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Psychostimulants as Adjuvant Analgesics

 
Eduardo Bruera and Sharon Watanabe; Journal of Pain and Symptom Management; 9(6); 412-415; 1994. Posted: circa 1998. Modified: 2005-12-24.
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See also:
Opioid Rotation in Patients with Cancer Pain - Bruera et al.; Cancer; 78(4); 852-857; 1996
Opiate Rotation, Incomplete Cross-Tolerance, and Hyperalgesic Metabolites – DeLuca; 2001
High-Dose Ketamine in the Management of Cancer-Related Neuropathic Pain - Tarumi et al.; J Pain Symptom Manage.; 19(6); 2000
 

Abstract
 
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 methylphenidate.

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 methylphenidate.

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 outcome measurement.

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 dysfunction.

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 very useful.

Future Research
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

References:

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, 1992.

5) Breitbart W, Mermelstein H. Pemoline: an alternative psychostimulant for the management of depressive disorders in cancer patients. Psychosomatics 33:352-356, 1992.

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