Psychostimulants have multiple roles in the
adjuvant treatment of pain. This article reviews the pharmacology of different
agents in this class. Studies will be discussed that demonstrate the efficacy of
these drugs in potentiating opioid analgesia, counteracting opioid-induced
sedation and cognitive impairment, allowing dose escalation in difficult pain
syndromes, and alleviating symptoms of depression. Practical guidelines will be
suggested, and areas for future research indicated.
Amphetamine derivatives have been found to potentiate opioid
analgesia, as well as to counteract opioid-induced sedation and
cognitive failure in patients with advanced cancer. These drugs
have also been used for the management of depression. This
article will outline some of the evidence relating to the role
of these drugs in cancer patients.
Clinical Effects of Psychostimulants
Since the 1940s, researchers have been reporting that
dextroamphetamine has analgesia-potentiating effects in
combination with morphine. In the 1970s, a randomized,
placebo-controlled, single-dose trial of 450 postoperative
patients found that dextroamphetamine enhanced pain relief in a
dose-dependent manner in a randomized, placebo-controlled,
single-dose trial. Our group performed a randomized,
double-blind, crossover trial comparing mazindol (a mild
amphetamine derivative) with placebo in a similar population of
30 patients with advanced cancer and mild-to-moderate pain.
While our patients experienced reduced pain intensity and
decreased need for analgesics, they had increased anxiety and
reduced appetite, and two patients developed acute delirium. Our
findings suggested that these drugs did not appear to improve
the general comfort of the patients, although we could reproduce
the analgesic potentiation described by other authors.
In a second study, we chose methylphenidate, a shorter-acting
amphetamine derivative with demonstrated safety in medically ill
and geriatric patients. A total of 32 patients with severe
cancer pain were randomized to receive methylphenidate 10 mg
with breakfast and 5 mg with lunch versus placebo in a
double-blind, crossover manner. Pain intensity, drowsiness, and
activity improved significantly with methylphenidate, and no
significant toxicity was observed. Both patients and
investigators expressed a blinded preference for
Our results suggested that amphetamine derivatives could have
a significant role in decreasing opioid-induced sedation and
cognitive failure. In a further open study, we administered
methylphenidate to 50 patients with advanced cancer in an effort
to decrease opioid-related somnolence (1). Forty-four patients
reported an improvement in somnolence within 48 hrs. Two
patients developed hallucinations and a paranoid aggressive
reaction, respectively. No other significant toxicity was noted.
The Wilwerding et al. study summarized in this issue of the
PCL confirms our initial observation. That team randomized 43
patients with cancer pain who received at least 80 mg/day
morphine, to receive either methylphenidate 15 mg/day or
placebo, in a double-blind, crossover study. Their results
suggest that methylphenidate could decrease narcotic-induced
drowsiness and increase nighttime sleep (2). No significant
toxicity was observed with methylphenidate. Yee and Berde have
reported a retrospective review on the use of methylphenidate or
dextroamphetamine in eight pediatric patients on opioids (3).
Somnolence was reduced without significant adverse effects.
Psychomotor abnormalities are one of the complications of
opioid therapy. Our group conducted a study that examined the
effects of methylphenidate on cognitive function in 20 patients
with advanced cancer who were receiving a continuous infusion of
opioids. Patients were randomized to receive methylphenidate 10
mg in the morning versus placebo for two days, followed by a
crossover. Significant improvement in cognitive function
occurred with methylphenidate treatment as measured by
finger-tapping speed, arithmetic problems, digit memory, and
visual memory. Visual analogue measurements of drowsiness and
confusion declined. Both patients and investigators preferred
Excessive sedation may prevent dose escalation in patients
with difficult pain syndromes. Our group conducted a trial in 15
patients with incident cancer pain who found sedation to be the
dose-limiting toxicity of opioid therapy (4). Patients received
methylphenidate 10 mg at 8 a.m. and 5 mg at noon as opioids were
gradually increased. The result was a significant reduction in
visual analogue measurements of both pain and sedation and an
increased mean equivalent daily dose of morphine. One patient
developed acute dysphoria on the drug, and the remaining
patients tolerated the drug for an average of 37 days.
Several reports have described the antidepressant properties
of psychostimulants in different medically ill populations.
Methylphenidate has been the most commonly used drug in these
patients, but pemoline, a mild central nervous stimulant that
has some structural similarities to amphetamine, has been
anecdotally reported to effectively treat depression in cancer
patients (5). To date no reports describe the use of pemoline to
enhance opioid analgesia or to counteract opioid-induced
sedation and cognitive impairment.
Guidelines for Clinical Usage
Psychostimulant drugs are indicated to counteract
opioid-induced sedation and cognitive decline. They may also
permit dose escalation of opioids in patients with difficult
pain syndromes; this should be done cautiously, however, because
respiratory depression may occur when the effects on arousal
wear off. They will likely not be useful purely for analgesia
potentiation in the absence of dose-limiting toxicity. The
psychostimulants are also useful as antidepressants, given their
more rapid onset of action and reduced toxicity as compared to
tricyclic antidepressants in the medically ill population. For
all indications, it is important to identify and follow the main
Psychostimulant drugs are contraindicated in patients with a
history of hallucinations, delirium, or paranoid disorders.
Depending on the state or country in which they are being
prescribed, these drugs may be considered controlled substances,
subject to strict regulation. They are relatively
contraindicated in patients with a history of substance abuse. Pemoline should be used with caution in patients with liver
Usual starting dose for methylphenidate is 10 mg in the
morning. If there is no evidence of adverse reactions, an
additional dose of 5 mg may be administered at noon. The
therapeutic effect should appear within two days. The usual
starting dose of dextroamphetamine is 2.5 mg in the morning.
Both methylphenidate and dextroamphetamine can only be
administered by the oral route.
Pemoline dose is usually initiated at 18.75 mg in the
morning, which can also advance to twice daily if the morning
dose is well tolerated. Pemoline comes in chewable tablet form
that can be absorbed through the buccal mucosa, and therefore
can be used by patients who cannot take oral medications.
Chemical structures of the various amphetamine derivatives is
quite different, so a significant lack of cross-tolerance or
cross-toxicity may be observed. For patients who develop rapid
tolerance or significant toxicity to one amphetamine derivative,
a trial of a different type of amphetamine derivative might be
Future studies should focus on a better characterization of
the role of different amphetamine derivatives. The best type and
dose of amphetamine derivative remains unestablished. It is
likely that the different amphetamine derivatives will be useful
for different, specific effects; e.g., the best psychostimulant
for analgesic potentiation may not be the best one for mood
improvement or sedation antagonism. Finally, researchers should
explore new indications for the psychostimulant drugs, such as
hypoactive, hypoalert delirium.
Eduardo Bruera, MD
1) Use of methylphenidate as an adjuvant to narcotic
analgesics in patients with advanced cancer. Bruera E, Brenneis
C, Paterson AHG, MacDonald RN. Journal of Pain and Symptom
Management 4(1):3-6, 1989.
2) A randomized, crossover evaluation of methylphenidate in
cancer patients receiving strong narcotics. Wilwerding M,
Loprinzi C, Mailliard J, et al. Supp Care Cancer (FULL JOURNAL
NAME??) 3:135-138, 1995.
3) Methylphenidate or dextroamphetamine as adjuvants in
opioid analgesia (abstract). Yee JD, Berde CB. Journal of Pain
and Symptom Management 6:162, 1991.
4) The use of methylphenidate in patients with incident
cancer pain receiving regular opiates. A preliminary report.
Bruera E, Fainsinger R, MacEachern T, et al. Pain 50:75-77,
5) Breitbart W, Mermelstein H. Pemoline: an alternative
psychostimulant for the management of depressive disorders in
cancer patients. Psychosomatics 33:352-356, 1992.