion.⁷ The mechanism involves signals along intracerebral projections in the cortex directly stimulating the vomiting center. Older studies had described the phenomenon in up to 25% of patients with poorly controlled symptoms by the fourth treatment cycle; however, the frequency appears to have decreased with the advent of more effective anti-emetic regimens. Patients with refractory NV are at higher risk of developing anticipatory NV. The intermediate-acting benzodiazepine lorazepam is helpful for treatment of anticipatory NV and as an adjunct in cases of refractory NV, with starting doses of 0.5-1mg oral or IV, and up to 2mg, every 6-8 hours as needed for anxiety and nausea.⁷

Resolution of the Case:
Based on her symptoms and previous history, Ms. Turner was started on dronabinol 5mg three times daily during her chemotherapy treatment while in the hospital, along with the scheduled ondansetron and haloperidol. A bowel regimen of senna (Senekot®) and polyethylene glycol 3350 (Miralax®) was also initiated, as opioid-induced constipation was likely contributing to her symptoms. Within 24 hours, she had resolution of emesis and improvement of her nausea, enabling her to resume oral intake.

Summary:
While standard anti-emetic therapies with 5-HT3 and dopamine antagonists are effective and well-tolerated in most cases of chemotherapy-induced nausea and vomiting, occasionally refractory symptoms necessitate addition of a second-line agent such as a cannabinoid, olanzapine, or metoclopramide. Patient characteristics such as age, previous experience with cannabinoids, and medical comorbidities will impact the choice of second-line agent. Dronabinol or nabilone may be most effective in younger patients and those with previous experience of tolerating cannabinoids. Olanzapine is preferable in elderly patients or populations for whom there may be a concern about the psychoactive properties of cannabinoids. Substitution of high dose IV metoclopramide for other dopaminergic and 5-HT3 medications could also be helpful in certain cases, especially if there are additional concerns about GI dysmotility or intolerance to standard 5-HT3 agents.

References:
1. Wood G, Shega J, Lynch B, Von Roenn J. Management of Intractable Nausea and Vomiting in Patients at the End of Life. JAMA 2007; 298(10): 1196-1207.
2. Basch E, Prestrud AA, Hesketh PJ. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011; 29:4189. Open Access PDF
3. Hesketh PJ. Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2008; 358(23):2482-94.
4. Wilner LS, Arnold R. Cannabinoids in the Treatment of Symptoms in Cancer and AIDS, 2nd edition. Fast Facts and Concepts. December 2007; 93.
5. Todaro B. Cannabinoids in the Treatment of Chemotherapy-Induced Nausea. J Natl Compr Canc Netw 2012; 10:487-492.
6. Nizukami N, Yamauchi M. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients Receiving Highly or Moderately Emetogenic Chemotherapy: A Randomized, Double-Blind, Placebo-Controlled Study. Journal of Pain and Symptom Management March 2014; 47 (3)542-550.
7. Roscoe J, Morrow G. Anticipatory Nausea and Vomiting. Support Care Cancer Oct 2011; 19 (10): 1533-1538. Open Access PDF


Pallimed Case Conference Disclaimer: This post is not intended to substitute good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in healthcare. Patient details have been changed by Pallimed editors to help with anonymity. Links and small edits are made for clarity and to abide by Pallimed editorial standards.

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Ms BB is a 57 year old woman with fallopian tube cancer with multiple mesenteric and peritoneal metastases and a history of large and small bowel obstructions. She presented with nausea, vomiting, and abdominal distention. She was found to have another bowel obstruction and had an NG tube placed with improvement in her symptoms. She then went to the OR for an exploratory laparotomy. She was found to have massive carcinomatosis and ascites and it was felt that a debulking was not possible so a venting gastrostomy tube (g-tube) was placed and the operation was aborted.

Palliative care was consulted to assist with postoperative nausea and vomiting. Despite placement of the venting gtube, the patient had persistent nausea and held a basin next to her during the interview to catch her frequent episodes of emesis. She was despondent because the surgeons had told her that the g-tube was working well and draining large amounts of fluid but that it was unable to keep up. Antiemetics were not helpful. The patient thought that there was nothing left to do and that she would have to live the rest of her life with this level of discomfort. A trial of octreotide 0.1mg subcutaneously three times daily was initiated in addition to continued drainage by her venting gtube. She was also given around-the-clock intravenous haloperidol and PRN intravenous ondansetron. By the next day, her g-tube output had decreased and her nausea and vomiting had resolved. Her pain was controlled with a hydromorphone PCA. She was eventually able to be discharged home with plans to follow up with her outpatient oncologist to consider next steps. With her symptoms controlled, she was able to move past her initial distress and talk openly about her hopes for the future and how she wanted to spend the time she had left.



Discussion:

Malignant bowel obstruction can occur with any cancer but is most commonly associated with advanced ovarian cancer, where it occurs in up to 50% of patients. It generally indicates a poor prognosis and carries a heavy symptom burden predominated by nausea, vomiting and abdominal pain. Patients with carcinomatosis, like Ms BB, are generally not candidates for surgical correction of the obstruction or endoscopic stenting. Fortunately, medical management can be very effective. Abdominal pain is treated with opioids and nausea is treated with metoclopramide in partial obstructions and haloperidol in complete obstructions. Corticosteroids are also often used for help in symptom control and because there is some indication that they may promote resolution of the obstruction presumably by decreasing inflammation and promoting salt and water absorption. Gastrointestinal secretions can be controlled with anticholinergics (such as scopolamine) and/or somatostatin analogues (such as octreotide).

Two prospective, randomized controlled trials suggest octreotide is superior to scopolamine. Octreotide works by inhibiting the release of several gastrointestinal hormones thereby reducing secretions, slowing motility, increasing water and electrolyte absorption, and reducing bile and splanchnic blood flow. It is generally dosed 0.1-0.3mg subcutaneously TID. Some palliative care units will use continuous infusions at higher doses with anecdotal success.

Current guidelines suggest placing a venting g-tube if medical management is unsuccessful. A venting g-tube is similar to a traditional g-tube but is used solely for drainage of the gastrointestinal secretions and the liquids taken by mouth that are unable to bypass the obstruction. This drainage prevents the backup of these fluids that would normally stretch the viscus and stimulate vomiting. As experience with this intervention increases, many clinicians advocate g-tube placement early in the treatment algorithm because it can provide more complete relief of vomiting and allow more extensive pleasure feeding. Venting g-tubes can, however, place the patient at greater risk for electrolyte imbalances.

Most guidelines and many clinicians consider venting g-tube placement and medical management with octreotide/ anticholinergics as two separate treatment pathways. This case highlights the fact that, occasionally, both may be needed simultaneously. Although Ms BB’s venting g-tube was draining effectively, she still experienced severe nausea and vomiting, and it was not until octreotide was added to the regimen that her symptoms became controlled. This scenario is borne out in some of the data regarding venting g-tubes.

In one series of patients with gynecological malignancy and upper intestinal obstruction, 4 in 31 had incomplete resolution of their symptoms with placement of a venting g-tube alone. All 4 had complete symptom relief when octreotide was added to the regimen. Clinicians need to be aware that venting gastrostomy tubes and medical management with octreotide/anticholinergics are not mutually exclusive treatment algorithms and a small percentage of patients will require both for adequate symptom control. Fortunately, as was the case with Ms BB, this approach can allow almost all patients with malignant bowel obstruction to regain some measure of comfort.

References:

1. Ripamonti CI, Easson AM, Gerdes H. Management of malignant bowel obstruction. Eur J Cancer (2008). doi:10.1016/j.ejca.2008.02.028

2. Campagnutta E et al. Palliative treatment of upper intestinal obstruction by gynecological malignancy: the usefulness of percutaneous endoscopic gastrostomy. Gynecologic Oncology. 1996;62:103-105. doi:10.1006/gyno.1996.0197

3. Ripamonti CI et al. Clinical-practice recommendations for the management of bowel obstruction in patients with endstage cancer. Support Care Cancer. 2001; 9:223-233. doi:10.1007/s005200000198



Pallimed Case Conference Disclaimer: This post is not intended to substitute good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in health care.

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Case:

Ms Emma N. 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 3 years ago. 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. 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 2 years ago. She presented to the Palliative Care clinic 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 Emma N’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© - prescribing insert) 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 in this case. 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 this case.

References:
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 - Open Access PDF

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




Pallimed Case Conference Disclaimer: This post is not intended to substitue good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in health care.