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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2593_Библиотеки_им_академика_М_И_Перельмана
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An official American Thoracic Society statement: update on the mechanisms,
assessment, and management of dyspnea. Am J Respir Crit Care Med.
2012;185(4):435–452; Mularski RA, Reinke LF, Carrieri-Kohlman V, et al. An
official American Thoracic Society workshop report: assessment and palliative
management of dyspnea crisis. Ann Am Thorac Soc. 2013;10(5):S98–S106;
Mercadante S. Episodic breathlessness in patients with advanced cancer:
characteristics and management. Drugs. 2018;78:543–547; Hallenbeck J.
Pathophysiologies of dyspnea explained: why might opioids relieve dyspnea and
not hasten death? J Palliat Med. 2012;15(8):848–853; Lok CW. Management of
breathlessness in patients with advanced cancer: a narrative review. Am J Hosp
Palliat Care. 2016;33(3):286–290; Afolabi TM, Nahata MC, Pai V. Nebulized
opioids for the palliation of dyspnea in terminally ill patients. Am J Health Syst
Pharm. 2017;74(14):1053–1061; Simon ST, Higginson IJ, Booth S, Harding R,
Weingärtner V, Bausewein C. Benzodiazepines for the relief of breathlessness in
advanced malignant and non-malignant diseases in adults. Cochrane Database
Syst Rev. 2016;10(10):CD007354.
Hospice patients generally do not have IV access (ie, an IV
catheter) into which medications can be easily administered. As a
result, medications are primarily administered orally and,
occasionally, by sublingual, buccal, transdermal, rectal, or
subcutaneous (if an infusion is warranted) routes of administration.
When patients lose the ability to swallow near the end of life (or have
a condition that precludes swallowing), the sublingual or buccal
routes of administration are the most useful, especially if drugs are
lipophilic. The use of ODTs may also be useful at this time. Morphine
is hydrophilic, and although some of it might be absorbed across the
mucous membranes, the primary clinical effect probably results from
GI absorption after the drug has trickled down the back of the throat.
Oral morphine sulfate, in a concentration of 100 mg/5 mL (20
mg/mL), is commonly dispensed in a 30-mL bottle at the beginning
of hospice care. This bottle of morphine can provide 60 doses of 10
mg, and, at this concentration, only 0.5 mL of morphine needs to be
administered. Patients should be provided with appropriate oral
dosing syringes or use the dropper provided by the manufacturer to
prevent dosing errors. Oxycodone or hydromorphone, in comparable
adjusted doses, can be substituted for morphine when needed.
There is no evidence demonstrating the superiority of any of these
over the others in severe cancer pain.
93
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Lorazepam. A short-acting benzodiazepine (eg, lorazepam 0.5
mg every 4 hours as needed) is useful for the treatment of anxiety
(see Chapter 83, Anxiety Disorders). Patients, especially those with
respiratory symptoms, can experience episodes of extreme anxiety
near the end of life, and low doses of a benzodiazepine can provide
effective palliation.94 Caution should be used to not overuse these
drugs in the elderly because they can increase the risk of falling or
cause paradoxic reactions and worsen delirium or restlessness. The
combined use of benzodiazepines with opioids increases the risk of
respiratory depression and potentially fatal overdose and should be
used with extreme caution in the lowest possible doses.
95,96
Haloperidol. Small doses of haloperidol (eg, 0.5–1 mg) are useful
for the treatment of restlessness, delirium, or nausea and
vomiting.
97,98
Olanzapine. Low-dose olanzapine (2.5–5 mg) can be used to
manage restlessness, delirium, or nausea and vomiting, and can be
used as an alternative to haloperidol.97 It is available in multiple
dosage forms including an ODT.
Anticholinergic agent. As death approaches, patients can have
difficulty in clearing pharyngeal secretions and, as a result, generate
a sound commonly known as a death rattle.
99,100
Although patients
are often unconscious at this point, this sound can be very
distressing to those nearby.
101,102
A long-standing practice is to use
an anticholinergic agent (eg, glycopyrrolate, hyoscyamine,
scopolamine, atropine) in an attempt to prevent these pharyngeal
secretions from forming. Systematic reviews found these agents to
be no more effective than placebo.
103,104
Nonetheless, anticholinergic
medications continue to be widely prescribed in end-of-life care.
Patient positioning and gentle suctioning can remove secretions
already present. If used, this treatment modality is usually initiated
after the patient has become obtunded; if begun too early, patients
might develop problems with thickened bronchial or pulmonary
secretions, tachycardia, delirium, dry mouth, urinary retention, or
other adverse anticholinergic effects.
105
Glycopyrrolate, available as
a tablet, injectable formulation, and oral solution, is a good choice for
an anticholinergic agent because it minimally crosses the blood–
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brain barrier. The 1-mg tablets could be crushed and placed under
the tongue every 8 hours. Hyoscyamine is available as oral tablets,
ODT, oral sustained-release tablets, sublingual tablets, oral liquid,
oral solution, and injection. The ODT, sublingual tablets, or oral
solution of hyoscyamine can be given in a 0.125- to 0.25-mg dose
sublingually every 4 hours as needed. Scopolamine transdermal
patches have a slow onset of action (blood levels are detected 4
hours after application)
106
and are of limited utility in this situation.
The oral or sublingual administration of atropine ophthalmic solution
1% is convenient to administer. Recent shortages and price
increases have made it less cost-effective.71 Families and caregivers
must be instructed not to use this in the eye.
CASE 6-1, QUESTION 4: The hospice nurse for M.P. has difficulty finding oral
morphine sulfate available from a pharmacy and difficulty in finding a pharmacy
willing to accept a faxed or an electronic prescription. Why is morphine so
difficult to obtain, and how should the nurse manage this problem?
Providing relief for pain or other symptoms with opioids is often
difficult owing to numerous barriers. Patients and caregivers are
often fearful of opioids, or mistakenly believe these medications will
cause addiction or hasten death.
107,108
Pharmacists can create
barriers by not having opioids in the pharmacy, sometimes because
of the fear of robbery, fear of investigation by drug regulatory
agencies, or insufficient appreciation of the usefulness of opioids in
pain management and palliative care.
109,110
In response to the opioid
crisis, recent legislative and regulatory changes in some states have
restricted quantities of controlled substances that can be dispensed
and mandated the use of prescription drug monitoring programs
(PDMPs). Patients with cancer and those who are terminally ill may
be exempt from these requirements.
111–113
Pharmacists who are
inexperienced in providing service to hospice patients might not be
knowledgeable about federal regulations governing the provision of
controlled substances to hospice patients. Federal statutes, as well
as most state statutes, permit prescriptions for Schedule II controlled
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substances for hospice patients to be faxed. According to the CFR
(21 CFR 1306.11) paragraph (g):
A prescription prepared in accordance with 1306.05 written for a
Schedule II narcotic substance for a patient enrolled in a hospice
care program certified and/or paid for by Medicare under Title XVIII
or a hospice program which is licensed by the state may be
transmitted by the practitioner or the practitioner’s agent to the
dispensing pharmacy by facsimile. The practitioner or the
practitioner’s agent will note on the prescription that the patient is a
hospice patient. The facsimile serves as the original written
prescription for purposes of this paragraph (g) and it shall be
maintained in accordance with 1304.04(h).
114
Electronic prescribing of controlled substances (EPCS), including
Schedule II medications, is now legal per federal DEA regulations in
all 50 states.
115,116
Some states mandate the electronic prescribing of
all controlled substances. The SUPPORT (Substance Use-Disorder
Prevention That Promotes Opioid Recovery and Treatment) for
Patients and Communities Act requires the use of EPCS for all
controlled substances under Medicare Part D by January 1, 2021,
although it has not been fully implemented.
117
The process of ordering controlled substances for use by hospice
patients at home can take many hours, and sometimes as much as
an entire day. Hospice providers should anticipate possible
difficulties when placing orders for Schedule II controlled substance
medications. M.P.’s nurse should take the time to address any
concerns that M.P.’s caregivers and family may have about these
medications (ie, how they may affect her, any worries about
addiction, side effects) and allow ample time to order them so that
symptoms can be managed as they develop.
CASE 6-2
QUESTION 1: G.G., a 40-year-old female, is admitted to hospice with stage IV
ovarian cancer, metastatic to her pelvis, liver, and lungs. She was diagnosed
after many months of nonspecific gastric distress and bloating. On laparotomy,
she was evaluated as stage III and underwent a total abdominal hysterectomy
and bilateral salpingo-oophorectomy and tumor debulking at that time. She has
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undergone subsequent chemotherapy and repeated tumor debulkings. In the
past 6 months, her weight has decreased from 175 pounds (79.37 kg) to 153
pounds (69.38 kg; she is 62 inches [157.48 cm] tall). Her primary problems are
constant nausea, constipation, and gripping abdominal pain, which she
characterizes as burning and twisting. She quantifies the pain as 8 of 10 (on a
0- to 10-point scale) and describes the pain as one that moves into her groin
and leg. Her family is unhappy about the drowsiness she experiences from her
medications; they believe she is overmedicated. She is starting to have difficulty
swallowing. She has no known allergies. Her current medications include
fentanyl transdermal system 75 μg/hour every 72 hours, extended-release
morphine sulfate capsules 50 mg three times daily (usually intended for oncedaily administration), docusate sodium 250 mg daily, lansoprazole 30 mg daily,
and lorazepam 0.5 mg every 4 hours as needed for nausea and anxiety.
What is the most accurate assessment of her pain management regimen?
G.G. is currently using two long-acting opioids (ie, fentanyl
transdermal and sustained-release morphine that is being dosed too
frequently), but is still unable to achieve relief of her pain, which is
probably neuropathic pain (described as burning and twisting). It is
estimated that up to 39% of patients with cancer pain have
neuropathic pain.
118–120
This may be caused by tumor growth around
nerves, postoperative nerve damage, chemotherapy-induced
neuropathy, or following radiation therapy. Opioids alone may be of
limited value or may require higher than usual dosing.
118
The addition
of adjuvant analgesics such as antidepressants, anticonvulsants,
and local anesthetics play an important role in treating neuropathic
pain
121
(see Chapter 55, Pain and Its Management).
The use of two long-acting agents is duplicative and should be
replaced with one opioid. Methadone may be a better long-acting
agent for G.G. because it has activity against neuropathic pain (see
Chapter 55, Pain and Its Management) and can reduce the amount
of medication she uses. Methadone is a μ-opioid receptor agonist,
blocks the NMDA receptor and monoaminergic reuptake transporter
for serotonin.
122–124
Clinicians find it very effective for intractable
neuropathic pain, but studies do not show methadone to be superior
to other opioids.
125,126
Advantages of using methadone for G.G.
include long half-life, high bioavailability, excellent absorption across
mucous membranes, lack of active metabolites, and lower cost. All
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dosage forms of methadone, including the oral solution are longacting ones. Use of the oral solution may be useful when patients
lose the ability to swallow as death approaches. Disadvantages in
using methadone are its long and variable elimination half-life, drug–
drug interactions, prolongation of the QTc interval, and the variability
of dosing equivalence with other opioids. Dosing methadone is
complex and should be undertaken by experienced clinicians.
124–127
When converting fentanyl and morphine to methadone, the
following should be considered: (a) patient adherence and ability to
follow prescription directions, (b) use of an appropriate conversion
formula, (c) converting a transdermal formulation of fentanyl to an
oral opioid formulation, and (d) a supplemental opioid for
breakthrough pain.
Because of its long and variable elimination half-life, the dose of
methadone should generally be adjusted only once every 5 to 7
days, and patients must be able and willing to precisely follow
directions for its use. The methadone prescribing information can be
used for the conversion, with a general rule of thumb being that the
initial methadone dose should not exceed 30 mg/day.
128
An
alternative, conservative dosing conversion scheme developed by a
panel of experts in hospice and palliative care for patients who are
opioid tolerant is presented in Table 6-3.
Table 6-3
Dosing Conversion to Methadone in Patients Who Are Opioid
Tolerant
Oral Morphine or OME/Day Oral Methadone Dose (No >30 mg Initially)
<60 mg oral morphine or OME Give 2.5–7.5 mg methadone/day
60–199 mg oral morphine or OME
AND patient age <65 years
10:1 conversion
10 mg OME:1 mg oral methadone
≥200 mg oral morphine or OME
AND/OR age >65 years
20:1 conversion
20 mg OME:1 mg oral methadone
OME, oral morphine equivalent.
Source: Adapted from McPherson ML, Walker KA, Davis MP, et al. Safe and
appropriate use of methadone in hospice and palliative care: expert consensus
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white paper. J Pain Symptom Manage. 2019;57(3):635–645.e4. © 2018 American
Academy of Hospice and Palliative Medicine. With permission.
Safety guidelines recommend electrocardiographic monitoring
before and during methadone use
129,130
; the need for this in
terminally ill patients should be balanced by life expectancy and
goals of care. Caution should be used in patients with electrolyte
abnormalities (hypokalemia or hypomagnesemia), impaired liver
function, heart disease, prolonged QT syndrome, or the use of other
QTc-prolonging drugs (eg, amiodarone, azithromycin, citalopram,
fluconazole, haloperidol, ondansetron).
127,129,130
Once the conversion is made, the calculated dose is adjusted and
the dosing interval is set at every 12, 8, or, rarely, every 6 hours,
based on patient age, previous use of opioids, and current clinical
status. Clinical judgment is vital in individualizing a regimen for each
patient based on his or her needs.
Before calculating the conversion to methadone for G.G., an
important consideration in patients using transdermal fentanyl is an
assessment of its absorption. Fentanyl from the transdermal system
is absorbed through several layers of the skin and deposited in the
subcutaneous fat, from which it is absorbed into the systemic
circulation.
131
It is generally observed that transdermal fentanyl is not
effective in very thin, cachectic patients. In those cases, the
conversion would be made without including the fentanyl. The patch
would be removed at initiation of the first methadone dose and
supplemented with medication for breakthrough pain if needed. In
patients using multiple patches, one patch can be removed every 3
days. Despite weight loss, G.G. (62 inches [157.48 cm] and 153
pounds [69.38 kg]) is not cachectic, and the fentanyl should be
included when calculating the conversion of her current opioid dose
to a comparable methadone dose. In this patient, her sustainedrelease morphine formulation (50 mg three times daily) is equivalent
to 150 mg/day of oral morphine. Her fentanyl transdermal system 75
μg/hour is equivalent to about 150 mg/day of oral morphine.
132
(This
is based on a conversion ratio of parenteral to oral morphine of 1:3 in
patients who are opioid tolerant, rather than the 1:6 ratio that is used
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in the dosing table in the Duragesic® prescribing information.) G.G.’s
total oral morphine equivalents (OMEs) per day are 150 plus 150
mg, or 300 mg. Her caregiver reports that she generally takes 150
mg of oral morphine solution daily for breakthrough pain, and
yesterday she used 180 mg. This brings the total daily OME to 480
mg, and we would use the 20:1 conversion from Table 6-3 for
conversion of OMEs to methadone. The calculated dose of oral
methadone is 24 mg/day. This is a conservative amount; in certain
situations, an experienced clinician may choose to start with a higher
daily dose. For example, the methadone prescribing information
uses a conversion for 480 OMEs of 8% to 12%, which would result in
a methadone dose of 48 mg/day.
128
G.G. can be started on methadone 7.5 mg every 8 hours or 10 mg
every 12 hours. Because she is relatively young, has been using
opioids for some time, and has severe pain (quantified at 8 of 10), a
methadone dose of 7.5 mg every 8 hours (ie, 22.5 mg/day) would be
appropriate. The dose can be increased, if needed, based on her
clinical response after 5 to 7 days. This smaller initial dose would
accommodate for some incomplete cross-tolerance from the
morphine and fentanyl and for any fentanyl that remains in her
system for the next several days. Patients who have been on much
higher doses of opioids, alternatively, can be converted during a
period of several days (eg, converting one-third of the previous daily
dose of opioid every 3 days). This is an especially useful method for
converting opioid doses for thin, cachectic patients who have been
on multiple transdermal patches. A clinician should be in touch with
G.G. frequently during the first several days after her conversion to
methadone. A telephone call should be made 2 to 4 hours after the
first dose to assess for efficacy and toxicity (primarily somnolence,
confusion, or nausea) and then daily for 5 days. If pain relief with the
first dose does not last for the entire dosing interval, it can be
adjusted, or G.G. can be instructed to take a one-time extra dose of
methadone.
An added benefit in changing to methadone for G.G. is a financial
one for the hospice. Outpatient prescription prices for long-acting
opioids are very steep and significantly add to hospice costs. The
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prudent use of methadone can improve overall pain management
and keep costs in check. When methadone is not appropriate,
generic extended-release morphine is a good second choice.
Transdermal fentanyl should be reserved for patients who cannot
take oral medication or for when there are significant compliance
issues. Extended-release oxycodone is an option when patients
cannot tolerate morphine, have significant renal impairment, or have
other contraindications to its use. By converting to methadone,
G.G.’s daily cost for the opioid alone will decrease substantially,
while still providing appropriate and effective pain management.
G.G. will also need a supplemental analgesic for breakthrough
pain. Some practitioners use small doses of methadone, 2.5 or 5 mg,
as often as every 3 hours. This is a good choice in a well-supervised
(ie, inpatient) setting with nurses familiar with the use of methadone.
However, if caregivers treat methadone as if it were morphine, which
is much more commonly used for breakthrough pain, the risk of
overmedicating the patient is very real. This can have disastrous
consequences, especially in frail, elderly patients. Because G.G. is
not in an inpatient setting and has tolerated morphine well in the
past, 30 mg or 1.5 mL of morphine 100 mg/5 mL (20 mg/mL) can be
prescribed to be taken every 2 hours as needed for breakthrough
pain.
G.G. should also start a bowel regimen; the use of a stool softener
alone is inadequate.
62–65
The nurse should perform a rectal
examination to determine if stool is present in the rectal vault. An
enema or suppository can be given if needed and then senna or
PEG can be taken on a routine basis.
Because the fentanyl transdermal patches and the extendedrelease morphine have been discontinued, they should be properly
discarded. The safe disposal of controlled substances is important in
preventing drug diversion. Hospices are required to educate patients
and their caregivers at the time of admission about proper drug
disposal and must have policies and procedures for the
management and disposal of controlled substances.18 Options for
disposal of controlled substances include take-back events, mailreturn programs, and DEA-registered collection receptacles.
133
With
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the enactment of the SUPPORT for Patients and Communities Act of
2018, hospice personnel are allowed to dispose of controlled
substances for their patients by following criteria specified in the law
(Section 3222, Disposal of Controlled Substances of a Hospice
Patient by Employees of a Qualified Hospice Program).
117
Aggressive Symptom Management and Palliative
Sedation
CASE 6-3
QUESTION 1: D.V., a 35-year-old male with gastric cancer metastasized to the
esophagus with periaortic involvement, is hospitalized. He was diagnosed 10
months ago, and his disease has progressed despite multiple courses of
chemotherapy. A double-lumen, peripherally inserted central catheter line has
been inserted. He has lost 65 pounds (29.48 kg) since diagnosis, weighs 150
pounds (68.04 kg) at 72 inches (182.88 cm) tall, and presents with abdominal
pain, severe nausea, vomiting, obstipation (intractable constipation), and
general malaise. D.V. describes his pain as a 7 of 10 in intensity and as
“burning like a knife through my stomach.” He uses 50- to 75 patient-controlled
analgesia (PCA) bolus doses every 24 hours. He has no other medical
problems. D.V. is referred to hospice care because he and his wife have agreed
to stop chemotherapy and do not want to go back to the hospital. He states a
history of allergic reactions to morphine, ondansetron, and diphenhydramine,
although these reactions are not noted. He is presently receiving
hydromorphone 2 mg/hour in an IV infusion with 1-mg PCA bolus dose every 5
minutes, hydromorphone 4 mg orally every 4 hours as needed for pain, fentanyl
transdermal 275 μg/hour every 3 days, ketamine 20 mg orally every 3 hours,
senna two tablets twice daily, docusate sodium 250 mg twice, PEG 3350 17 g
daily, lactulose 15 mL as needed for constipation, lorazepam 2 mg orally every
4 hours as needed for nausea or vomiting, metoclopramide 10 mg orally every 6
hours as needed for nausea or vomiting, ondansetron 4 mg IV every 8 hours as
needed for nausea or vomiting, baclofen 10 mg orally every 8 hours as needed
for hiccups, and pantoprazole 40 mg orally once daily.
What is your assessment of D.V.’s medication regimen?
D.V.’s drug regimen is unnecessarily complicated for a patient at
home. It may be possible to simplify it by looking at each problem
anew. His pain is poorly managed as evidenced by his pain intensity
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