Dr. Jim Joyner, PharmD, CGP
A hiccup is an involuntary reflex involving the respiratory muscles of the chest and diaphragm, mediated by the phrenic and vagus nerves and a central (brainstem) reflex center. A single episode can last for a few seconds to as long as several days. Persistent hiccups can last for months. There are a wide range of possible causes for hiccups including; stress or excitement, esophageal or gastric distension, liver disease, CNS lesions, or cancer. Irritation of the vagus nerve or the diaphragm is a common mechanism.
Many drug and non-drug treatments have been used, but there is little evidence of any one superior approach to management; virtually all current data are anecdotal. When choosing a drug treatment strategy for hiccups, consider the suspected etiology, patient’s drug-allergy history, potential drug-disease state contraindications, and potential adverse effects from any proposed drug therapy.
Chlorpromazine (Thorazine) is the only drug with an FDA approved indication for treatment of hiccups. Haloperidol (Haldol) is a useful alternative. Chlorpromazine and Haloperidol should not be used in patients with Parkinson’s disease because they may exacerbate involuntary movements. Metoclopramide (Reglan) increases GI motility and may be especially useful if hiccups are related to esophageal or gastric distention. The muscle relaxant, Baclofen (Lioresal), is thought to have a direct relaxation effect upon the diaphragm and may be most useful in patients where an irritation of the diaphragm is suspected. Dexamethasone (Decadron) may be appropriate as an adjunct to one of the previously mentioned drugs if there is hepatomegaly or tumor involvement. All of these drugs are available as relatively low cost generics, so the choice of therapy should be based upon the suspected etiology behind the hiccups, the patient’s drug allergy history, and other health conditions that may predispose the patient to adverse drug effects. In difficult cases it may be necessary to combine two to three of the drugs listed below in order to achieve adequate results (haloperidol and chlorpromazine should not be combined because they exert a similar mechanism of action that would represent at therapeutic duplication).
Common Doses for Hiccups:
Chlorpromazine (Thorazine) 25-50mg Q6h po,pr
Haloperidol (Haldol) 1– 2mg Q6h po, sl
Metoclopramide (Reglan) 10-15mg Q6h po
Baclofen (Lioresal) 5 –10mg Q6h po
Dexamethasone (Decadron) 2-6mg daily po
Dr. Jim Joyner, PharmD, CGP
Opioids are the mainstay of treatment for management of severe dyspnea in late stage CHF and COPD. The use of opioids in dyspnea is supported by extensive experience as well as clinical studies with the use of both oral and parenteral opioids, specifically morphine. The mechanism of action is unclear and it is interesting that opioids can alleviate dyspnea in many patients without changing the respiratory rate or producing any measurable changes in blood gas parameters. Speculation as to the actual mechanism of action has centered around the probability that opioids decrease brainstem responsiveness to carbon dioxide and diminish reflex vasoconstriction caused by increased PCO2 levels, decreasing the perception of dyspnea. There is also the opioid induced effect of decreased anxiety which often accompanies dyspnea.
Morphine and other opioids are often administered in small doses orally, sublingually, or by injection (SC & IV) for dyspnea management. Nebulized inhaled opioids are also used for this purpose, but to a much lesser extent. The use of the inhaled route of administration is favored by some in the palliative care community because of the possibility of a more rapid onset than oral or sublingual routes and possibly less side-effects than systemically administered opioids.
There are no controlled trials to confirm the perception that nebulized opioids have any clear benefits over the other more conventional routes including oral, sublingual, subcutaneous, and intravenous. One extensive review of 18 randomized, double-blind, controlled trials of opioids for management of dyspnea in terminally ill patients concluded that there was adequate evidence to support the use of oral or IV opioids for dyspnea, but not the use of nebulized opioids. (1) An earlier published report evaluated blood levels after nebulized morphine and orally administered morphine which demonstrated rapid absorption by the inhaled route compared with oral morphine, but significantly more variability. (2)
Disadvantages of administering opioids via nebulizer would include to the following:
• Increased cost over other routes (nebulizer & preservative-free drug solutions)
• More complex method of administration
• Lack of portability (nebulizer)
If opioids are to be used via nebulizer, the “preservative-free”, sterile solutions for injection are preferred in order to avoid respiratory irritation. The drug solution is diluted in 2 to 3ml of “preservative-free” normal saline prior to administration. Doses used fall within these ranges:
Morphine 2.5 – 10mg
Hydromorphone 0.25 – 1mg
Fentanyl 25- 50mcg
The majority of hospice patients with dyspnea will benefit from non-inhaled opioids and tolerate them well. The nebulized opioid alternative may be appropriate for those few patients who may refuse oral or injectable opioids or those who have exhibited certain adverse effects to systemic therapy.
(1) Jennings, Davies, Higgins et al. Opioids for the palliation of breathlessness in terminal illness. Cochrane Database Syst Rev. 2001; 4CD002066
(2) Masood, Thomas. Systemic absorption of nebulized morphine compared with oral morphine in healthy subjects. Br J Clin Pharmcol. 1996; 41:250-2
Dr. Stephanie Cheng, PharmD, MPH
Striverdi Respimat was given FDA approval on July 31, 2014 and is indicated for use as a long-term, once-daily maintenance bronchodilator treatment of COPD, including chronic bronchitis and/or emphysema. The active ingredient, olodaterol, is a long-acting beta2-adrenergic agonist (LABA) bronchodilator that is formulated as a liquid spray for use via the latest type of inhalation device called a Respimat. The recommended dose is 2 inhalations once daily. Each actuation of the device delivers 2mcg of olodaterol.
Thus far, Striverdi Respimat has only been indicated for use in COPD and has not been studied in patients with asthma. As with all LABA, it is not for use for the relief of acute symptoms and is contraindicated in patients with asthma without use of a long-term asthma control medication. Striverdi Respimat should not be initiated in patients with acutely deteriorating COPD and should be used with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis or sensitivity to sympathomimetic drugs. A life-threatening paradoxical bronchospasm can occur and Striverdi Respimat should be discontinued immediately. The most common adverse reactions include: nasopharyngitis, upper respiratory tract infection, bronchitis, urinary tract infection, cough, dizziness, rash, diarrhea, back pain and arthralgia.
Safety and Efficacy
Compared to other LABA bronchodilators (formoterol, indacaterol, salmeterol, and arformoterol), olodaterol has demonstrated similar safety and efficacy.
Advantages of Striverdi Respimat
Striverdi Respimat is being promoted with two advantages over the current LABA on the market. The first advantage is Striverdi Respimat is dosed as once daily. All of the other LABA, aside from Arcapta Neohaler (indacaterol), are dosed BID.
The second promoted advantage of Striverdi Respimat is the drug delivery system. The Respimat Inhaler system is a multi-dose, propellant-free, hand-held liquid inhaler. The device delivers a pre-measured amount of medication in a slow-moving mist, which the patient inhales through a mouthpiece. This method of medication delivery allows more of the drug to enter the lungs instead of the esophagus compared to devices with a propellant, such as a Metered Dose Inhaler (MDI). Compared to the LABAs that come as a Dry-Powder Inhaler (DPI) (formoterol, indacaterol and salmeterol), a patient requires less force to inhale the medication. There have also been studies done which show that patients preferred the Respimat device over the other types of inhaled drug delivery devices, particularly if the patient has vision problems or arthritis.
These advantages are hoped to improve patient compliance with the medication.
Disadvantages of Striverdi Respimat
One of the main disadvantages of Striverdi Respimat is that in patients with COPD, positive inhalation pressure becomes a problem as the disease progresses. Most patients with severe or end-stage COPD are unable to inhale deep enough for inhalers to be effective and are generally switched to the nebulized form of LABAs (Brovana or Perforomist).
Another disadvantage of Striverdi Respimat is that it requires more training and education for a patient to use it correctly. One clinical trial comparing a patient’s proper technique in using the Respimat or a MDI for the first time demonstrated that the proportion of patients demonstrating good technique was higher for the MDI (80%) versus the Respimat (48%). By the final attempt, 98% of patients demonstrated satisfactory inhaler technique with the MDI compared to 96.4% with the Respimat.
Cost is a third disadvantage of Striverdi Respimat. Similar to other long-acting beta agonist bronchodilators currently available (Arcapta, Foradil, Serevent), Striverdi Respimat is also relatively expensive. Cost for these products may range between $6 - $8 per day based upon average wholesale price (AWP).
Place in Hospice Therapy
Although Striverdi Respimat provides another option for patients with COPD that could help with improving patient compliance with the medication, it is largely cost prohibitive in the hospice setting. Additionally, because of the training required for proper inhaler technique and the inability of most severe or end-stage COPD patients to have enough positive inhalation, this dosage form may not be as efficacious compared to other dosage forms.
1. [Package Insert] Striverdi Respimat (olodaterol) Inhalation Spray. Boehringer Ingelheim Pharmaceuticals, Inc. Aug 2014.
2. Anderson P. Use of Respimat Soft Mist Inhaler in COPD patients. Int J Chron Obstruct Pulmon Dis. Sept 2006;1(3):251-259.
3. Feldman GJ, Bernstein JA, Hamilton A, et.al. The 24-h FEV1 time profile of olodaterol once daily via Respimat and fomoterol twice daily via Aerolizer in patients with GOLD 2-4 COPD: results from two 6-week crossover studies. Springerplus. 2014 Aug 9;3:419.
4. Koch A, Pizzichini E, Hamilton A, et.al. Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulmon Dis. 2014 Jul 5;9:697-714.
Dr. Jim Joyner, PharmD, CGP
The results of a clinical trial of ABH topical gel vs placebo for the management of nausea in cancer patients were recently published in the Journal of Pain and Symptom Management.(1) ABH topical gel is a pharmacy-compounded product consisting of Lorazepam (Ativan), Diphenhydramine (Benadryl), and Haloperidol (Haldol) usually prepared in a pluronic lecithin organogel (PLO) base. It has been used frequently in some palliative care settings for management of nausea and vomiting, despite very limited scientific data to support continued use. The product has gained a following due to the ease of use (topical administration) and perceived efficacy.
This recent study was a well designed, randomized, double-blind, placebo controlled, crossover clinical trial to compare the effectiveness of ABH topical gel against a placebo gel. The trial was completed with 20 patients who had an active cancer diagnosis. Nausea in these patients was related to the following: pain, pain medication, bone marrow transplant, or related to their cancer. Results of this trial showed no difference in efficacy between ABH topical gel or the placebo gel for treating nausea or vomiting. The researchers concluded that ABH topical gel should not be used in cancer patients experiencing nausea.
The results of this trial are consistent with earlier research on healthy volunteers who received topical ABH gel and had serial blood samples drawn at various intervals up to 4 hours after application.(2) Blood levels of each of the 3 drugs were evaluated. That small study on 10 volunteers, published in 2012, demonstrated that none of the three medications in the ABH gel formulation were absorbed to any significant degree. The researchers concluded that topical application of this product was ineffective.
The data is conclusive that ABH topical gel is not an efficacious product and cannot be recommended.
(Also see our previous 2011 blog article on ABH Gel.)
1. Fletcher, Coyne, Dodson, et al. A Randomized Trial of the Effectiveness of Topical ABH Gel vs Placebo in Cancer Patients with Nausea. Journal of Pain and Symptom Management. Vol 48;5.
2. Smith, Ritter, Poklis, et al. ABH Gel is not Absorbed From the Skin of Normal Volunteers.
Journal of Pain and Symptom Management. Vol 43;5 May 2012
Jennifer Chen, PharmD
A new formulation of Spiriva will be available on the market in January 2015. Both Spiriva Handihaler and Spiriva Respimat contain the same active ingredients – tiotropium. Tiotropium is an anticholinergic bronchodilator indicated for the long-term, once-daily, maintenance treatment for COPD. This new formulation turning the inhalation powder of tiotropium into inhalation spray is called Spiriva Respimat. The dry-powder inhalation, Spiriva HandiHaler, will continue to be available on the market. Spiriva Respimat provides a pre-measured amount of medicine in a slow-moving mist that helps patients inhale the medicine and is intended to deliver medication in a way that does not depend upon how fast the dry powder is breathed in from the inhaler. This new formulation may reduce the errors involving the inadvertent oral administration of Spiriva HandiHaler capsules for inhalation.
The results from clinical trial (TIOSPIR) shows Spiriva Respimat had a safety profile and exacerbation efficacy similar to Spiriva HandiHaler device(1). The most common side effects reported include sore throat, cough, dry mouth and sinus infection. One study assessed the effect of switching from HandiHaler to Respimat in patients with COPD shows similar effects and usability but patients experienced cough for the first 4 weeks of switching before they got used to the new formulation. The other finding was that dry mouth appeared to improve after switching to Respimat. However, this study was done on a small group of COPD patients (about 30 patients) and these patients were followed for 12 weeks after switching(2).
With similar costs and efficacy, the use of Spiriva Respimat may be limited in the hospice setting due to its requirement of active inhalation for effectiveness of drug delivery and training of inhaler technique as most end-stage COPD patients do not have effective positive force to inhale medication contents from the inhalers.
1. Wise RA, Anzueto A, Cotton D, et al. Tiotropium Respimat Inhaler and the Risk of Death in COPD. N Engl J Med 2013;369:1491-501.
2. Asakura Y, Nishimura N, Maezawa K, et al. Effect of switching tiotropium HandiHaler to Respimat Soft Mist Inhaler in patients with COPD: the difference of adverse events and usability between inhaler devices. J Aerosol Med Pulm Drug Deliv 2013 Feb;26(1):41-5.
Jim Joyner, PharmD, CGP
Hysingla ER, extended-release hydrocodone, has recently been approved by the FDA on November 20, 2014. This is the second single-entity, extended release hydrocodone medication to be approved in a little over 1 year. Last fall, Zohydro ER was approved and detailed on the Outcome Resources blog in March of 2014. Both of these products are intended for routine management of chronic severe pain.
Hydrocodone analgesics were previously only available in combination with acetaminophen (as Lortab, Norco, or Vicodin) or in combination with ibuprofen (Vicoprofen). These new products represent a significant increase in hydrocodone unit strengths. The older combination products contained hydrocodone in strengths of 5 or 10mg, while the two new extended release products are available in single tablet or capsule strengths as high as 50mg (Zohydro ER capsule) or 120mg (Hysingla ER tablet). The availability of hydrocodone in these new strengths, which are 5 to 10 times greater than the old combination products, have many clinicians very concerned about the potential for serious dosing errors, mis-use, or abuse of these new high-potency opioid products. Both of these products are being touted by the manufacturers as being free from the risk of acetaminophen induced liver toxicity that may occur with high doses of the older combination products. While this is true, the greater risk may actually be associated with the much higher strengths of hydrocodone available in these new products.
Hysingla ER has been formulated to reduce the potential for abuse when the drug is chewed and then taken orally, or crushed and snorted, or injected. The tablet is difficult to crush, break or dissolve. It also forms a viscous hydrogel (thick gel) and cannot be easily prepared for injection. The FDA has determined that the physical and chemical properties of Hysingla ER are expected to make abuse by these routes difficult. However, abuse of Hysingla ER by these routes is still possible. Zohydro ER is not currently available in an abuse deterrent dosage-form, however, the manufacturer has applied to the FDA for approval of a new version of the product that would have similar deterrents built into it. FDA approved Zohydro ER last year amid significant criticism related to the product’s lack of abuse deterrent attributes. If approved, the new abuse deterrent version of Zohydro ER would be available in the spring of 2015.
Hysingla ER is designed to release drug over a 24 hour period. It should be taken just once a day (every 24 hours) on a routine schedule. It is not appropriate for “prn” usage for breakthrough pain. Several strengths will be available: 20, 30, 40, 60, 80, 100 and 120mg. Tablets must be swallowed whole.
Zyhydro ER is designed to release drug over a 12 hour period. It should be taken every 12 hours on a routine schedule. Like Hysingla ER, it is not appropriate for “prn” use either. Zohydro ER is available in the following strengths: 10, 15, 20, 30, 40, and 50mg. Capsules must be swallowed whole. Alcohol must be avoided in patients taking Zohydro. Consumption of alcoholic beverages or the use prescription or non-prescription products that contain alcohol while taking Zohydro ER may result in increased plasma levels and a potentially fatal overdose of hydrocodone.
The role of these new long-acting hydrocodone products in hospice patients will be very limited due to factors such as high cost and the availability of other long-acting opioids with established track records of efficacy in severe chronic pain (Methadone tablets and solution, Morphine Extended Release dosage-forms, etc.)
Jim Joyner, PharmD, CGP
Yesterday, (11/24/2014), Aurobindo Pharma issued a voluntary recall of their Gabapentin 300mg capsules due to some of the capsules being empty. Other strengths are not affected. Only product from this manufacturer is affected. This recall is extended to the patient level. Empty capsules could result in missed dose(s) of gabapentin resulting in adverse health consequences that could range from no effect, short term reduction in efficacy, short term withdrawal effect, or status epilepticus that could be life-threatening. Aurobindo Pharma has not received any reports of adverse events related to this recall as of yesterday, but has received four complaints for empty capsules.
The affected Gabapentin lot is GESB14011-A, Expiration 12/2015 and is packaged in 100-count bottles, NDC 16714-662-01. The product can be identified by the imprint D on yellow cap and 03 on yellow body with black edible ink. Product was distributed through Northstar label to retail outlets nationwide.
Outcome Resources is including this information on our blog for the hospice clinicians since Gabapentin is widely used in hospice for a variety of indications and this news may impact your patients. It is advisable to check with your patients who have current orders for Gabapentin and evaluate if they are affected by this recall. If you suspect that one of your patients has the affected product, call the pharmacy which dispensed the prescription and have the prescription label in hand to provide necessary information to the pharmacist. In the event you encounter the recalled product, return it to the pharmacy that dispensed it for a replacement.
Sora Yoon, Pharm.D. Candidate 2015, Western University of Health Sciences
FDA has recently approved a new medication for opioid-induced constipation: Movantik (naloxegol), an opioid antagonist manufactured by AstraZeneca. Used in adults with long-lasting chronic pain that is not caused by cancer. Movantik is dosed once daily on empty stomach 1 hour before first meal of day in the morning or 2 hours after meal. It should not be taken concomitantly with other laxatives.
According to AstraZeneca website, Movantik 25mg was studied in 446 patients lasting 12 weeks. Results showed 44% of patients had ≥3 spontaneous bowel movements (SBMs) per week and a change from baseline of ≥1 SBM per week for at least 9 out of 12 weeks as well as 3 out the last 4 weeks. 61-70% of patients had a SBM within the first 24 hours of first dose. Safety and efficacy were studied in 1146 patients for six to twelve months supporting the safety and tolerability profile of Movantik.
Movantik does carry two specific warnings: gastrointestinal perforation and opioid withdrawal. Gastrointestinal perforation has been reported with use of another peripherally acting opioid antagonist in patients who may have localized or diffused reduction of structural integrity in the wall of their gastrointestinal tract. Hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning are consistent with opioid withdrawal symptoms. Combination of three or more of these symptoms are defined as possible opioid withdrawal, but must occur within the same day and not related to gastrointestinal system. Patients who receive methadone for pain control have experienced higher frequency of gastrointestinal adverse reactions related to opioid withdrawal than any other opioids. Also, patients who may have disruptions in the blood-brain barrier (BBB) may be at increased risk for opioid withdrawal or reduced analgesia. The most common adverse reactions reported in ≥3% of patients are abdominal pain, diarrhea, nausea, flatulence, vomiting, and headache. Movantik will be distributed with a medication guide that instructs on its use and information on potential risks.
Currently, on the market is Relistor (methylnaltrexone) with same indication for use and limited ability to cross the BBB. It mainly blocks the µ-opioid receptors in the gastrointestinal tract that causes opioid-induced bowel dysfunction and does not interfere with analgesic effects. It is administered subcutaneously, making it an invasive medication, which may not be appropriate for patients at end-of-life.
Movantik is a schedule II controlled substance due to its structural similarity to noroxymorphone; however, AstraZeneca has filed a petition to US DEA for descheduling, as it has no risk of abuse or dependency. Proposed planned launch of Movantik will be the first half of 2015.
Opioids are the most commonly prescribed class of drugs in the U.S., accounting for over 240 million prescriptions a year. They are increasingly being used to treat chronic pain, both cancer and non-malignant conditions. At end-of-life, long-term pain management with opioids is highly required for palliative care, with that comes opioid-induced constipation. Therefore, it is important to start patients on laxatives when starting opioids. In hospice care, Movantik would be last line of use, due to its cost and specific warnings. With many patients having a decline in debility, this drug may not be warranted for use as it can cross the BBB, which can then affect patients’ ability to take medications by mouth and lead to further complications. Once a patient has exhausted other options, can this medication be considered given the patient’s current state at that time.
1. Movantik [package insert]. Wilmington, DE: AstraZeneca; 2014. http://www.azpicentral.com/movantik/movantik.pdf#page=1
2. Tack, J. and Corsetti, M. “Naloxegol for the treatment of opioid-induced constipation.” Expert Review of Gastroenterology & Hepatology. 2014:1-7.
Outcome Resources' second Annual Pathways to Success Conference by the Bay was held last week, November 12th-13th, at the Claremont Hotel Club and Spa in Berkeley, California. Hospice and palliative care professionals from around the nation gathered to hear real-world success stories from top leaders and implement their strategies for success. Topics included medication management of dementia, providing pediatric concurrent care, cost reduction strategies, strategic management and compliance, discussions about grief and hospice advocacy and policy in the year ahead. In addition to her session “Helping People Find Hope after Loss,” top grief expert Dr. Gloria Horsley filmed interviews of participants for the Open to Hope YouTube Channel, NHPCO’s VP of Public Policy Jon Keyserling shared major policy changes faced by hospices and the overall policy environment, and a panel of industry leaders reviewed difficult hospice patient case studies in a session with interactive audience participation. This year’s Dr. MJ McDonough Award for Distinguished Service in Hospice was presented to Kitty Whitaker, CEO of Hospice by the Bay. In addition to valuable education, participants were also treated to a fun San Francisco Bay Dinner Cruise, complete with beautiful views of the city skyline, Alcatraz, and the Bay and Golden Gate Bridges. Outcome Resources would like to thank all the hospice nurses, clinicians, medical directors, administrators, CEO’s, and speakers that helped to make this year’s Pathways to Success a success. And a special thank you also to our sponsors who help make our conference possible: Complete Delivery Solution, Sharp HospiceCare, Accreditation Commission for Health Care, CVS Health, Mumms Software, Elsevier, Neptune Society of Northern California, Horizon Oxygen and Medical Equipment, and Coalition for Compassionate Care. We hope you will join us at a future Outcome Resources event!
Jim Joyner, PharmD, CGP
The Drug Enforcement Agency (DEA) recently released new regulations governing the disposal of controlled drugs by the ultimate user (patient to whom the medication was prescribed). The new regulation does not prohibit the patient or family member (member of the same household) from disposing of medications in their home. It expands the options for this disposal to include and encourage the use of authorized collectors which will include pharmacies, hospitals, clinics with pharmacies, certain manufacturers, distributors, and law enforcement agencies. All of the aforementioned collection options are voluntary and the regulation does not require the patient to utilize any of these methods for disposal of controlled substances. This regulation does not prohibit the patient (or family member within the household) from using current existing lawful methods for drug disposal. Any method of drug disposal that was valid prior to the new regulation continues to be valid. In the event that the patient has died, any person lawfully entitled to dispose of the decedent’s property may dispose of the controlled substances. The hospice should encourage their clients to use authorized collectors for this disposal to help protect the environment and reduce the risk of drug diversion, but it is not mandatory.
We have included some downloadable files with more details:
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