VIENNA, AustriaAmong the CNS effects of opioids are cognitive
failure, organic hallucinations, myoclonus, hyperalgesia, and severe
sedation. Regular, repeated assessments of cognition should be
performed in patients taking opioids, and any changes should be
evaluated by the physician to exclude other underlying
etiologies, Carla Ripamonti, MD, said at the World Congress on Pain.
Delirium or cognitive impairment, for example, can be caused by
several drugs other than opioids, including tricyclic
antidepressants, NSAIDs, ranitidine (Zantac), benzodiazepines, or
antipsychotic drugs, said Dr. Ripamonti, deputy director, Palliative
Care Program, National Cancer Institute, Milan, Italy.
Dr. Ripamonti reported that among patients with cancer pain taking
opioids and benzodiazepines who had cognitive impairment, 80%
improved when the benzodiazepines alone were discontinued. She also
noted that the combination of ranitidine and an opioid can lead to
Metabolic abnormalities such as hypercalcemia or hypermagnesemia are
a common cause of cognitive impairment, and may be precipitated or
worsened by renal insufficiency. Renal insufficiency can also cause
altered sensorium in patients receiving opioids that have active
metabolites, such as morphine, oxyco-done, fentanyl, hydromorphone,
and meperidine. Sepsis, intracranial metastases, and drug
interactions can also be the source of CNS effects, she said.
Dehydration can cause cognitive impairment in cancer patients,
particularly in those who are receiving opioids that have active
metabolites. When we rehydrated patients with more than 500 mL
per day of fluids, either intravenous, subcutaneous or orally, there
was a significant decrease in nausea and drowsiness, Dr.
Dealing With Sedation
Sedation is common when opioids are first given to patients or when
the dose of the opioid is increased, but this may represent
relaxation and release from stress rather than overdosage. If a
patient who is on an opioid is sedated, Dr. Ripamonti advised the following:
Make sure that the patient is well hydrated.
Reduce or eliminate benzodiazepines and other unnecessary centrally
acting antidepressant drugs.
Change the opioid or the route of opioid administration.
Consider adding a psychostimulant such as methylphenidate.
But do not use naloxone to reverse sedation, since it will
likely precipitate withdrawal symptoms, she said.
There are few clinical trials on the use of psychostimu-lants to
reverse sedation, but there have been several small studies
demonstrating the efficacy of methylphenidate, dextroamphetamine, and
pemoline (Cylert) for opioid-induced sedation, she said.
Myoclonus can be caused by opioids alone or in association with other
drugs, Dr. Ripamonti said. It generally occurs with either
intrathecal opioids or when opioids are needed in high doses. One
study showed that the occurrence of myoclonus was greater when
morphine sulfate was given in combination with NSAIDs or
antidepressants, and less in patients receiving corticosteroids.
There are no clinical trials demonstrating the optimal method of
managing myoclonus, she said, but there have been reports of the use
of baclofen, benzodiazepines, midazolam (Versed), or epidural
bupivacaine. Changing to another opioid and ensuring that the patient
is adequately hydrated are other methods used to manage myoclonus.
Organic hallucinosis may be seen with the use of opioids, but it is
infrequently reported by patients. We need to ask our patients
repeatedly whether they are experiencing hallucinations of any type
while taking any opioid, she said.
Adequate hydration has been reported in the literature to reduce the
incidence of hallucinations due to opioids that have active
metabolites, as has using haloperidol, she noted.
A study by William Breitbart, MD, of the Department of
Psycho-oncology, Memorial Sloan-Kettering Cancer Center, showed that
haloperidol or chlorpromazine significantly improved delirium better
than did lorazepam. Other drugs that have been reported to be useful
for managing hallucinations include midazolam via continuous
infusion. Moreover, a reduction of the dose of opioid should be
considered to control the symptom, Dr. Ripamonti said.
When a patient has significant side effects due to an opioid,
switching to another opioid may be helpful, she said. Retrospective
studies and case reports have shown that switching from any opioid to
another (for example, from morphine to oxycodone or from fentanyl to
hydromorphone and vice versa) can improve CNS side effects.
She also reported that methadone produced significantly fewer
episodes of dry mouth with similar analgesia when compared with
morphine and that patients treated with transdermal fentanyl
(Dur-agesic) seem to need fewer laxatives than patients treated with
Route of administration also affects the occurrence of opioid-related
side effects, and changes in the route of administration may help
manage some of the side effects seen in patients receiving chronic
opioids for cancer pain.
Continuous Subcutaneous Infusion
Dr. Ripamonti said that some studies have shown that intermittent
dosing of morphine (eg, every 4 hours), either orally or
subcutaneously, caused more constipation, nausea, and drowsiness than
continuous subcutaneous infusion. Rectal morphine suppositories also
caused less nausea than morphine sulfate given orally, she said.
A study by Kalso et al compared subcutaneous or epidural infusion of
morphine with orally administered morphine sulfate. These researchers
found that pain at rest was less with subcutaneous vs oral
administration; pain with movement was less with subcutaneous and
epidural administration vs oral administration; but there was no
significant difference between subcutaneous and epidural morphine
administration for either pain at rest or pain with movement. Side
effects were greater with the oral route, compared with the
In summary, Dr. Ripamonti recommended that for cancer patients who
are receiving opioids for chronic pain, it is important to make sure
that there are no biochemical abnormalities, that they are adequately
hydrated to eliminate any active metabolites, and that their drug
regimen is reviewed and any other centrally acting drugs that may
impair cognitive status are eliminated.
When a side effect occurs due to opioid use, Dr. Ripamonti suggested
several management possibilities: adding an adjuvant drug to manage
the side effect, such as methylphenidate for sedation; changing the
type of opioid, the dosing schedule, or the route of administration
to lessen the adverse effects; or, if possible, lowering the opioid
To understand the problems pain patients may be having with
opioid side effects, we only need to listen carefully to the patient.
Treatment must be individualized to the patient, she said.