++
There are several additional important issues related to the
use of opioids in the palliative care context. Details of each of
these are covered in other chapters in this text, and only major
points will be reviewed here.
+++
Routes of Administration
++
A wide variety of routes of administration are available, including
oral, intravenous, subcutaneous, rectal (morphine, oxymorphone,
hydromorphone, or methadone suppositories), sublingual (concentrated
morphine elixir or hydromorphone), and transdermal and oral transmucosal
(fentanyl citrate). Continuous intravenous infusion with the possibility
of frequent additional doses of small boluses, generally administered
through a patient-controlled (PCA) system, usually provides both
the most consistent blood concentrations as well as the most rapid
response to breakthrough pain. The continuous infusion facilitates
maintenance of the minimum reliably effective blood concentration,
minimizing some of the adverse effects (including sedation and confusion) that
can accompany the bolus effects of intermittent dosing. During a
phase of life in which final interactions with others can be of
the utmost importance, minimizing these adverse effects is particularly
important.
++
Continuous intravenous infusion with self-administered breakthrough
bolusing however requires an alert patient and continuous intravenous
access. The former may not be the case during the terminal phase
of illness, and the latter may not be desired by the patient, particularly
in the home setting. To achieve a stable level of the minimum reliably
effective blood concentration without intravenous access, slow-release
preparations are preferred. For breakthrough dosing, the most rapidly
acting available preparation and route should be used. If decreased
level of consciousness is not a reason for concern from the patient’s
perspective, it may be possible to achieve analgesia with maximal
convenience by giving higher doses at longer intervals.
++
As new forms of opioid delivery have become available, cost has
become an increasing factor. Transdermal preparations of fentanyl
citrate, for example, provide stable blood levels in most patients,
but at far greater cost than slow-release forms (either oral or
rectal) of morphine or oxycodone. Similarly, oral transmucosal fentanyl
citrate has been shown to be highly effective for breakthrough pain
in alert patients, but again at far greater cost than other alternatives.
Often pharmacy colleagues can be helpful not only in creatively
shaping an approach that is well-suited to an individual patient’s
circumstances, but also in choosing the most cost-effective approach
if there is more than one clinically suitable alternative.
++
As discussed in detail elsewhere (See Chapter 60), optimal use
of opioids requires careful attention to identifying and treating
their undesirable effects, and to preventing their occurrence whenever
possible. Since the beneficial effects of the opioid can sometimes
be adequately achieved at a lower dose, that should always be considered
first. Opioid rotation can also be helpful.40 Other
alternatives include: using localized routes of administration (e.g.,
spinal) that do not generate such high circulating drug levels;
using non-opioid analgesics, either as adjuvants that allow reduction
in the opioid dose or as substitutes; continuing the opioid while
adding pharmacologic agents that counteract the undesirable effect(s);
and nonpharmacologic approaches (See Chapters 58, 60, 62).
++
Common opioid effects that will be addressed briefly here include
constipation, nausea, vomiting, sedation, and delirium. For all
of these except constipation, tolerance may develop and patients should
be counseled that even if the undesirable effects are significant
with initial doses, a trial of at least a few days may be warranted
before deciding that an alternative medication should be used or
that the dose of the opioid can be reduced. In the meantime, symptoms
should be monitored closely and vigorously treated.
++
Constipation is a predictable effect of chronic opioid use. In
the palliative care setting, where patients frequently have markedly
reduced levels of physical activity and other serious comorbidities,
it is even more significant, and can become a cause of significant
abdominal discomfort. A proactive bowel regimen designed to prevent
constipation, with daily monitoring of its effectiveness, is a mandatory
component of chronic opioid therapy in this setting. Bulk-forming
agents should generally be avoided unless the patient is physically
active, since an increase in the volume of stool can pose difficulties
for the bed-bound patient.
++
Nausea and vomiting can be treated with a variety of pharmacologic
agents, including trials of compazine, haloperidol, metaclopromide,
and ondasteron. If tolerance to these adverse effects does not develop,
alternative opioids should be tried.40 It is important
to keep in mind, however, that many palliative care patients are
suffering from illnesses or taking other medications which may themselves
be the cause of the nausea or vomiting, and the opioid may be only
partially to blame, or may even be an entirely innocent bystander.
++
Delirium is a common problem for patients in the terminal setting,
with estimated prevalence rates ranging from 25% to 85%.41–48 Many
of these patients are receiving opioids, but even when administration
of the opioid is the precipitating factor, the cause is frequently
multifactorial,49 including the contributing factors
indicated in Table 47-2.
++
++
Delirium can take both agitated and non-agitated forms,50 with
the latter more frequently unrecognized. When the delirious state
is clearly distressing to the patient, its evaluation and treatment should
have the same urgency as that of uncontrolled pain. In some cases,
however, it is unclear whether or not the delirious patient is suffering
from his or her loss of mental clarity, and some near-death experiences
that many would categorize as delirious are reported by patients
as extremely peaceful, reassuring, and pleasant.41,51 Nonetheless,
even when the patient is not clearly suffering the delirious state
interferes with his or her ability to have meaningful interactions
with loved ones, and it thus warrants close attention.
++
Because some forms of delirium do not manifest themselves with
obvious behavioral abnormalities, it is important to screen all
patients at risk, which includes virtually all patients receiving
opioids in the terminal phase of illness. The simplest and most
commonly used assessment tool is the Mini-Mental State Exam (MMSE).52 When
evidence of delirium is detected, a comprehensive evaluation of
potentially contributing factors is warranted, with efforts to treat
the underlying cause(s) whenever the benefits of doing so would
outweigh the burdens from the patient’s perspective. Although
delirium in the terminal care setting may not be reversible in the
majority of cases, some authors estimate that up to 33% of
cases are.41,44,46,53,54
++
Changing the opioid can be useful.53 In addition,
a variety of pharmacologic agents can be used to treat delirium,
and nonpharmacologic approaches can also be useful.41,55 Haloperidol
has generally been considered the drug of choice, and has been shown
superior to lorazepam and chlorpromazine in a double-blind, controlled
study of the treatment of delirium in hospitalized patients with
AIDS.56 In one small series, all four patients
who developed delirium while taking an opioid improved after being
switched to an alternative opioid supplemented by haloperidol.57 An
alternative agent that may be considered is methotrimeprazine.58 In
some cases of agitated delirium, only sedation is effective.59–62 If
benzodiazepines are used for this purpose, close monitoring for
a paradoxical increase in agitation (attributed to the disinhibiting
effects of benzodiazepines) is warranted.41
++
Sedation is an effect of opioids that can be either desirable
or undesirable in the palliative care setting. If the latter, and
if dose reduction is not possible without a return of unacceptable
symptoms, a psychostimulant such as methylphenidate, caffeine, or
amphetamine should be tried unless there is a specific contradindication.63–65 Modafinil,
a relatively new agent, may prove useful for this purpose in the
future,66 since it may be useful ameliorating the
sedation of other sedating medications.
++
Finally, if other efforts to address undesirable side effects
have been unsuccessful, careful titration of an extremely low dose
of an opioid antagonist (e.g., naloxone via continuous intravenous administration,
or repeated parenteral boluses of nalmefene, essentially a long-acting
form of naloxone) may be a viable option. There is preliminary evidence
to suggest that opioid antagonists, in extremely low doses, may
exhibit the potential to increase analgesia, diminish side effects,
and diminish tolerance.67 The use of larger, conventional
bolus doses of an opioid antagonist to attempt to reverse opioid
side effects is usually ill-advised in the palliative care setting, because
of the substantial risk of precipitating recurrent pain or even
a withdrawal syndrome.27,68,69