Lorazepam, diphenhydramine, and haloperidol transdermal gel for rescue from chemotherapy-induced nausea/vomiting: results of two pilot trials

Haloperidol Transdermal Gel for Rescue From Results of Two Pilot TrialsJacob Bleicher, Achala Bhaskara, MD, Tim Huyck, MD, Susan Constantino, MD, Aditya Bardia, MD, MPH, Charles L. Loprinzi, MD, and Peter T. Silberstein, MD Abstract Despite their use of prophylactic antiemetic therapies, cancer
Cpleasan hemotherapy-induced nausea and vomit- ing (CINV), a significant medical prob-lem,1–4 has been commonly cited by patients continue to consider chemotherapy-induced nausea and vom- iting (CINV) to be a significant problem. Patients frequently use various t and distressing” side effects associated “breakthrough” medications for these symptoms. Unfortunately, there is with chemotherapy.5 Acute nausea occurs in ap- a paucity of trials regarding treatment of breakthrough CINV. This study proximately 30%–50% of patients receiving che- investigated the efficacy of “ABH,” a topical gel containing lorazepam motherapy, and acute emesis occurs in about 15% (Ativan), diphenhydramine (Benadryl), and haloperidol (Haldol), in re- of such patients, especially those receiving highly ducing breakthrough CINV. Adults receiving standard recommended emetogenic chemotherapy.6 CINV may impair prophylactic antiemetics as outpatients were instructed to use 0.5 mL of quality of life significantly and necessitate chemo- the gel topically when they experienced significant CINV. Patients then therapeutic dose reductions, treatment delays, and were contacted retrospectively to respond to a questionnaire rating discontinuation of therapy.7,8 Finally, it may cause their nausea and/or vomiting and their response to ABH-gel treatment. a substantial number of lost work days for patients The results were collected during two trials: Trial I began in April 2003, and considerable costs to the healthcare system, and Trial II began in March 2006. During Trial I, 23 patients were evalu- resulting in a substantial economic burden.9,10 ated; 17 patients (74%) reported that use of the gel decreased their CINV, Currently, the mainstay of prophylactic anti- with 15 (70%) reporting relief within 30 minutes of its application. Three emetic therapy for CINV involves the combined patients believed that the gel caused sedation; no troubles with skin irri- use of 5-hydroxytryptamine (5-HT )-receptor an- tation or muscle spasms were reported. In Trial II, all 10 patients believed tagonists (eg, dolasetron [Anzemet], granisetron that the treatment was effective. When the severity of CINV was quanti- [Kytril], ondansetron, palonosetron [Aloxi], the fied on a scale of 0–10, the mean CINV score decreased significantly from investigational agent tropisetron), dexametha- a 6.1 before gel application to a 1.7 as evaluated 30 minutes following sone, and neurokinin-1 antagonists (eg, aprepitant gel application (P < 0.005). Topical use of ABH gel appears to be a promis- [Emend]).3,6,11–17 The various 5-HT serotonin an- ing and safe rescue therapy for breakthrough CINV that occurs despite tagonists have similar efficacy and adverse effects; prophylactic antiemetic therapy. These results warrant further confirma- in fact, recent guidelines stated that these drugs tion in a large, randomized, placebo-controlled trial.
may be used interchangeably.15,18 Other therapies that have shown some benefit in preventing CINV include benzodiazepines,19 phenothiazines,20 acu- puncture,21 cannabinoids,22 and metoclopramide.23 Even with the availability of these prophylactic therapies, nausea and/or vomiting continues to Funding: Health Future Foundations, 8/1/03–6/2006 remain a significant problem for cancer patients Correspondence to: Peter T. Silberstein, MD, Chief, Hematol- receiving chemotherapy.6,8,24,25 However, few trials ogy/Oncology Division, Creighton University Medical Center, have assessed the best treatment for breakthrough 601 North 30th Street, Suite 2565, Omaha, NE 68132-2867; CINV occurring despite use of prophylaxis. Ide- telephone: (402) 280-4364; fax: (402) 280-4638; e-mail: peter ally, in such situations, patients need rescue medi- 2008 Elsevier Inc. All rights reserved.
Lorazepam, Diphenhydramine, and Haloperidol Transdermal Gel for Rescue From CINV *Yields 120 doses of 0.5 mL in amber syringes. The dose of the active agents in the 0.5-mL aliquot was 2 mg of lorazepam, 25 mg of diphenhydramine, and 2 mg of haloperidol.
Abbreviations: ABH = lorazepam (Ativan), diphenhydramine (Benadryl), and haloperidol Guidelines issued by the American Society of Clinical On- cology15 and the National Comprehensive Cancer Network (NCCN)26 recommend that physicians use agents of different classes for breakthrough CINV. For example, they recommend that additional agents (eg, the dopamine antagonists, loraz- epam [Ativan], corticosteroids) be considered. In addition, the NCCN guidelines recommend that physicians consider using an intravenous (IV) or rectal route of administration for patients with vomiting, since an oral route may not be Was the gel helpful in controlling your nausea? practical.26 However, they do not specify whether these agents Vomiting
should be used sequentially or in combination, what the dura- tion of therapy should be, or which route of administration would be best. IV medications are difficult to give to patients at home, and rectal suppositories often are uncomfortable and A topical compound consisting of lorazepam, diphenhydr- Did you experience relief from vomiting after using the gel? amine (Benadryl), and haloperidol (Haldol; ABH) has yielded promising results when used anecdotally in hospice patients. A similar compound, consisting of lorazepam, diphenhydramine, haloperidol, and metoclopramide (Reglan; ABHR), was toler- Weschules28 noted that of 11,181 ABHR prescriptions pro- vided for patients, 6,529 (58.4%) were for a topical gel, and 4,312 (38.6%) were for a rectal suppository. Less than 0.5% of patients discontinued treatment due to adverse side effects. This study reported ABHR gel to be tolerable, but it did not analyze the effectiveness of this formulation. Another retro- spective study29 reported use of an ABHR gel to be 98% ef- fective in hospice patients. There were no adverse reactions; however, problems arose when patients with bowel obstruc-tions were treated. Apart from these results, prospective data effects.33 Lorazepam is a benzodiazepine that binds to the γ- about the efficacy of ABHR are lacking.
aminobutyric acid receptor in the central nervous system and All of the components of ABH gel appear to be beneficial in helps to prevent anticipatory nausea34,35; although it is not an patients with CINV. Haloperidol is a competitive dopamine- antiemetic, per se, it reportedly augments the efficacy of other receptor antagonist that particularly affects the mesolimbic dopaminergic system and mediates its antiemetic effects via Combined use of these agents in one compound has several blockade of postsynaptic dopamine.30–32 Diphenhydramine is potential advantages. First, the compound effectively manages another antiemetic that predominantly works by blocking his- CINV in cancer patients, as suggested by anecdotal reports tamine-1 receptors; however, it also has some anticholinergic and retrospective review.27 Second, the incidence of extrapy- Table 3
Trial II: Patient Diagnoses, Chemotherapy, and Antiemetic Regimens
Palonosetron, dexamethasone, ondansetron Palonosetron, dexamethasone, aprepitant, ondansetron Dexamethasone, palonosetron, aprepitant, ondansetron Palonosetron, dexamethasone, ondansetron, aprepitant Palonosetron, dexamethasone, aprepitant, ondansetron Promethazine, ondansetron, prochlorperazine, chlorpromazine, aprepitant Dexamethasone, granisetron, prochlorperazine Abbreviations: FOLFIRI = 5-fluorouracil (5-FU), leucovorin, and irinotecan; FOLFOX = 5-FU, leucovorin, and oxaliplatin; CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone ramidal side effects observed with haloperidol should be lower mately 1–3 minutes to facilitate its transdermal absorption. with use of this combination due to the anticholinergic effects Thereafter, patients were contacted by telephone by an of diphenhydramine.28,37 Third and finally, the combination investigator, generally within 1 month of using the gel. No is available as a topical agent, which makes it a convenient written consent was required by this IRB; however, the pa- product for patients experiencing CINV.
tients provided verbal informed consent when called to an- This report describes a pilot study examining the efficacy of swer questions about their progress with the ABH gels. The topical ABH in reducing CINV among cancer patients.
investigator conducted a directed interview using a standard-ized questionnaire (Table 2) that asked patients to rate their CINV and to indicate whether they believed the gel to cause The two different, but related, trials of this study defined sedation, skin irritation, or muscle spasms.
nausea as any sickness of the stomach that created an urge to vomit. Vomiting was defined as any emesis whatsoever that occurred. Both studies used the same gel formulation; the gels The second trial was approved by the Creighton Univer- were distributed to patients in the same manner.
sity IRB in March 2006. This trial involved adult patients who had been given a prescription for ABH gels when they received emetogenic chemotherapy; the patients were not All patients involved in this trial were adults; they were chosen for any particular diagnoses. The chemotherapy and diagnosed with different types of cancers, were treated with antiemetic regimens, along with patients’ diagnoses, appear a variety of chemotherapy regimens as outpatients, and were given standard prophylactic antiemetics similar to those rec- Two of the 10 patients received high-dose cisplatin-based ommended in established guidelines.3,6,11–17 This method was chemotherapy, and 1 patient received low-dose cisplatin. The initiated in the clinical practice of one physician (PTS), who two patients given high-dose cisplatin received dexametha- noted that hospice patients appeared to benefit from this ther- sone, a 5-HT antagonist, and aprepitant, whereas the oth- apy. To obtain more detailed information about whether this ers were given a standard antiemetic regimen consistent with therapy was alleviating CINV, a protocol was developed and practice guidelines. The patients were instructed to apply the approved by the Creighton University Institutional Review Board (IRB) in April 2003.
The patients were given a prescription for six prefilled, capped, 1.0-cc, tuberculin syringes of ABH gel when they re- ceived emetogenic chemotherapy. The components of the gel The involved patients were asked, on a scale of 0–10, with 0 being “no nausea or vomiting” and 10 being “the worst nausea and/or vomiting experienced” to rate The patients were instructed to use the ABH gel when they developed significant nausea and/or vomiting in the days fol ow- Nausea/vomiting prior to applying ABH gel ing chemotherapy and were given the option of repeating the Nausea/vomiting 30 minutes after applying ABH gel treatment at 6-hour intervals. They were instructed to place 0.5 Nausea/vomiting 4 hours after applying ABH gelDid you feel the treatment was effective? mL of the gel on the palmar aspects of their wrists using a prefil ed Did you have any side effects from the drug? syringe (without a needle). After applying the gel, the subjects were instructed to rub their wrists together gently for approxi- Abbreviation: ABH = lorazepam (Ativan), diphenhydramine (Benadryl), and haloperidol (Haldol) Lorazepam, Diphenhydramine, and Haloperidol Transdermal Gel for Rescue From CINV Abbreviation: ABH = lorazepam (Ativan), diphenhydramine (Benadryl), and haloperidol (Haldol) scale at baseline, 0.5 hours, and 4 hours after applying the ABH gel. The rating scale that patients used ranged from 0 (no nau- sea or vomiting) to 10 (worst imaginable nausea or vomiting).
STATISTICAL METHODS
Al statistics were performed using statistical software JMP (version 6.0; SAS Institute; Cary, NC), which reports continu- ous variables as means and categorical variables in numbers and percentages. Given the smal sample size and uncertainty about Abbreviation: ABH = lorazepam (Ativan), diphenhydramine (Benadryl), and haloperidol normal distribution of the study sample, a nonparametric statis- tical test (Wilcoxon signed rank test) was used to calculate the mean difference in the nausea score before and after treatment. A P value of < 0.05 was considered to be statistical y significant.
Table 6
Trial I: Nausea Relief and Time to Relief
In all, 24 patients were contacted for the first trial between April 2003 and August 2003. One had not developed any CINV and was excluded from analysis. Nausea scores for the remaining 23 patients are provided in Table 5. A total of 74% (17/23) of the patients believed that the gel decreased their nausea, and 70% (16/23) experienced relief from vomiting. Further, 70% (16/23) of all patients obtained relief within 30 Abbreviation: ABH = lorazepam (Ativan), diphenhydramine (Benadryl), and haloperidol minutes after applying the gel (Table 6). The mean reported nausea score significantly decreased from a 4 before patients applied the gel to a 2 when patients assessed their condition ABH gel if they developed nausea and/or vomiting in the days 30 minutes following its application (P < 0.0001).
Three patients (13%) reported mild fatigue after using the Again, following receipt of verbal consent, an investigator gel; no patients reported skin irritation or muscle spasms.
used a structured interview methodology (by telephone or in person); the questions addressed in this second trial (Table 4) were applicable to the first dose of the ABH gel. Patients then A total of 10 patients were involved in the second trial, were asked to rate the severity of their CINV on a combined which took place between March 2006 and July 2006. Table 7 includes data on patients’ CINV scores reported before the ABH gel was used and 30 minutes and 4 hours after it was ap- Importantly, this study was a pilot retrospective study with a plied. The mean reported nausea score significantly decreased smal sample size that sought data to support initiation of a more from a 6.1 at baseline to a 1.7 when patients assessed their formal, randomized, placebo-controlled clinical trial to better condition 30 minutes after using the gel (P < 0.0005). All 10 determine the utility of this approach. A randomized, double- patients reported that the treatment was effective. None of blind, controlled trial to evaluate ABH gel versus placebo in a the patients reported any significant side effects.
cooperative group setting is being planned to better evaluate the efficacy and toxicity associated with using this gel in clinical Discussion
practice. The data from the current trial support an additional Extensive literature searches provided no proof of appropri- study using this approach; however, currently available data are ate evidence-based practice for use of rescue medications for not sufficiently definitive to recommend use of ABH gels for CINV. In the current two trials, the vast majority of subjects routine clinical practice. Additional studies may explore the reported a significant decrease in their severity of CINV after role of this formulation for treating cancer patients with chemo- applying transdermal ABH gels. The patients’ side effects from therapy-independent nausea and/or vomiting and for anyone using these topical agents were minimal; patients experienced suffering from acute nausea and/or vomiting.
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