in Practice
Lessons Learned from Hospice Care Pharmaceutical care of the hospice patient offers unique challenges in the management of pain and other symptoms. Lessons learned in providing hospice care can be used in the care of nonterminal patients as well to optimize patient-specific care, regardless of care setting or life expectancy. KEY WORDS: Elderly, Fentanyl, Hospice, Medication, Nausea, Pain, Pharmacy, Pruritus, Vomiting. Abbreviations: CTZ = Chemoreceptor trigger zone, t1/2 = Plasma half-life, TCA = Tricyclic antidepressant, TDF = Transdermal fentanyl, tmax = Time to maximum concentration.
Caren McHenry Martin
A
s a consultant pharmacist in the long-term care setting for 15 years, I was confident in my knowledge of geriatric pharmacotherapy. I was comfortable performing medication reviews in nursing and assisted living facilities where I felt that the patients were fairly homogeneous and where medication choice was often driven as much by the nursing facility regulatory environment as it was by clinical expertise. This comfortable feeling changed dramatically when I began working in a hospice setting a couple of years ago. In hospice, there are two simple goals: Make the patient as comfortable as possible and maximize the quality of the patient’s remaining life. I quickly
learned that this type of pharmaceutical care requires an all-encompassing understanding of a patient’s complaints, diseases, and symptoms to determine a medication recommendation that is truly patient-specific. I learned a lot about pain management, and I now realize how much I’d neglected it when I had performed my long-term care reviews. I have come to realize that geriatric patients in the long-term care facility—whom I’d been treating as if they were a homogeneous group—are not as homogeneous as I had once thought. Listed below are some of the important lessons I’ve learned about treating pain and other symptoms in patients receiving hospice care that could—and should—be applied to the long-term care setting as well.
The Consultant Pharmacist october 2013 Vol. 28, No. 10
605
Lessons Learned from Hospice Care
Lesson #1: There’s a lot to know about dosing, converting, and monitoring transdermal fentanyl. The transdermal fentanyl (TDF) system is a unique opioid-delivery system designed to provide up to 72 hours of medication release via a transdermal patch applied to the patient’s upper torso. The ease of administration of this product can lead to an incorrect assumption among long-term care prescribers, nurses, and caregivers that the dosing and use of TDF is simple. In reality, there is much that must be considered when dosing, converting, and monitoring this therapy. • Fentanyl is about 75-100 times more potent than morphine on a mg-to-mg basis.1 • Fentanyl use in opioid-naïve patients can result in fatal respiratory depression. It is only indicated in opioidtolerant patients, defined as patients taking daily, for a week or longer, at least 60 mg of oral morphine, 30 mg of oral oxycodone, or at least 8 mg of oral hydromorphone or an equianalgesic dose of another opioid. This means fentanyl should never be used as an initial opioid for any patient. (The package labeling states that the use of TDF as an initial opioid has not been systematically evaluated, including the 12 mcg/h patch.1) Pharmacists must be particularly attuned to the patient’s current opioid use before recommending or dispensing TDF. • TDF has a delayed-onset of action. It takes about 12 hours to obtain minimally effective blood concentrations of fentanyl after a patch is applied; time to maximum fentanyl concentration after patch application is approximately 36 hours. Patients may need to continue their current pain medications during the first 12 hours after the TDF is placed and have adequate as-needed medications to control pain during the first 36 hours after the TDF is placed.1,2 Pharmacists should counsel patients and caregivers about this unique delivery system to ensure realistic and consistent pain management expectations. • It may take three to six days to reach steady-state concentrations with TDF. This means that the initial dose of TDF can be titrated after three days, but it may take six days after increasing the dose to reach equilibrium
606
on the new dose. Titrating TDF sooner than six days (usually the duration of two patches) may result in overdosing.1 Pharmacists and other clinicians should be on the lookout for TDF dosing changes that are too rapid or too frequent.
Fentanyl should never be used as an initial opioid for any patient; its use in opioid-naïve patients can result in fatal respiratory depression. • After a patch is removed from the body, serum levels fall gradually. About half of the drug has been eliminated after 17 hours, and it can take almost 72 hours before fentanyl is completely eliminated. This needs to be taken into consideration when changing from TDF to a different opioid. Pharmacists can counsel prescribers, patients, and caregivers to consider waiting 12 hours before starting the new opioid on a scheduled basis and providing adequate as-needed medication for use during this time. One method of converting is to begin the new opioid regimen at 50% of the calculated dose (while continuing to provide adequate as-needed medication), beginning 12 hours after TDF is removed and increasing to 100% of the calculated scheduled dose 24 hours after the patch is removed.1,2 • Concomitant use of TDF with a cytochrome P4503A4 inhibitor (ketoconazole, amiodarone, erythromycin, diltiazem, grapefruit juice, etc.) can result in increased plasma concentrations.1 • Approximately 20% of patients receiving TDF may require a shorter application interval of 48 hours because of interpatient variability in skin integrity, clearance, volume of distribution, and interactions with other medications.1-3 • Elevated body temperature (104°) from illness, electric blankets, heating pads, etc. can increase TDF absorption by one-third.1 Patients and caregivers should be counseled to avoid applying heat to the patch area. • The dose-conversion guidelines provided in the TDF package insert are conservative and unidirectional. As stated in the product packaging, the dosing table
The Consultant Pharmacist october 2013 Vol. 28, No. 10
Lessons Learned from Hospice Care
should only be used to convert from other therapies to TDF and not for converting from TDF to other therapies, as it may result in overdosing.1 Some experts recommend using a 2:1 conversion ratio, whereby 2 mg/morphine per day converts to 1 mcg of TDF per hour, and vice versa.2 • TDF patches still contain a significant amount of medication even after being worn by the patient for several days. On April 18, 2012, the Food and Drug Administration (FDA) alerted health care providers and consumers about the importance of proper storage, application, and disposal of TDF to prevent dangerous, accidental exposure (www.fda.gov/Drugs/DrugSafety/ ucm300747.htm). FDA recommends disposing of used patches immediately after taking them off the skin by folding the patch in half so that the sticky sides meet, and then flushing it down the toilet. Used or unneeded TDF patches should not be placed in the trash, but some facilities do allow them to be placed in the “sharps” container along with used syringes, since items placed in these receptacles become inaccessible once placed in the container.
Lesson #2: Patient-specific treatment of nausea and vomiting can yield better results. Standing orders (predetermined order sets used for routine symptom management within a nursing facility) for the treatment of nausea and vomiting are commonplace, and they generally consist of one or two medication choices. Nausea can come from multiple sources, however, such as delayed gastric emptying, stimulation of the chemoreceptor trigger zone (CTZ) in the brain, or from stimulation of the brain’s “vomiting center” or the vestibular apparatus in the inner ear. Using a “one-size fits all” approach to antiemetic medication makes less sense once a clinician understands more about the sources of nausea, and targeting medication selection to the specific source of nausea can often provide better results. • Patient complaints of postprandial nausea and vomiting, or a feeling of being “full,” bloated, or constipated may point toward nausea caused by delayed gastric emptying. Metoclopramide, a prokinetic agent that also
inhibits peripheral dopamine and serotonin receptors, can be a good initial treatment. As noted in the “2012 American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults,” this medication can cause tardive dyskinesia in the elderly patient, so should be used at the lowest effective dose for the smallest amount of time necessary to control symptoms, and monitoring for movement disorders should be performed routinely.4 • Nonspecific complaints of nausea and vomiting in patients receiving opioids may be the result of opioid stimulation of the CTZ, and treatment then focuses on inhibiting dopamine and/or serotonin receptors in the CTZ. Dopamine receptor-antagonists such as prochlorperazine or haloperidol can be highly effective for opioid-induced nausea. Haloperidol is available as a 2 mg/mL oral solution that can be administered buccally (and then passively swallowed), and may be a useful alternative for patients whose nausea makes it difficult for them to swallow pills. Serotonin receptor-antagonists such as ondansetron can also help with opioid-induced vomiting. However, because serotonin antagonists work primarily within the gastrointestinal (GI) tract (their central effects are secondary), these agents are generally more useful for preventing nausea related to chemotherapy, radiation, or postoperative sickness, rather than for treating opioid-induced nausea.5 • For patients whose nausea and vomiting seem to be related to movement or vertigo, antihistamines such as promethazine (which are active at the vomiting center and vestibular apparatus) are usually the preferred treatment. Keep in mind that these agents are usually less effective for opioid-induced nausea or from nausea caused by decreased GI motility. • Anticholinergic medications such as scopolamine can also be effective for movement-associated nausea and work by inhibiting acetylcholine within the vomiting center. The scopolamine patch has a delayed onset of action of four hours (with peak concentrations at 24 hours), and, thus, may be inappropriate for asneeded use.6
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Lessons Learned from Hospice Care
• Patients with intractable nausea and vomiting may need a combination of agents for effective symptom management.
Lesson #3: There are better options than amitriptyline. The tricyclic antidepressant (TCA) amitriptyline can be used off-label for the treatment of neuropathic pain, but this tertiary amine is more likely to cause sedation, anticholinergic side effects, and orthostatic hypotension than a secondary amine such as nortriptyline or desipramine. Tertiary TCAs are specifically mentioned in the 2012 Beers criteria as medications to avoid in the elderly.4 When choosing a TCA, consider nortriptyline or desipramine to minimize the potential for side effects. Lesson #4: There are numerous options for itching. Pruritus (itching) can be caused by numerous diseases and conditions. Antihistamines such as diphenhydramine or hydroxyzine are often tried first-line, but have little effect on conditions other than chronic urticaria, and can have problematic anticholinergic side effects in the elderly patient. Antidepressants such as mirtazapine, fluvoxamine, and paroxetine can relieve itching in patients with cancers, chronic kidney disease, cholestasis, and liver disease, and they can be particularly beneficial in nocturnal pruritus. Neuroleptics such as gabapentin and pregabalin can also be useful for pruritus from chronic kidney disease and from postherpetic neuralgia or other neuropathic causes of itching.7 Lesson #5: Use pharmacokinetics for dosing and titrating pain medications. Pain is prevalent in both hospice and long-term care patients, and pharmacists can play an important role in dosing, titrating, and monitoring pain medications, and selecting an agent based on the patient’s comorbidities. Morphine, codeine, hydrocodone, and hydromorphone may not be drugs of choice for a patient with significant renal impairment, for example, as the morphine-6 glucuronide and the 3-glucuronide metabolites of hydromorphone and hydrocodone (which are renally excreted) can build to toxic levels and cause myoclonus and other
610
side effects. The normeperidine metabolite of meperidine can cause central nervous system excitation and seizures, and should generally be avoided, as well. The elimination half-life of oxycodone is lengthened in patients with renal dysfunction, so dose adjustments may be necessary. Fentanyl and methadone are generally considered to be safe in patients with renal insufficiency.2 Since the liver is the major site of drug metabolism, impaired liver function may result in increased accumulation of the parent drug in the body with repeated administration. In general, patients with severe liver disease require lower doses of opioids with extended dosing intervals. Methadone undergoes hepatic metabolism and is generally not advised for patients with severe liver dysfunction because of the risk of accumulation.
Patients may need to continue their current pain medications during the first 12 hours after a transdermal fentanyl patch is placed. Dosing and titration of opioids is also not “one size fits all.” Proper dosing and subsequent dose escalation relies on an understanding of the medication’s pharmacokinetics (Table 1). This information allows the clinician to adjust medication dosing based on the medications’ plasma halflife (t1/2) and time to maximum concentration (tmax)in the body as follows: • Assess the patient’s pain at the drug’s tmax, which represents the time when the medication is at its maximum level. If pain is not adequately controlled, dose can be titrated at an interval equal to the drug’s t1/2. This means short-acting oral single-agent opioids that have a half-life of two hours can be safely dose-escalated every two hours, while sustained-release oral opioids can be escalated every 24 hours.2 • If a patient is having an acute pain crisis, it may be reasonable (in a closely monitored setting) to provide a more rapid dose titration, whereby the opioid dose is titrated at an interval equal to its tmax (rather than its t1/2), until the pain is under control.2
The Consultant Pharmacist october 2013 Vol. 28, No. 10
Table 1. Pharmacokinetics of Select Opioids
Opioid
Onset (minutes)
Peak Effect (tmax) (minutes)
Duration (hour)
Plasma Half-life (t 1/2) (hours)
Morphine immediaterelease oral tablet/liquid
30-60
120
4-6
2-4
Morphine sustained-release 30-90 oral formulations (MS Contin, Kadian, Oramorph)
210
8-12
12-24
10-30 (IM);
60 (IM, SQ);
4-5 (IM);
1.5-4.5
5 (IV)
20 (IV)
2-4 (IV)
Oxycodone immediaterelease
10-15
30-60
3-6
2-3
Oxycodone controlledrelease*
30-60
60-80
12
4.5
Methadone oral tablet/solution
30-60
60-480
4-8
8-59
Hydromorphone immediate-release tablet/solution
30
30-60
4
2-3
Hydromorphone injectable
15 (IM);
30-60 (IM);
4-5 (IM);
2-3
10-15 (IV)
15-30 (IV)
2-3 (IV)
Morphine injectable
*This medication has an immediate-release component combined with a sustained-release component. Source: References 8-10. Abbreviations: IM = Intramuscular, IV = Intravenous, SQ = Subcutaneous, t1/2 = Plasma half-life, tmax = Maximum drug concentration.
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Lessons Learned from Hospice Care
• Dose increases need to be at least 25% above baseline for the patient to notice a change in analgesia. Dose increases of 25% to 50% can be used for mild-tomoderate pain and increases of 50% to 100% for moderate-to-severe pain.2 • Short-acting medications for breakthrough pain should be dosed at 10% to 15% of total daily opioid dose equivalent. For example, in a patient receiving extended-release morphine 60 mg twice daily (total daily dose 120 mg), an as-needed dose of morphine 15 mg (approximately 13% of the total daily dose of 120 mg) every four hours is reasonable.2 Pharmacists should be on the lookout for as-needed medication dosing that may be either subtherapeutic or excessive, based on the total daily dose of the scheduled opioid. • During dose titration, as with opioid use in general, patients should be monitored for signs of opioid toxicity, which can include decreased respiratory rate, excessive sedation, and pinpoint pupils.
Dose increases need to be at least 25% above baseline for the patient to notice a change in analgesia.
Conclusion A patient-specific approach to medication management provides benefit to elderly patients, regardless of their care setting or life expectancy. Armed with a thorough understanding of pain management principles and symptom-management strategies, pharmacists can ensure all of their patients receive the highest quality of pharmaceutical care. n
612
Caren McHenry Martin, PharmD, CGP, is a consultant pharmacist in Greensboro, North Carolina, and a contributor to The Consultant Pharmacist. Disclosure: No funding was received for the development of this manuscript. The author has no potential conflicts of interest. Consult Pharm 2013;28:605-12. © 2013 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2013.605.
References 1. Duragesic fentanyl transdermal system [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2012. 2. McPherson ML. Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing. Bethesda, MD: American Society of HealthSystem Pharmacists Inc.; 2010. 3. Donner B, Zenz M, Strumpf M et al. Long-term treatment of cancer pain with transdermal fentanyl. J Pain Sympt Manage 1998;15:168-75. 4. The American Geriatrics Society 2012 Beers Criteria Update Expert Panel (2012). American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc 2012;60:616-31. 5. Wood GJ, Shega JW, Lynch B et al. Management of intractable nausea and vomiting in patients at the end of life. JAMA 2007;298:1196-207. 6. Transderm Scōp (transdermal scopolamine) [package insert]. Mountain View, CA: ALZA Corporation; 2006. 7. Patel T, Yosipovitch G. The management of chronic pruritus in the elderly. Skin Therapy Letter.com. Available at http://www. skintherapyletter.com/2010/15.8/2.html. Accessed April 10, 2013. 8. Lexi-Comp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc. Accessed May 13, 2013. 9. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc.; March 2005. Accessed May 13, 2013. 10. DRUGDEX System [Internet database]. Greenwood Village, CO: Thomson Healthcare; updated periodically. Accessed May 13, 2013.
The Consultant Pharmacist october 2013 Vol. 28, No. 10
Lessons Learned from Hospice Care Pharmaceutical care of the hospice patient offers unique challenges in the management of pain and other symptoms. Lessons learned in providing hospice care can be used in the care of nonterminal patients as well to optimize patient-specific care, regardless of care setting or life expectancy. KEY WORDS: Elderly, Fentanyl, Hospice, Medication, Nausea, Pain, Pharmacy, Pruritus, Vomiting. Abbreviations: CTZ = Chemoreceptor trigger zone, t1/2 = Plasma half-life, TCA = Tricyclic antidepressant, TDF = Transdermal fentanyl, tmax = Time to maximum concentration.
Caren McHenry Martin
A
s a consultant pharmacist in the long-term care setting for 15 years, I was confident in my knowledge of geriatric pharmacotherapy. I was comfortable performing medication reviews in nursing and assisted living facilities where I felt that the patients were fairly homogeneous and where medication choice was often driven as much by the nursing facility regulatory environment as it was by clinical expertise. This comfortable feeling changed dramatically when I began working in a hospice setting a couple of years ago. In hospice, there are two simple goals: Make the patient as comfortable as possible and maximize the quality of the patient’s remaining life. I quickly
learned that this type of pharmaceutical care requires an all-encompassing understanding of a patient’s complaints, diseases, and symptoms to determine a medication recommendation that is truly patient-specific. I learned a lot about pain management, and I now realize how much I’d neglected it when I had performed my long-term care reviews. I have come to realize that geriatric patients in the long-term care facility—whom I’d been treating as if they were a homogeneous group—are not as homogeneous as I had once thought. Listed below are some of the important lessons I’ve learned about treating pain and other symptoms in patients receiving hospice care that could—and should—be applied to the long-term care setting as well.
The Consultant Pharmacist october 2013 Vol. 28, No. 10
605
Lessons Learned from Hospice Care
Lesson #1: There’s a lot to know about dosing, converting, and monitoring transdermal fentanyl. The transdermal fentanyl (TDF) system is a unique opioid-delivery system designed to provide up to 72 hours of medication release via a transdermal patch applied to the patient’s upper torso. The ease of administration of this product can lead to an incorrect assumption among long-term care prescribers, nurses, and caregivers that the dosing and use of TDF is simple. In reality, there is much that must be considered when dosing, converting, and monitoring this therapy. • Fentanyl is about 75-100 times more potent than morphine on a mg-to-mg basis.1 • Fentanyl use in opioid-naïve patients can result in fatal respiratory depression. It is only indicated in opioidtolerant patients, defined as patients taking daily, for a week or longer, at least 60 mg of oral morphine, 30 mg of oral oxycodone, or at least 8 mg of oral hydromorphone or an equianalgesic dose of another opioid. This means fentanyl should never be used as an initial opioid for any patient. (The package labeling states that the use of TDF as an initial opioid has not been systematically evaluated, including the 12 mcg/h patch.1) Pharmacists must be particularly attuned to the patient’s current opioid use before recommending or dispensing TDF. • TDF has a delayed-onset of action. It takes about 12 hours to obtain minimally effective blood concentrations of fentanyl after a patch is applied; time to maximum fentanyl concentration after patch application is approximately 36 hours. Patients may need to continue their current pain medications during the first 12 hours after the TDF is placed and have adequate as-needed medications to control pain during the first 36 hours after the TDF is placed.1,2 Pharmacists should counsel patients and caregivers about this unique delivery system to ensure realistic and consistent pain management expectations. • It may take three to six days to reach steady-state concentrations with TDF. This means that the initial dose of TDF can be titrated after three days, but it may take six days after increasing the dose to reach equilibrium
606
on the new dose. Titrating TDF sooner than six days (usually the duration of two patches) may result in overdosing.1 Pharmacists and other clinicians should be on the lookout for TDF dosing changes that are too rapid or too frequent.
Fentanyl should never be used as an initial opioid for any patient; its use in opioid-naïve patients can result in fatal respiratory depression. • After a patch is removed from the body, serum levels fall gradually. About half of the drug has been eliminated after 17 hours, and it can take almost 72 hours before fentanyl is completely eliminated. This needs to be taken into consideration when changing from TDF to a different opioid. Pharmacists can counsel prescribers, patients, and caregivers to consider waiting 12 hours before starting the new opioid on a scheduled basis and providing adequate as-needed medication for use during this time. One method of converting is to begin the new opioid regimen at 50% of the calculated dose (while continuing to provide adequate as-needed medication), beginning 12 hours after TDF is removed and increasing to 100% of the calculated scheduled dose 24 hours after the patch is removed.1,2 • Concomitant use of TDF with a cytochrome P4503A4 inhibitor (ketoconazole, amiodarone, erythromycin, diltiazem, grapefruit juice, etc.) can result in increased plasma concentrations.1 • Approximately 20% of patients receiving TDF may require a shorter application interval of 48 hours because of interpatient variability in skin integrity, clearance, volume of distribution, and interactions with other medications.1-3 • Elevated body temperature (104°) from illness, electric blankets, heating pads, etc. can increase TDF absorption by one-third.1 Patients and caregivers should be counseled to avoid applying heat to the patch area. • The dose-conversion guidelines provided in the TDF package insert are conservative and unidirectional. As stated in the product packaging, the dosing table
The Consultant Pharmacist october 2013 Vol. 28, No. 10
Lessons Learned from Hospice Care
should only be used to convert from other therapies to TDF and not for converting from TDF to other therapies, as it may result in overdosing.1 Some experts recommend using a 2:1 conversion ratio, whereby 2 mg/morphine per day converts to 1 mcg of TDF per hour, and vice versa.2 • TDF patches still contain a significant amount of medication even after being worn by the patient for several days. On April 18, 2012, the Food and Drug Administration (FDA) alerted health care providers and consumers about the importance of proper storage, application, and disposal of TDF to prevent dangerous, accidental exposure (www.fda.gov/Drugs/DrugSafety/ ucm300747.htm). FDA recommends disposing of used patches immediately after taking them off the skin by folding the patch in half so that the sticky sides meet, and then flushing it down the toilet. Used or unneeded TDF patches should not be placed in the trash, but some facilities do allow them to be placed in the “sharps” container along with used syringes, since items placed in these receptacles become inaccessible once placed in the container.
Lesson #2: Patient-specific treatment of nausea and vomiting can yield better results. Standing orders (predetermined order sets used for routine symptom management within a nursing facility) for the treatment of nausea and vomiting are commonplace, and they generally consist of one or two medication choices. Nausea can come from multiple sources, however, such as delayed gastric emptying, stimulation of the chemoreceptor trigger zone (CTZ) in the brain, or from stimulation of the brain’s “vomiting center” or the vestibular apparatus in the inner ear. Using a “one-size fits all” approach to antiemetic medication makes less sense once a clinician understands more about the sources of nausea, and targeting medication selection to the specific source of nausea can often provide better results. • Patient complaints of postprandial nausea and vomiting, or a feeling of being “full,” bloated, or constipated may point toward nausea caused by delayed gastric emptying. Metoclopramide, a prokinetic agent that also
inhibits peripheral dopamine and serotonin receptors, can be a good initial treatment. As noted in the “2012 American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults,” this medication can cause tardive dyskinesia in the elderly patient, so should be used at the lowest effective dose for the smallest amount of time necessary to control symptoms, and monitoring for movement disorders should be performed routinely.4 • Nonspecific complaints of nausea and vomiting in patients receiving opioids may be the result of opioid stimulation of the CTZ, and treatment then focuses on inhibiting dopamine and/or serotonin receptors in the CTZ. Dopamine receptor-antagonists such as prochlorperazine or haloperidol can be highly effective for opioid-induced nausea. Haloperidol is available as a 2 mg/mL oral solution that can be administered buccally (and then passively swallowed), and may be a useful alternative for patients whose nausea makes it difficult for them to swallow pills. Serotonin receptor-antagonists such as ondansetron can also help with opioid-induced vomiting. However, because serotonin antagonists work primarily within the gastrointestinal (GI) tract (their central effects are secondary), these agents are generally more useful for preventing nausea related to chemotherapy, radiation, or postoperative sickness, rather than for treating opioid-induced nausea.5 • For patients whose nausea and vomiting seem to be related to movement or vertigo, antihistamines such as promethazine (which are active at the vomiting center and vestibular apparatus) are usually the preferred treatment. Keep in mind that these agents are usually less effective for opioid-induced nausea or from nausea caused by decreased GI motility. • Anticholinergic medications such as scopolamine can also be effective for movement-associated nausea and work by inhibiting acetylcholine within the vomiting center. The scopolamine patch has a delayed onset of action of four hours (with peak concentrations at 24 hours), and, thus, may be inappropriate for asneeded use.6
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Lessons Learned from Hospice Care
• Patients with intractable nausea and vomiting may need a combination of agents for effective symptom management.
Lesson #3: There are better options than amitriptyline. The tricyclic antidepressant (TCA) amitriptyline can be used off-label for the treatment of neuropathic pain, but this tertiary amine is more likely to cause sedation, anticholinergic side effects, and orthostatic hypotension than a secondary amine such as nortriptyline or desipramine. Tertiary TCAs are specifically mentioned in the 2012 Beers criteria as medications to avoid in the elderly.4 When choosing a TCA, consider nortriptyline or desipramine to minimize the potential for side effects. Lesson #4: There are numerous options for itching. Pruritus (itching) can be caused by numerous diseases and conditions. Antihistamines such as diphenhydramine or hydroxyzine are often tried first-line, but have little effect on conditions other than chronic urticaria, and can have problematic anticholinergic side effects in the elderly patient. Antidepressants such as mirtazapine, fluvoxamine, and paroxetine can relieve itching in patients with cancers, chronic kidney disease, cholestasis, and liver disease, and they can be particularly beneficial in nocturnal pruritus. Neuroleptics such as gabapentin and pregabalin can also be useful for pruritus from chronic kidney disease and from postherpetic neuralgia or other neuropathic causes of itching.7 Lesson #5: Use pharmacokinetics for dosing and titrating pain medications. Pain is prevalent in both hospice and long-term care patients, and pharmacists can play an important role in dosing, titrating, and monitoring pain medications, and selecting an agent based on the patient’s comorbidities. Morphine, codeine, hydrocodone, and hydromorphone may not be drugs of choice for a patient with significant renal impairment, for example, as the morphine-6 glucuronide and the 3-glucuronide metabolites of hydromorphone and hydrocodone (which are renally excreted) can build to toxic levels and cause myoclonus and other
610
side effects. The normeperidine metabolite of meperidine can cause central nervous system excitation and seizures, and should generally be avoided, as well. The elimination half-life of oxycodone is lengthened in patients with renal dysfunction, so dose adjustments may be necessary. Fentanyl and methadone are generally considered to be safe in patients with renal insufficiency.2 Since the liver is the major site of drug metabolism, impaired liver function may result in increased accumulation of the parent drug in the body with repeated administration. In general, patients with severe liver disease require lower doses of opioids with extended dosing intervals. Methadone undergoes hepatic metabolism and is generally not advised for patients with severe liver dysfunction because of the risk of accumulation.
Patients may need to continue their current pain medications during the first 12 hours after a transdermal fentanyl patch is placed. Dosing and titration of opioids is also not “one size fits all.” Proper dosing and subsequent dose escalation relies on an understanding of the medication’s pharmacokinetics (Table 1). This information allows the clinician to adjust medication dosing based on the medications’ plasma halflife (t1/2) and time to maximum concentration (tmax)in the body as follows: • Assess the patient’s pain at the drug’s tmax, which represents the time when the medication is at its maximum level. If pain is not adequately controlled, dose can be titrated at an interval equal to the drug’s t1/2. This means short-acting oral single-agent opioids that have a half-life of two hours can be safely dose-escalated every two hours, while sustained-release oral opioids can be escalated every 24 hours.2 • If a patient is having an acute pain crisis, it may be reasonable (in a closely monitored setting) to provide a more rapid dose titration, whereby the opioid dose is titrated at an interval equal to its tmax (rather than its t1/2), until the pain is under control.2
The Consultant Pharmacist october 2013 Vol. 28, No. 10
Table 1. Pharmacokinetics of Select Opioids
Opioid
Onset (minutes)
Peak Effect (tmax) (minutes)
Duration (hour)
Plasma Half-life (t 1/2) (hours)
Morphine immediaterelease oral tablet/liquid
30-60
120
4-6
2-4
Morphine sustained-release 30-90 oral formulations (MS Contin, Kadian, Oramorph)
210
8-12
12-24
10-30 (IM);
60 (IM, SQ);
4-5 (IM);
1.5-4.5
5 (IV)
20 (IV)
2-4 (IV)
Oxycodone immediaterelease
10-15
30-60
3-6
2-3
Oxycodone controlledrelease*
30-60
60-80
12
4.5
Methadone oral tablet/solution
30-60
60-480
4-8
8-59
Hydromorphone immediate-release tablet/solution
30
30-60
4
2-3
Hydromorphone injectable
15 (IM);
30-60 (IM);
4-5 (IM);
2-3
10-15 (IV)
15-30 (IV)
2-3 (IV)
Morphine injectable
*This medication has an immediate-release component combined with a sustained-release component. Source: References 8-10. Abbreviations: IM = Intramuscular, IV = Intravenous, SQ = Subcutaneous, t1/2 = Plasma half-life, tmax = Maximum drug concentration.
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Lessons Learned from Hospice Care
• Dose increases need to be at least 25% above baseline for the patient to notice a change in analgesia. Dose increases of 25% to 50% can be used for mild-tomoderate pain and increases of 50% to 100% for moderate-to-severe pain.2 • Short-acting medications for breakthrough pain should be dosed at 10% to 15% of total daily opioid dose equivalent. For example, in a patient receiving extended-release morphine 60 mg twice daily (total daily dose 120 mg), an as-needed dose of morphine 15 mg (approximately 13% of the total daily dose of 120 mg) every four hours is reasonable.2 Pharmacists should be on the lookout for as-needed medication dosing that may be either subtherapeutic or excessive, based on the total daily dose of the scheduled opioid. • During dose titration, as with opioid use in general, patients should be monitored for signs of opioid toxicity, which can include decreased respiratory rate, excessive sedation, and pinpoint pupils.
Dose increases need to be at least 25% above baseline for the patient to notice a change in analgesia.
Conclusion A patient-specific approach to medication management provides benefit to elderly patients, regardless of their care setting or life expectancy. Armed with a thorough understanding of pain management principles and symptom-management strategies, pharmacists can ensure all of their patients receive the highest quality of pharmaceutical care. n
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Caren McHenry Martin, PharmD, CGP, is a consultant pharmacist in Greensboro, North Carolina, and a contributor to The Consultant Pharmacist. Disclosure: No funding was received for the development of this manuscript. The author has no potential conflicts of interest. Consult Pharm 2013;28:605-12. © 2013 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2013.605.
References 1. Duragesic fentanyl transdermal system [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2012. 2. McPherson ML. Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing. Bethesda, MD: American Society of HealthSystem Pharmacists Inc.; 2010. 3. Donner B, Zenz M, Strumpf M et al. Long-term treatment of cancer pain with transdermal fentanyl. J Pain Sympt Manage 1998;15:168-75. 4. The American Geriatrics Society 2012 Beers Criteria Update Expert Panel (2012). American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc 2012;60:616-31. 5. Wood GJ, Shega JW, Lynch B et al. Management of intractable nausea and vomiting in patients at the end of life. JAMA 2007;298:1196-207. 6. Transderm Scōp (transdermal scopolamine) [package insert]. Mountain View, CA: ALZA Corporation; 2006. 7. Patel T, Yosipovitch G. The management of chronic pruritus in the elderly. Skin Therapy Letter.com. Available at http://www. skintherapyletter.com/2010/15.8/2.html. Accessed April 10, 2013. 8. Lexi-Comp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc. Accessed May 13, 2013. 9. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc.; March 2005. Accessed May 13, 2013. 10. DRUGDEX System [Internet database]. Greenwood Village, CO: Thomson Healthcare; updated periodically. Accessed May 13, 2013.
The Consultant Pharmacist october 2013 Vol. 28, No. 10
