Alternatives to Oral Opioids for Cancer Pain

Alternatives to Oral Opioids for Cancer Pain

ABSTRACT: Although the optimal route of administration of opioids is by mouth, some patients may require alternative routes during the course of their illnesses for several reasons. These include bowel obstruction, severe emesis, or severe dysphagia. In these cases, the alternatives include the subcutaneous or rectal route. The transdermal route also provides a simple, comfortable method that produces stable blood drug concentrations. The high potency and lipid solubility of fentanyl make it suitable for this route of administration. Iontophoresis can provide a rapid drug delivery rate, but no clinical studies exist to document the long-term effectiveness of this method in controlling pain. The transmucosal route is recommended only for those opioids with high solubility, such as buprenorphine, the fentanyl series, and methadone. Oral transmucosal fentanyl (Actiq) provides a rapid onset of pain relief and is appropriate for treating episodes of breakthrough pain. [ONCOLOGY 13(2):215-225, 1999]


Most patients with cancer pain respond to the
oral administration of analgesic drugs given regularly to prevent
recurrence of pain. The optimal route of administration of opioids is
by mouth. Studies have shown that oral opioids can often be continued
until, or near to, death.[1,2]. However, some patients, may be unable
to take drugs orally because of bowel obstruction, severe emesis, or
severe dysphagia due to neurologic impairment or drowsiness. In these
cases, the preferred routes of opioid administration are the
subcutaneous and rectal routes.[3].

When adverse effects prevail with oral opioid administration, the
analgesic response may be improved by changing the route of
administration. In a survey documenting the strategies used by pain
control physicians to select opioid drugs and routes of
administration, the route of administration was changed in 61% of
cases because of convenience or because of discomfort or
complications with the original route. Changing the route of
administration achieved better pain control with fewer adverse
effects. At the time of discharge, transdermal and intravenous routes
were each chosen for 18% of the cases and subcutaneous routes for
5%.[4] Approximately 70% of patients benefited from the use of an
alternative route for opioid administration for hours, days, or
months before death.[5]

This review presents the principal indications and contraindications
for the most common alternative routes to oral opioid administration
for the relief of cancer pain. These alternative
routes—subcutaneous, rectal, transdermal, oral transmucosal, and
inhalational—do not require close supervision and can be used
for most patients at home.

Subcutaneous Route

Although the intravenous route allows patients to receive a
continuous infusion of opioids, it is complicated to maintain. Also,
since this route requires prolonged venous access and close
supervision, it may prevent many patients from returning home.

Continuous intravenous infusion may continue to have a role in cases
in which large volumes of opioids are administered. In most other
cases, the subcutaneous route should be considered the standard
alternative systemic route. The main indications for using the
subcutaneous route are vomiting, bowel obstruction, dysphagia,
comatose state, breakthrough pain, and initial titration with
frequent dose changes.

Multiple Benefits

The ability to provide subcutaneous infusions in the home has had a
profound impact on patient care. Before beginning this approach,
patients and caregivers need to consider the choice of pump, drug,
mode of infusion, dosing schedule, family and community health-care
system resources, and cost.[6]

A plastic cannula can be easily inserted in the patient’s
anterior chest or abdomen to avoid multiple injections. When opioids
are administered by a parenteral route, there is a short time to peak
analgesic effect, which facilitates a more rapid dose adjustment.[4]

The continuous subcutaneous infusion of opioids has been shown to be
effective in the treatment of pain from advanced cancer. It may
reduce the peaks and valleys in plasma opioid concentrations inherent
in intermittent administration.[7]

The subcutaneous route has been shown to be equianalgesic to the
intravenous administration of morphine when administered as a
continuous infusion.[8] Pharmacokinetic studies have demonstrated
that subcutaneous and intravenous infusions of identical doses of
both morphine and hydromorphone produced no difference in plasma
opioid concentrations [9,10], and that both provide satisfactory
analgesia with comparable adverse effects. The absorption at higher
doses may differ, however, and this may account for the possible need
for dose increases with subcutaneous infusions.[8]

Studies have also shown that subcutaneous morphine provided effective
analgesia with less severe nausea and vomiting in patients who did
not achieve satisfactory analgesia with oral morphine.[11,12] No
significant differences were detected in either pain relief or
adverse effects between subcutaneous and epidural administration. The
ratio between subcutaneous and epidural morphine was close to 3:1,
although the conversion ratios should be individually determined and
may vary from 1 to 10. A recent paper[13] indicates that there is no
significant benefit to be gained from administering morphine
intrathecally rather than subcutaneously, but further data are needed
to confirm this preliminary observation.

Reducing Adverse Effects

Adverse effects reported with oral administration of morphine can be
reduced by administering the drug through the subcutaneous or the
epidural route.[14] This observation has been attributed to the lower
metabolite/morphine ratios reported with parenteral rather than oral
administration of morphine, demonstrating that morphine metabolism is
significantly lower during parenteral than during oral administration.

In a survey of cancer patients followed at home, the preferred
alternative route to oral administration of opioids was the
subcutaneous route, while the intravenous route was most often used
in patients who already had central vascular access. Subcutaneous
administration was rarely being employed at the time of referral for
home care, but was chosen for short periods, mainly in the last week
of life, due to neurologic derangement, nausea and vomiting, or
analgesia side effects.[2]

Although continuous subcutaneous infusion offers stable blood drug
levels, it has not been shown to control pain more effectively than
intermittent administration, which is a very simple technique that
does not require infusors or pumps. Intermittent injections of
subcutaneous morphine are safe and effective in decreasing the
intensity of dyspnea without modifying oxygen saturation, respiratory
rate, or the end tidal pCO2.[15]

During the steady-state administration of subcutaneous morphine,
there is a large interindividual variation in plasma morphine, with a
poor relationship to the daily administered dose. Measurements of
morphine, morphine-3-glucuronide, and morphine-6-glucuronide in
cerebrospinal fluid did not show any overt relationship to analgesia
or side effects.[16] The prevalence of myoclonus among patients
receiving oral morphine was threefold higher than among those
receiving parenteral morphine. Neither myoclonus nor cognitive
impairment, however, was significantly associated with the
morphine-6-glucoronide/morphine ratio after adjustments were made for
other variables.[17]

Drugs Used Subcutaneously

Hydromorphone has been safely administered subcutaneously, and
reports indicate that it results in pain control and toxicity similar
to morphine. Because hydromorphone is more soluble than morphine, it
can be administered in higher daily doses in very low volumes.[6] The
limited capacity of subcutaneous tissue to absorb fluid is a relevant
advantage when patients need very high doses of opioids.

Fentanyl has also been used both intravenously and subcutaneously in
patients who have refractory cancer pain.[18-20] Subcutaneous
starting doses ranged from 100 to 1,000 mg/d.

When the fentanyl dose needed was too large for the portable syringe
driver being used, the more potent opioid sufentanil (Sufenta) was
substituted. The clinically derived mean relative potency of fentanyl
to morphine infusions was 68:1, whereas the potency of su-fentanil
relative to fentanyl was about 20:1.[19]

A patient with acute renal impairment and bowel obstruction was
successfully treated with a subcutaneous continuous infusion (25
mg/h) of fentanyl and 12.5-mg boluses for the last days of life. This
limited the worsening of the patient’s dramatic clinical picture
of bowel obstruction combined with renal failure. Plasma drug level
ranged from an initial detectable value of 0.12 ng/mL to a maximum of
1.04 ng/mL.

No local toxicity of subcutaneous fentanyl has been reported.[20] No
formal pharmacokinetic studies of the subcutaneous infusion of
fentanyl have yet been conducted.

Side Effects/Contraindications

Minor erythema or thickening at the injection site has been reported
in 52% of patients using regular subcutaneous bolus morphine via an
indwelling cannula, and more severe local reactions occurred in 4% of
patients.[11] Local toxicity requiring frequent site changes seems to
be unrelated to dose, opioid used, duration of site use, triceps skin
fold, age, or gender.[21] Adverse skin reactions have been reported
with the use of subcutaneous methadone, seeming to contraindicate
continuous subcutaneous infusion of this agent.[22] The use of the
subcutaneous route is problematic in patients with coagulation
disorders, severe immunosuppression, fluid retention at the infusion
site, or low skin perfusion.[3,5]


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