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Ritalin revisited: does it really help in neurological injury?

Abstract: Methylphenidate (Ritalin) is a commonly used central nervous stimulant. It has been used in various neurological conditions, including attention deficit disorder, depression, and narcolepsy. Methylphenidate has been advocated in patients with traumatic brain injury and stroke for a variety of cognitive, attention, and behavioral problems. It also has been shown to speed recovery from post-stroke depression so that patients can participate more fully in rehabilitation programs. Research suggests that it also may have a role in augmenting activity of injured neuronal tissue in the comatose patient, thus facilitating a return to consciousness. The neuroscience nurse plays an important role in monitoring response to Ritalin, including identifying its side effects. A review of the limited studies on the use of Ritalin, its mechanisms of action, dosing, and weaning provide a current understanding of this adjunctive agent's role in treatment for the neurological population.

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Psychostimulants such as amphetamine, dextroamphetamine (DEA), nortriptyline, and methylphenidate have been used to enhance cognition and memory, modulate behavior, and arouse the neurological population for many years. These drugs exercise a positive effect on memory and attention and control behavioral disturbances such as hyperactivity, impulsivity, and emotional lability (Challman & Lipsky, 2000). Animal research has indicated that psychostimulants can influence recovery when given at early or later time points after brain injury (Walker-Batson, Smith, Curtis, Unwin, & Greenlee, 1995). A single dose of DEA was reported to produce an enduring acceleration of motor recovery after experimental lesions in the rat (Feeney, Gonzales, & Law, 1982). Intermittent dosing (every fourth day) also helped recovery in the cat (Hovda & Feeney, 1984). A recent study showed that water maze performance was enhanced after brain-injured rats received methylphenidate (Kline, Yan, Bao, Marion, & Dixon, 2000). Findings suggest that these drugs, which enhance catecholamine neurotransmission, might be a useful adjunct in some neurobehavioral sequelae following head injury in humans (Kline et al.).

Although researchers have suggested the use of various drugs in behavioral recovery for humans, evidence for its clinical application is limited (Walker-Batson et al., 1995). Methylphenidate (Ritalin) is commonly prescribed, specifically for stroke and brain injury patients, in the neuroscience setting. However, its mode of action in humans is not completely understood; it presumably modulates the neurotransmitters dopamine, serotonin, and norepinephrine (Kimko, Cross, & Abernathy, 1999). This article discusses the clinical usefulness of Ritalin in the neurologic patient population and reviews pharmacokinetics and clinical studies from 1984 to 2000.

Pharmacokinetics and Side Effects of Ritalin

Ritalin is a mild central nervous system stimulant whose mode of action is not completely understood (Kimko et al., 1999). It causes a dose-dependent change in behavior very similar to that of amphetamine. Amphetamine is thought to increase extracellular serotonin and dopamine in the caudate putamen and norepinephrine in the hippocampus, which in turn stimulates other circuits in the brainstem and cortex. Ritalin, in comparison, is thought to cause a smaller increase in norepinephrine, has no effect on serotonin, and exerts many of its effects through dopamine uptake blockade instead of a release of dopamine (Kuczenski & Segal, 1997). One recent study suggested that Ritalin enhanced working memory by modulating the frontal and posterior parietal regions in the human brain (Mehta et al., 2000).

Ritalin is a short-acting stimulant with a 1-4 hour duration of action and a half-life of 2-3 hours. However, sustained-release formulations are now available. Because of individual variability in the dose-response relationship, dosage must be divided and titrated up for optimal effect and to avoid toxicity (Stein et al., 1996; Volkow et al., 1998). Ritalin is absorbed well from the gastrointestinal tract and easily passes to the brain. It has mild side effects as compared to amphetamine, with an onset of action of 24-48 hours as compared to 1-2 weeks for antidepressants such as nortriptyline (Kimko et al., 1999).

Adverse effects of Ritalin are related to sympathetic nervous system stimulation, especially with long-term use. These effects include nervousness, insomnia, decreased appetite, nausea and vomiting, dizziness, drowsiness, blurred vision, increased blood pressure and pulse, and rash, pruritis, and fever. Symptoms of overdose include increased agitation, tremors, muscle twitching, confusion, hallucinations, sweating, hypertension, and cardiac arrhythmias (Long, 1999).

Potential adverse effects of Ritalin are of specific concern in patients with neurological injury. An incident of stroke due to cerebral arteritis caused by Ritalin use in an 8-year-old boy (Schteinschnaider et al., 2000) was recently reported. Wang et al. (1994) demonstrated that Ritalin decreased cerebral blood flow 5-10 minutes after its administration, warning that Ritalin should be used with caution when chronically prescribing the drug for patients with cerebrovascular compromise. Clinical evidence has shown that Ritalin may lower the seizure threshold. Hence, clinicians are reluctant to use Ritalin in the brain-injured patient with seizures. However, Wroblewski, Leary, Phelan, Whyte, and Manning (1992) concluded that Ritalin could be used safely in 26 brain-injured patients with active seizure disorders and actually was associated with a trend toward a reduction rather than an increase in seizure frequency. Finally, there is a potential for abuse with any psychostimulant. Deaths have been reported from both parenteral and intranasal abuse of Ritalin (Masello & Carpenter, 1999).

Clinical Uses

Attention-Deficit/Hyperactivity Disorder and Narcolepsy

Methylphenidate is a commonly used medication in the United States. The Food and Drug Administration (FDA) has approved its use for the treatment of attention-deficit/hyperactivity disorder and narcolepsy. It is used with other remedial measures (e.g., psychological, educational, social) for a stabilizing effect in children with distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. In narcolepsy, it improves the signs and symptoms of hypersomnia and hypoarousal (Kimko et al., 1999).

Depression

Depression in the hospitalized patient who is elderly has an effect on several outcome measures, including prolonged recovery from medical illness, decreased motivation toward recovery, and noncompliance and decreased participation with medical therapy. Even though Ritalin is not FDA approved for treating depression, two early studies found the drug to be a safe and effective treatment of depression in the medically ill elderly (Koenig, Shelp, Goli, Cohen, & Blazer, 1989; Morris, Robinson, Andrzejewski, Samuels, & Price, 1993). Ritalin has an advantage over antidepressants such as nortriptyline because of its quick observable response and fewer side effects. Based on clinical data, the use of Ritalin in severe depression is cautioned, however, because it may exacerbate behavior disturbance and thought disorder symptoms. Also, the use of Ritalin with tricyclic antidepressants (TCAs) may increase side effects of these drugs (Emptage & Semla, 1996).

Use in the Neurological Patient Population

Ritalin has been used for patients with traumatic brain injury, post-stroke depression and recovery, the neurobehavioral deficits caused by brain tumors, and coma (Challman & Lipsky, 2000). These are all non-FDA-approved uses. There are limited studies involving the use of psychostimulants in the neurological patient. The current literature, which primarily consists of uncontrolled studies, dates back to 1984 and suggests a role for the use of Ritalin (Kraus, 1995).

Brain Injury

The cognitive and behavioral disturbances seen after head injury in both children and adults have been well documented in the clinical literature (Levin, Benton, & Grossman, 1982). Cognitive functions particularly vulnerable to head injury are memory and attentional and intellectual skills. It is common for patients with moderate to severe head injury to display behavioral disturbances, such as impulsivity and hyperactivity, after injury, and then to be treated with psychiatric medications such as antiepileptic drugs, neuroleptics, TCAs, and lithium to control neurobehavioral sequalae. However, these drugs can have an adverse effect on cognition, memory, and attention by blocking re-uptake of norepinephrine and serotonin (Evans et al., 1987).

Thus, attention has turned to psychostimulants for behavior control in the head-injured population, based on the positive effects already seen in animal studies (Boyeson, Krobert, Grade, & Scherer, 1993; Goldstein & Davis, 1990; Hovda & Feeney, 1984; Hurwitz, Dietrich, McCabe, Alonson, & Watson, 1991; Jonason, Lauber, Robbins, Meyer, & Meyer, 1970; Sutton & Feeney, 1992). Psychostimulants in brain-injured rats and cats showed an increase in metabolic activity in regions surrounding the site of injury with the addition of tactile stimulation, an increase in cortical excitability, and, in rats, an increase in synaptogenesis and sprouting.

The rationale for psychostimulant use for individuals with brain injury dates back to Luria, Naydin, and Tesvetkova (1968). Drug treatment was used for the psychopathic symptoms that sometimes follow brain injury such as depression, psychosis, or aggression; drugs were used to correct the cognitive deficits like inattention and memory problems; the dopamine agonists enhanced the course of cortical recovery. Positive effects are apparent within days or within hours after an optimal dose is achieved. Methylphenidate (MPH) and DEA are the stimulants most frequently prescribed (Gualtieri & Evans, 1988).

Another rationale for the use of psychostimulants following brain injury is the effect of the drug on attention deficit hyperactivity disorder. This stimulant improves problems of inattention, distractibility, disorganization, hyperactivity, impulsiveness, and emotional lability in children and adults; similar problems are seen in the brain-injured population. Ritalin probably exercises a therapeutic effect by modulating or enhancing dopaminergic neurotransmission to rostral and axial brain structures, especially in the frontal neocortex and axons. Therefore, Ritalin may be especially beneficial for the patient with injuries to the frontal lobe and brain stem, the most common sites of head injury (Gualtieri & Evans, 1988).

Clinical studies on the use of Ritalin in pediatric traumatic brain injury (TBI) are limited and conflicting (Table 1). A retrospective review of 10 children with mild to severe TBI showed that Ritalin appeared to be an effective treatment for post-TBI cognitive and behavioral sequelae, as well as improved arousal in one minimally responsive brain-injured child (Hornyak, Nelson, & Hurvitz, 1997). However, a controlled study of 10 children who received Ritalin 8 months to 2 years after TBI showed no significant differences between Ritalin and placebo when assessing behavior, attention memory, and processing speed. Ritalin may not be effective so long after injury; the therapeutic window is considered to be 30 days in most of the literature (Williams, Ris, Ayyangar, Schefft, & Berch, 1998).

Clinical studies on the use of Ritalin in the adult brain injury population are more numerous (Table 1). The first reported study (Evans, Gualtieri, & Patterson, 1987) was with a 21-year-old male 2 years after TBI. MPH and DEA were administered in separate low- and high-dose trials of the psychostimulants. This case study showed better cognitive and behavioral responses to the higher dose and positive improvements in verbal memory, learning skills, and ability to maintain attention at school 1 week later. Because DEA has a higher potency than Ritalin, the patient was maintained on DEA for a "sustained" effect (Evans et al.).

In another adult study (N = 15), participants received either a low or high dose of Ritalin or a placebo and were evaluated at baseline, 12 days, monthly, and 1 year after administration (Gualtieri & Evans, 1988). Participants were between 5 months and 12 years after the injury. Fourteen participants reported that the drug was superior to placebo and that they experienced improved mood; increased performance at work, school, or household tasks; greater alertness and organization; and better memory. Over the course of the year, scores improved on the Adult Activity Scale, mood, cooperation, selective reminding, and Digit symbols. It was hypothesized that the drug changed the "responsiveness" of the neurons to enhance the natural recovery process (Gualtieri & Evans). After drug withdrawal, one patient deteriorated 4 weeks later. Because of the limited number of patients who remained on the drug for a year (n = 3), the long-term efficacy of Ritalin is questionable.

Because anger and temper outbursts can be serious problems after brain injury, Mooney and Haas (1993) specifically looked at the effects of Ritalin on brain injury-related anger. This randomized study of 38 males who had suffered serious brain injuries and who were beyond the period of rapid, spontaneous recovery received either 30 mg/day of Ritalin or placebo for 6 weeks. Results suggested that Ritalin helped with anger and memory, but did not have any effect on attention (Mooney & Haas). Another double-blind, placebo-controlled study on 12 individuals 1-8 years after TBI showed that Ritalin did not have any effects on most aspects of sustained attention or measures of motor speed; significant improvement, however, was seen in the speed of mental processing (Whyte et al., 1997).

Kaelin, Cifu, and Matthies (1996) examined the effects of Ritalin in the more acute stage of brain injury (1-11 weeks) and concluded that Ritalin was well tolerated. Participants who received Ritalin demonstrated a significant improvement in attention compared to those in natural recovery in a rehabilitation setting and had a quicker functional recovery as measured by the Disability Rating Scale (Kaelin et al.). These authors advocated the use of Ritalin in the early post-injury phase. This is the time when cerebral edema resolves, neurotransmitter levels stabilize, and new synapses form, allowing the recovering brain to be the most susceptible to therapeutic interventions such as psychostimulants (Kaelin et al.).

One double-blind, placebo-controlled study of 12 patients, 1-8 years after head injury, did not support the use of Ritalin in the treatment of head injury patients (Speech, Rao, Osmon, & Sperry, 1993). No significant differences in attention, learning, and cognitive processing speed were found between Ritalin and placebo. The authors concluded that head injury may produce permanent, disabling changes in cognitive and social behavior; the more chronic the head injury, the less chance of Ritalin being effective (Speech et al.).

In summary, the use of Ritalin for the brain-injured population may be beneficial more so in adults. There are differences in positive effects based on when treatment was begun after injury (i.e., acute versus chronic). Perhaps in the acute stage of recovery. Ritalin as a stimulant acts to "jump start" cortical recovery. Studies have not been able to show Ritalin's long-term efficacy. More well-designed studies are also needed for the pediatric brain injury population.

Post-stroke Depression

Depression is a major problem for stroke survivors. Its prevalence has been found to be 30%-50%, increasing between 6 months and 2 years following stroke to 60% (Beckson & Cummings, 1991; Robinson, Starr, & Price, 1984). Depression is especially problematic because it interferes with the rehabilitation process and can affect the interpersonal relationships already altered by the stroke. Treatment modalities include antidepressants, electroconvulsive therapy (ECT), and the use of psychostimulants such as Ritalin and DEA (Masand, Murray, & Pickett, 1991). Animal studies suggest that stroke-induced lesions produce widespread depletion of biogenic amines, which tricyclic antidepressants and Ritalin can possibly correct (Lipsey, Robinson, Pearigin, Rad, & Price, 1985; Robinson, Shoemaker, Schlumpf, & Coyle, 1975).

The suggestion that Ritalin was an effective treatment for post-stroke depression was first seen in the literature in anecdotal case reports (Table 2). When elderly patients with post-stroke depression were given Ritalin, family members or caregivers reported decreased depression (Kaufman, Cassem, Murray, & Jenike, 1984). Retrospective studies followed. A retrospective chart review on 25 patients who were treated with Ritalin for post-stroke depression within 2 years of their stroke was conducted by Lingam, Lazarus, Groves, and Oh (1988). Thirteen (52%) of the patients responded rapidly (within 48 hours) and completely recovered from their major depression. Another retrospective study of 17 patients who were treated with either Ritalin (n = 6) or DEA (n = 11) during a 5-year period indicated that 82% of the patients showed at least some improvement; 47% were rated as markedly (i.e., complete/near complete remission of all depressive symptoms) or moderately improved (i.e., improvement but without complete remission; Masand et al., 1991). The patients improved quickly, usually within the first 2 days of treatment. The authors found no significant differences in efficacy between the two psychostimulants (Masand et al.).

Johnson, Roberts, Ross, and Witten (1992) reviewed the records of 10 patients treated with Ritalin for post-stroke depression during an inpatient rehabilitation program over a 9-month period. All patients received concomitant supportive psychotherapy. Seven of the 10 patients showed clinical improvement; 4 of the patients were discharged home on Ritalin. Each patient who improved also was described as having an attention-deficit disorder; improvement in mood and attention span were the earliest responses to therapy (Johnson et al.).

A retrospective comparison of Ritalin and nortriptyline on 28 patients with major post-stroke depression revealed that 53% of the Ritalin patients experienced complete remission of depressive symptoms, as compared to 43% of the patients in the nortriptyline group (Lazarus, Moberg, Langsley, & Lingam, 1994). The speed of response was significantly better in the Ritalin group (2.4 days) compared to 27 days for the nortriptyline group. The authors concluded that the rapid effects of Ritalin may be especially useful to speed recovery from depression so that patients can participate more fully in rehabilitation programs (Lazarus et al.).

Another later report of a 76-year-old patient with post-stroke depression confirmed that Ritalin markedly improved the patient's depression (Masand & Chaudhary, 1994). Only one controlled study on the effects of Ritalin on post-stroke depression is documented in the literature. Ten patients who met the DSM-III-R criteria for major depression were given two doses of Ritalin (morning and noon). A total of 80% of the patients showed either a full (50%) or partial (30%) treatment response within 2 weeks of treatment. No adverse effects were reported (Lazarus et al., 1992).

In summary, the use of Ritalin for post-stroke depression appears to either totally or partially relieve depressive symptoms. Its rapid effects and few side effects may be especially useful in speeding recovery from depression so that patients can participate more fully in rehabilitation programs. However, further controlled studies are needed.

Post-stroke Recovery

Stroke recovery encompasses motor as well as cognitive aspects. Both animal and human research studies have indicated potential benefits with the use of psychostimulants to enhance stroke recovery. The first studies looked at recovery from brain lesions in cats and rats with amphetamine. The animals showed an enduring acceleration of motor recovery when amphetamine was administered days to weeks after injury (Feeney et al., 1982).

The first reported human trials, which specifically looked at motor recovery, were done with the psychostimulant amphetamine. Hemiplegic stroke patients who received a single dose of amphetamine 45 minutes before intensive physical therapy scored 40% better on a standardized motor scale than those on placebo. The patients were studied during the acute period (<10 days after stroke onset) but were followed for only 24 hours (Crisostomo, Duncan, Propst, Dawson, & Davis, 1988).

Walker-Baston et al. (1995) conducted a randomized, placebo-controlled study on 10 patients with severe motor deficits in the subacute period (16-30 days). They were given DEA or placebo every fourth day, paired with physical therapy. Recovery rate was accelerated, and their final level of motor recovery was increased as assessed by the Fugl-Meyer Motor Scale. The increase in motor recovery was significant 1 week after the drug session was begun and was maintained at the 12-month follow-up. The authors concluded that the use of psychostimulants might allow the nervous system to adapt unused or alternative pathways.

The use of Ritalin specifically for motor recovery from stroke (Table 2) was first evaluated in 1998 (Grade, Redford, Chrostowski, Toussaint, & Blackwell, 1998). A randomized, double-blind, placebo-controlled study included 21 stroke patients in a rehabilitation setting. Patients received a 3-week treatment of Ritalin or placebo in conjunction with physical therapy; starting at a 5mg dose, gradually increasing to 30 mg, and then tapering off before discharge. Outcome measures assessed weekly included depression, cognitive status, and motor functioning. Patients receiving Ritalin scored lower on the Hamilton Depression Rating Scale (p = .028) and higher on both the Functional Independence Measure (p = .032) and Fugl-Meyer Motor Scale (p = .075) with few side effects. Results of this study indicated that Ritalin was a safe and effective adjunct treatment for the rehabilitation of acute stroke patients (Grade et al.).

A recent study by Unwin and Walker-Batson (2000) also confirmed the safety of amphetamine administration in stroke rehabilitation. Forty-four patients with hemiplegia and/or aphasia 16-42 days after stroke onset were given either 10 mg of amphetamine or placebo every third to fourth day. Thirty minutes after drug/placebo administration, patients were started on physical and/or language therapy, depending on their deficits, for a total of 10 sessions. Blood pressure measurements in the amphetamine-treated patients were compared with those in the placebo-treated patients. Results showed no significant difference from baseline to within 90 minutes of therapy sessions on either systolic or diastolic measurements. Results confirmed limited side effects of amphetamine (Unwin & Walker-Batson).

Only amphetamine has been studied for its effects in promoting recovery of speech and language deficits following stroke. Three studies have been done to explore the long-term effects of amphetamine administration. Between days 16 and 30 after stroke onset, patients received either amphetamine or placebo every fourth day for 10 sessions, paired with speech therapy. Results indicated that amphetamine enhanced recovery from language deficits with no side effects (Walker-Batson, Curtis, Wolf, & Porch, 1996; Walker-Batson, Devous, Curtis, Unwin, & Greenlee, 1990; Walker-Batson et al., 1992).

The effects of Ritalin specifically on other stroke-related cognitive deficits have been studied, although to a limited degree (Table 2). A patient with apathy secondary to multiple subcortical infarcts was treated successfully with Ritalin. Single photon emission computed tomography (SPECT) and reaction time testing during treatment showed improvement of frontal system function (Watanabe et al., 1995).

The usefulness of Ritalin versus placebo in the treatment of organic amnesia for patients with stroke lesions (n = 2) was assessed with a neuropsychological battery of tests. However, no significant benefit of Ritalin was seen in any of the cognitive tests (Tiberti, Sabe, Jason, Leiguarda, & Starkstein, 1998).

In summary, Ritalin appears to be a safe and effective intervention in early post-stroke rehabilitation that may expedite recovery. It offers the advantage of mild side effects and immediate onset of action. However, more controlled studies are needed, because they are limited.

Brain Tumors

Patients with malignant glioma develop progressive neurobehavioral deficits, caused by the disease itself as well as by radiation and chemotherapy. Two studies investigated whether Ritalin treatment could improve the patients' neurobehavioral functioning despite their neurological deterioration (Table 3). In the first study, three patients with a primary brain tumor and with impairments of arousal and psychomotor speed benefited from this stimulant therapy, as evidenced by an increase in wakefulness and participation in activities of daily living (Weitzner, Meyers, & Valentine, 1995).

In the second study of 30 patients with primary brain tumors, significant functional improvements were seen with a 10-mg twice-daily dose (Meyers, Weitzer, Valentine, & Levin, 1998). Improvements included improved gait, increased stamina, and motivation to perform activities and in one patient, increased bladder control. The authors concluded that Ritalin, although not a cure, should be more widely considered as an adjunct to brain tumor therapy to help with the debilitating effects of the disease (Meyers et al.).

Coma

The efficacy of the use of Ritalin in the treatment of coma has been reported in the literature in two case studies: the first patient was comatose from a traumatic brain injury and the second patient was in a comatose state secondary to a subdural hematoma that occurred after a fall (Table 3). The first patient was a 19-year-old male who was transferred to a nursing home with a Glasgow Coma Scale (GCS) score of 8, minimally responsive to pain (Worzniak, Fetters, & Comfort, 1997). The patient was started on Ritalin 10 mg twice a day. Within 24 hours there was a dramatic improvement in the patient's level of consciousness; he appeared more alert, his pupils were more active and he exhibited other spontaneous movements (GCS = 10). The dosage was increased to 20 mg twice a day; and he began responding to voice commands (GCS = 14). On day 9 of treatment, the patient began to feed himself and was able to briefly stand on his own and transfer into a chair. After 18 days of treatment, he was verbal, ambulatory; and following commands (GCS = 15). He was transferred to a head injury facility for more intensive speech and physical therapy (Worzniak et al., 1997).

The second case report was a 89-year-old woman who transferred to a long-term-care home, totally unresponsive, requiring total care (GCS = 3). Six days after the initiation of Ritalin 5 mg twice a day; the patient exhibited spontaneous eye movement and spoke a few words (GCS = 10). On day 15 of treatment, the GCS was 14. On day 27 of treatment, dosage was increased to 10 mg twice a day; with the patient becoming more alert (GCS = 15) and in contact with her surroundings. Further improvement occurred after the dosage was increased to three times a day. The feeding tube was removed, she was fed orally, and she could sit in a chair and converse (Worzniak et al., 1997).

Even though these case reports are limited, the authors concluded that treatment with Ritalin might provide neurostimulation by augmenting the activity of injured neuronal tissue within the reticular activating system. Furthermore, it may be a low-cost, potentially effective intervention for reducing coma duration, for preventing life-threatening and costly complications, and for promoting early ambulation and recovery. However, further research on this neurological population using more rigorous research designs is needed (Worzniak et al., 1997).

The Neuroscience Nurse's Role in Treatment

In general, Ritalin appears to be a reasonable treatment choice for certain types of mood, behavior, and cognitive symptoms following neurological injury. However, larger scale, controlled studies are needed to adequately assess the clinical usefulness of this drug. Also, each neurological event is different. The clinical studies reviewed were limited and the sample sizes were small; very few were controlled. Different psychostimulants, as well as various dosages, were used, and the drugs were administered at different times of recovery. Various and different outcome measures also were used. All of this makes the generalizability of the clinical results difficult.

Ritalin continues to be prescribed as adjunct therapy in both the acute and subacute rehabilitation settings. So what can the neuroscience nurse learn from these studies? Ritalin can be administered in the acute or subacute stage, perhaps in the earlier stages of recovery. However, the therapeutic window is considered to be 30 days after injury. If there is no improvement in 1 month, discontinuation of the drug should be considered (Kaelin et al., 1996). Nurses also must be knowledgeable that Ritalin can be used in patients with various neurological injuries and what side effects to watch for.

There are no clear guidelines established for daily dosage of Ritalin. It is not recommended for children younger than 6 years. Long-term efficacy and the side effect profile in the pediatric population have not been established. In the adult, gradual titration of dosage with close monitoring of side effects is essential due to Ritalin's variability in dose response.

Multiple administrations versus single are better. Divided doses, starting at 5 mg twice a day and gradually increasing to 5-10 mg every 2 days, are recommended. The daily average dose is 20-30 mg, but some patients tolerate and require 40-60 mg per day; a daily dosage of >60 mg is not recommended because of the possibility of sympathetic nervous system overstimulation (Stein et al., 1996; Volkow et al., 1998).

With each increase in dose, the neuroscience nurse should monitor the patient's tolerance to the drug. Any side effects such as nausea, vomiting, nervousness, hypotension, or headache must be reported to the physician, so the dose can be reduced or the second dose omitted. Because of Ritalin's stimulating effects, doses should be spaced and should not be administered after 6 pm (Long, 1999). With discontinuation, it is also recommended that the patient be weaned off the drug because severe depression can be unmasked. The time of administration should coincide with periods of greatest activity of the patient (e.g., 30-60 minutes before therapies or academic or behavioral executions). Ritalin is extensively absorbed after oral administration within minutes, peaking at 2 hours (Kimko et al., 1999).

Patients with an element of agitation may react adversely to Ritalin; it is also not recommended for patients with severe, underlying depression (Emptage & Selma, 1996). Ritalin should be used cautiously with pressor agents and MAO inhibitors. Because Ritalin may inhibit anticoagulant, antidepressant, and anticonvulsant metabolism, it is important to monitor therapeutic levels and increase the dosage of these drugs as necessary. Laboratory monitoring such as complete red blood cell (CBC) and platelet count is advised during prolonged therapy (Long, 1999).

New Approaches

A new wakefulness-promoting agent, modafinil (Provigil), has recently been used on the neurological population. It is similar to MPH and amphetamine but has fewer side effects. Even though it has been approved for narcolepsy only, it has been shown to significantly improve fatigue associated with multiple sclerosis and depression (Menza, Kaufman, & Castellanos, 2000; Rammohan, Rosenberg, Pollak, Lynn, Blumenfeld & Nagaraja, 2000; Terzoudi, Gavrielidou, Heilakos, Visviki, & Karageorgiou, 2000).

Modafinil's mechanism of action is unknown; it supposedly works by increasing the neuronal activation in the hypothalamus-cortical pathways. It does not cause the widespread central nervous system stimulation seen in Ritalin and has a low potential for abuse. Dosage is one time, 200 mg, in the morning. Side effects, which are minimal, include headache, nausea, vomiting, and anxiety (Cochran, 2001).

Two recently published studies show some promising benefits of modafinil on other neurological diseases. In a retrospective review of 25 patients with Alzheimer's, stroke, multiple sclerosis, Parkinson's disease, head injury, and brain tumor who received modafinil for the treatment of fatigue, Cochran (2001) showed modafinil was effective in 84% of the patients. It was well tolerated even when used in combination with other medications such as Ritalin. However, the author concluded that the potential for an interaction of modafinil with other drugs used for the treatment of neurological diseases has not been fully determined. The second study looked at the effect of modafinil on the treatment of excessive daytime sleepiness associated with brain injury. Increased wakefulness, attention, and other cognitive benefits were seen in 10 patients within 1-2 hours of taking modafinil (Teitelman, 2001).

Summary

Limited controlled studies have shown that Ritalin helps enhance cognition, attention, behavior, and recovery for a variety of neurological conditions. Its immediate action and limited side effects make it the drug of choice over antidepressants and more potent psychostimulants such as amphetamine. Even though there are no standardized treatment protocols or outcome measures established, the literature does show Ritalin's benefits in enhancing recovery for the neurological patient. More controlled studies are needed, however, especially in comparison with the new wakefulness-producing drug modafinil. At this time Ritalin cannot claim to change the result, but perhaps it can help get the patient there faster.
Table 1. Review of the Literature: Use of Ritalin in Brain Injury
in Pediatric and Adult Populations

 Reference Sample Design

 Brain Injury: Pediatric

Hornyak, Nelson, 10 children; mild to Retrospective chart
& Hurvitz, 1997 severe traumatic brain review; outcome
 injury (TBI); given measures: parent/
 Ritalin teacher reports,
 evaluation by in- out-
 patient rehabilitation
 team

Williams, Ris, 10 children; mild to Double-blind placebo-
Ayyangar, severe TBI; 8 months-2 controlled, crossover
Schefft, & years post-injury; trial; outcome
Berch, 1998 given Ritalin or measures: Conner's
 placebo Hyperactivity Index and
 Verbal Intelligence
 Quotient

 Brain Injury: Adult

Evans, Gualtieri, 21-year-old male; Case report, medication
& Patterson, 1987 moderate head injury; trial, which was
 2 years post-injury; double-blind, placebo-
 given Ritalin 0.15 controlled, dose-
 or 0.30 mg/kg or response; outcome
 Dexedrine 0.10-0.20 measures: Adult
 mg/kg or placebo Activity Scale (AAS),
 Neuropsychological
 Battery

Gualtieri & 15 mild to moderate Double-blind,
Evans, 1988 closed head-injured randomized, placebo-
 (CHI) patients, 5 to 12 controlled, crossover
 months post-injury; study; outcome
 given Ritalin 0.15 measures: San Diego
 mg/kg or 0.30 mg/kg Battery, AAS, self-
 twice a day or placebo rating scale (at
 baseline, 12 days,
 monthly, and 1 year)

Mooney & Haas, 38 males with severe Randomized, pretest,
1993 CHI; given Ritalin 30 posttest, placebo-
 mg/day or placebo for controlled, single-
 6 weeks blind study; outcome
 measures: anger
 outcome measures

Whyte et al., 12 individuals, 1-8 Double-blind, placebo-
1997 years after TBI given controlled, repeated
 Ritalin 0.3 mg/kg crossover study; out-
 twice a day or placebo come measures: tasks
 measuring attentional
 function

Kaelin, Cifu, & 11 individuals, 1-11 Prospective multiple
Matthies, 1996 weeks after TBI; given baseline study
 Ritalin 15 mg twice a (A-A-B-A); outcome
 day or placebo measures: 9
 neuropsychological
 subtests, Disability
 Rating Scale, pre and
 post

Speech, Rao, 12 chronic CHI Double-blind,
Osmon, & Sperry, individuals; given randomized, placebo-
1993 Ritalin or placebo controlled, crossover
 study; outcome
 measures: cognitive
 tests of attention,
 learning and cognitive
 processing speed

 Reference Results Implications

 Brain Injury: Pediatric

Hornyak, Nelson, Improved cognition, Effective treatment
& Hurvitz, 1997 behavior; improved after TBI for cognitive
 arousal in minimally and behavioral sequelae
 responsive child

Williams, Ris, No significant Calls into question
Ayyangar, differences between effectiveness of
Schefft, & Ritalin and placebo on Ritalin in pediatric
Berch, 1998 measures assessing head injury population
 behavior, attention,
 memory, and processing
 speed

 Brain Injury: Adult

Evans, Gualtieri, Best improvement with Same positive response
& Patterson, 1987 higher dose of either to either drug, but
 drug in verbal memory patient was maintained
 and learning skills, on Dexedrine due to its
 ability to maintain "sustained" reaction
 sustained attention
 and overall behavior

Gualtieri & 14 of 15 with improved Stimulants may act to
Evans, 1988 subjective measures enhance the course of
 of mood, better cortical recovery
 performance at work/ following brain injury;
 school, more alert, long-term use is
 organized, even- questionable
 tempered; 10 of 15
 improved objective
 measures of behavior,
 mood, memory, attention

Mooney & Haas, Ritalin helped with Ritalin has minimal or
1993 anger and memory; no absent cognitive
 effect on attention toxicity and is well
 tolerated by head-
 injured individuals

Whyte et al., Improvement in the Ritalin may be useful
1997 speed of mental for symptoms attributed
 processing; no effect to slowed mental
 on sustained attention processing
 and motor speed

Kaelin, Cifu, & Digit Span, Mental Ritalin is well
Matthies, 1996 Control and Symbol tolerated and
 Search improved; participants
 improvement in demonstrated a
 Disability Rating significant improvement
 Scale scores in attention

Speech, Rao, No significant Does not support the
Osmon, & Sperry, differences between clinical use of Ritalin
1993 Ritalin and placebo in the treatment of
 closed head injury

Table 2. Review of Literature: Use of Ritalin in Patients with Stroke

 Reference Sample Design

 Stroke: Depression

Kauffman, Cassem, Elderly patients with Anecdotal case reports;
Murray, & post-stroke depression; outcome measures:
Jenike, 1984 received Ritalin caregiver report

Lingam, Lazarus, 25 patients who met Retrospective chart
Groves, & Oh, DSM-III-R criteria for reviews; placed in
1988 major depression with groups of responders
 onset within 2 years of (complete remission)
 given Ritalin 20 mg/day and nonresponders
 for 5 days (partial, no, or
 worsening of symptoms)

Masand, Murray, 17 patients with Retropective chart
& Pickett, 1991 depression 2 weeks-10 reviews; categorized as
 years post-stroke; markedly improved
 given Dexedrine or (complete or nearly
 Ritalin complete remission of
 depressive symptoms) or
 moderately improved

Johnson, Roberts, 10 patients with post- Retrospective chart
Ross, & Witten, stroke depression given review; outcome
1992 Ritalin 5-15 mg twice measures:
 a day for 5 days to 1 subjective measurement
 month along with of response by
 psychotherapy psychiatrist

Lazarus, Moberg, Patients who met Retrospective chart
Langsley, & DSM-III-R criteria review; outcome
Lingam, 1994 for major depression, measures: subjective
 given Ritalin (N = 28) measurement of
 or Pamelor (N = 30) remission of depressive
 symptoms, speed of
 response

Masand & 76-year-old male with Case report; outcome
Chaudhary, 1994 post-stroke depression measures: subjective
 given Ritalin measurement of

Lazarus et al., 10 poststroke patients Controlled study;
1992 who met DSM-III-R outcome measures:
 criteria for major Hamilton Rating Scale
 depression; given for Depression (HAM-D),
 Ritalin 10-40 mg/day side effects checklist

 Stroke: Motor Recovery

Grade, Redford, 21 post-stroke Randomized, double-
Chrostowski, patients; given Ritalin blind, placebo-
Toussaint, & 30 mg twice a day or controlled study;
Blackwell, 1998 placebo for 3 weeks in outcome measures:
 conjunction with Hamilton Depression
 physical therapy Rating Scale (HAM-D)
 and Zung Self-Rating
 Depression Scale (ZDS),
 Mini-Mental State Exam
 (MMSE), Fugl-Meyer
 Scale (FMS), Functional
 Independence Measure
 (FIM) instrument, side
 effects checklist

 Stroke: Cognition

Watanabe, Martin, One patient with apathy Case report; outcome
Deleon, Gaviria, secondary to multiple measures: reaction time
Pavel, & subcortical infarcts, testing, SPECT scan
Trepashko, 1995 given Ritalin

Tiberti, Sabe, Four patients with Randomized, double-
Jason, Leiguarda, amnesia due to stroke, blind, placebo-control-
& Starkstein, given Ritalin (10, 20, led study; outcome
1998 30 or 40 mg) or placebo measures: neuropsycho-
 logical battery

 Reference Results Implications

 Stroke: Depression

Kauffman, Cassem, Family/caregiver Stimulants (Ritalin)
Murray, & reports of decreased are effective in elder
Jenike, 1984 depression patients with
 poststroke depression

Lingam, Lazarus, 52% with complete Ritalin may be a
Groves, & Oh, recovery within 48 valuable treatment for
1988 hours post-stroke depression
 because of its rapid
 response and lack of
 significant side
 effects

Masand, Murray, Overall 82% showed Psychostimulants appear
& Pickett, 1991 improvement, 47% with to be a safe and
 marked or moderate rapidly effective
 improvement alternative to
 tricyclic
 antidepressants

Johnson, Roberts, 7 of 10 with improved Ritalin in the
Ross, & Witten, mood, depression, treatment of poststroke
1992 attention within 1-4 depression merits
 days further study

Lazarus, Moberg, Ritalin group: 53% with The rapid effects of
Langsley, & remission in 2.4 days; Ritalin may be useful
Lingam, 1994 Pamelor group: 43% with to speed recovery from
 remission in 27 days depression so that
 patients can
 participate more fully
 in rehabilitation
 programs

Masand & Markedly improved Psychostimulants are
Chaudhary, 1994 depression depressive effective in post-stroke
 symptoms patients with depression

Lazarus et al., >50% with reduction in Ritalin is a safe and
1992 HAM-D scores within effective treatment for
 1-2 weeks of receiving post-stroke depression
 Ritalin; 25% with
 partial response; no
 adverse side effects

 Stroke: Motor Recovery

Grade, Redford, Patients receiving Ritalin is a safe and
Chrostowski, Ritalin scored lower on effective adjunct
Toussaint, & the HAM-D and ZDS, treatment for the
Blackwell, 1998 higher on the FIM and rehabilitation of acute
 FMS instruments; no stroke patients as it
 difference in the MMSE showed improvements in
 between Ritalin and mood, ability to
 placebo; no significant conduct activities of
 side effects daily living, and motor
 functioning

 Stroke: Cognition

Watanabe, Martin, Showed selective impro- Ritalin may improve
Deleon, Gaviria, vement of frontal subcortical circuits
Pavel, & system function with and behavior in the
Trepashko, 1995 increase in reaction patient with multi-
 time testing infarct apathy

Tiberti, Sabe, No significant benefit Not effective for
Jason, Leiguarda, of Ritalin for any of organic amnesia
& Starkstein, the cognitive tests following stroke;
1998 warrants further study

Table 3: Review of Literature: Use of Ritalin in Patients with
Brain Tumors or in Coma

 Reference Sample Design

 Brain Tumors

Weitzner, Myers, 3 patients with glio- Case report; subjective
& Valentine, 1995 blastoma multiform responses
 brain tumor related
 organic brain dysfunc-
 tion;, given Ritalin

Meyers, Weitzner, 30 patients with prima- Pre- and post-test
Valentine, & ry brain tumors, neuropsychological
Levin, 1998 treated with Ritalin assessment, ability to
 function in activities
 of daily living

 Coma

Worzniak, Fetters, 19-year-old male in Case reports; outcome
& Comfort, 1997 semi-comatose state measures: Glasgow Coma
 after closed head Scale (GCS), subjective
 injury, 89-year-old functional improvements
 female in comatose
 state after fall; given
 Ritalin 20 mg three
 times a day or 10 mg
 twice a day

 Reference Results Implications

 Brain Tumors

Weitzner, Myers, Improved Ritalin can alleviate
& Valentine, 1995 some of the observed
 psychomotor retardation
 seen in brain tumor
 patients undergoing
 treatment

Meyers, Weitzner, Significant improvement Ritalin should be more
Valentine, & in cognitive function, widely considered as
Levin, 1998 improved gait, adjuvant brain tumor
 increased stamina and therapy
 motivation, and
 increased bladder con-
 trol in one patient

 Coma

Worzniak, Fetters, Patient 1: GCS 8 [right Ritalin is a low-cost
& Comfort, 1997 arrow] 15 and Patient effective intervention
 2: GCS 3 [right arrow] for reducing the dura-
 15 tion of coma, and for
 preventing complications


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Questions or comments about this article may be directed to: Marylyn Kajs-Wyllie, MSN RN CCRN CNS, via e-mail at marylyn.kajswyllie@stdavids.com or by phone at 512/404-8564. She is a neuroscience clinical nurse specialist at the Neuroscience Center at St. David's Medical Center, Austin, TX.
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