NEUROLOGICAL REVIEW Potential Effects of Common Drugs on Recovery

Larry B. Goldstein, MD

tudies in laboratory animals clearly show that the rate and extent of functional recovery after focal brain injury can be modulated by drugs affecting certain neurotransmitters in the central nervous system. Preliminary clinical studies suggest that similar drug ef- fects occur in humans recovering from stroke. Understanding these pharmacological ef- fectsS is important because several of the classes of drugs that impair recovery in laboratory experi- ments are used to treat coincident medical problems in patients who have had a stroke. Arch Neurol. 1998;55:454-456

Clinicians have long recognized that most to the cerebral cortex and cerebellum, also stroke survivors recover over time, albeit impair motor recovery after a subsequent to varying degrees. Although the initial se- unilateral cortical lesion. verity of the patient’s neurologic deficit is Several areas of the brain may be in- the single most powerful predictor of even- volvedinmediatingtheeffectsofnorepineph- tual functional status, a variety of other fac- rine. Unilateral injury to the cerebral cortex tors can affect the final levels of impair- in rats results in a bilateral reduction of ex- ment, disability, and handicap resulting tracellularlevelsofnorepinephrineinthecer- from stroke. Findings from experiments ebellum,andinfusionofnorepinephrineinto performed in the laboratory seem to indi- thecerebellarhemispherecontralateraltobut cate that the rate and degree of recovery not ipsilateral to the side of a cortical lesion can be affected by certain neurotransmit- enhances motor recovery. In addition, selec- ters in the central nervous system (CNS). tive creation of a lesion of the contralateral Because many of the drugs used to treat but not ipsilateral dorsal noradrenergic coincident medical problems in patients bundle (through which fibers from each lo- who have had a stroke affect the CNS, these cusceruleusprojecttothecerebralcortexand drugs also may have an unrecognized ef- subcortical structures) impairs motor recov- fect on the recovery process. ery after a subsequent cortical lesion.4 Thus, Motor function is one of the most im- these experiments are consistent not only portant determinants of the level of post- with the hypothesis that motor recovery af- stroke independence in activities of daily liv- ter damage to the cerebral cortex is, at least ing. Several lines of evidence suggest that inpart,modulatedthroughtheeffectsofnor- motor recovery after injury to the cerebral epinephrine on the CNS but also with the cortex can be modulated through the ef- hypothesis that the effects of norepineph- fects of on the CNS. De- rine may be mediated in the contralateral tailed reviews have been published.1-3 For cerebral and cerebellar hemispheres. example, in rats, central infusion of norepi- These studies were designed in con- nephrine hastens locomotor recovery after junction with a complementary series of a unilateral sensorimotor cortex lesion. In experiments in which the levels of norepi- contrast, the administration of DSP-4 [N- nephrine in the CNS or its effects were ma- (chloroethyl)-N-ethyl-z-bromobenzyl- nipulated pharmacologically (Table). In a amine], a that leads to the deple- provocative initial experiment, Feeney and tion of norepinephrine in the CNS, has the Sutton1 found that, when combined with opposite effect and delays the recovery pro- task-relevantexperience,asingledoseofdex- cess. In addition, bilateral or unilateral se- troamphetamine given the day after a uni- lective lesions of the locus ceruleus, the ma- lateral sensorimotor cortex ablation in the jor source of noradrenergic projection fibers rat resulted in an enduring enhancement of motor recovery. The amphetamine effect From the Departments of Medicine () Veterans Affairs Medical Center and found by Feeney and Sutton was extended Center for Clinical Health Policy Research, Duke University, Durham, NC. to functional deficits that occur after focal

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 lesions produced through a variety of mechanisms, to le- sions affecting other areas of the cortex, and to other be- Selected Laboratory and Clinical Studies of Drug Effects haviors. Given the hypothesis that the effect of amphetamine on Recovery After Focal Brain Injury* on recovery is exerted through its effect on norepinephrine, Recovery Effect other drugs that enhance the release of norepinephrine or Transmitter or decrease its metabolism would be expected to be beneficial. Drug Class/Drug Action Laboratory Clinical In fact, yohimbine and idazoxan (␣2-adrenergic receptor Norepinephrine bitartrate . . . + . . . antagonists that increase the release of norepinephrine in Amphetamine sulfate Sympathomimetic + +/Neutral the CNS) facilitate motor recovery when given as a single Phentermine Sympathomimetic + . . . dose after unilateral sensorimotor cortex injury. Phenter- Phenylpropanolamine Sympathomimetic + . . . mine, an amphetamine analog with weaker cardiovascu- Methylphenidate Sympathomimetic + ? Yohimbine ␣ -AR antagonist + . . . lar effects, phenylpropanolamine, and methylphenidate 2 Idazoxan ␣2-AR antagonist + . . .

hydrochloride also accelerate motor recovery after experi- ␣2-AR agonist − (−)

mental focal brain injury. Haloperidol ␣1-AR antagonist − (−) If drugs that enhance norepinephrine release are ben- Prazosin ␣1-AR antagonist − (−) eficial, then drugs that decrease norepinephrine release, Propranolol ␤-AR antagonist Neutral . . . increase its metabolism, or block its postsynaptic effects GABA . . . − . . . GABA agonist − (−) would be hypothesized to be harmful. In experiments de- Muscimol GABA agonist − . . . signed to test this hypothesis, a single dose of the ␣2- Antiepileptic drugs adrenergic receptor agonist clonidine hydrochloride, given Phenytoin . . . − (−) the day after cortex injury, was found to have a pro- Phenobarbital . . . − . . . longed detrimental effect on motor recovery in rats and Dizocilpine maleate . . . −/Neutral . . . to reinstate the deficit in recovered animals. Prazosin and Carbamazepine . . . Neutral . . . phenoxybenzamine, ␣ -adrenergic receptor antagonists that Vigabatrin . . . Neutral . . . 1 act on the CNS, also interfere with recovery. In contrast, Trazodone 5-HT reuptake −+ propranolol, a nonselective ␤-adrenergic receptor antago- blocker nist, has no effect. 5-HT reuptake Neutral + In addition to the effect of noradrenergic agents on blocker motor recovery, several other classes of drugs that act on Desipramine NE reuptake + ... blocker the CNS may affect recovery from other types of behav- Amitriptyline Mixed 5-HT and −/Neutral . . . ioral deficits (Table). For example, agents NE reuptake may influence recovery from neglect caused by prefron- blocker tal cortical injury. Apomorphine, a dopamine agonist, re- Dopamine duces the severity of experimentally induced neglect, and Haloperidol Butyrophenone − (−) spiroperidol, a dopamine receptor antagonist, reinstates Fluanisone Butyrophenone − . . . Droperidol Butyrophenone − . . . neglect in recovered animals. Concurrent administra- Spiroperidol Antagonist − . . . tion of haloperidol also blocks amphetamine-promoted Apomorphine Agonist + . . . recovery, and haloperidol, as well as other butyrophe- nones (fluanisone, droperidol), transiently reinstates the *The effects of selected drugs on recovery in laboratory animal models deficits in recovered animals. and in preliminary clinical studies in humans recovering from stroke. GABA indicates ␥-aminobutyric acid; AR, adrenergic receptor; 5-HT, is common after stroke and often prompts serotonin; NE, norepinephrine; +, a beneficial effect; ?, the drug has been the use of medications. The administra- insufficiently tested in humans to reach preliminary conclusions about its tion of a single dose of trazodone transiently slows mo- effect on recovery; −, a detrimental effect; symbols in parentheses, drugs that were included in the list of potentially harmful agents in the 2 tor recovery in rats with sensorimotor cortex injury and retrospective studies reviewed but have not been examined separately; reinstates the in recovered animals. A single and ellipses, lack of data. dose of desipramine facilitates motor recovery. In con- trast, fluoxetine and amitriptyline have no demon- strable effect on motor recovery after experimental fo- tex in laboratory studies. In contrast, neither carbamaz- cal brain injury. epine nor vigabatrin has detrimental effects.6 Intracortical infusion of ␥-aminobutyric acid (GABA) Although the cellular mechanisms underlying the ef- was found to increase the hemiparesis produced by a small fects on recovery of drugs that act on the CNS remain largely motor cortex lesion in rats. The short-term administra- speculative, several general principles have emerged from tion of the benzodiazepine diazepam, an indirect GABA the experimental studies. First, individual drugs can have agonist, permanently impedes recovery from the sen- varying effects based on the dosage. For example, amphet- sory asymmetry caused by damage to the anteromedial amine has increasing and then decreasing benefit with in- neocortex in the rat.5 Antianxiety agents that do not act creasing dosages. Second, the timing of drug administra- through the GABA-benzodiazepine receptor complex, tion may be crucial. Some drugs, such as benzodiazepines, such as gepirone, do not seem to impair recovery in simi- that may be neuroprotective when given soon after the lar animal models. The deleterious effect of GABA on mo- stroke are harmful when given later. Amphetamine may tor recovery after motor cortex injury is increased by the no longer be effective after a therapeutic window of op- peripheral administration of phenytoin. Phenobarbital also portunity has passed. Last, the effects of many drugs, par- delays behavioral recovery after injury to the cerebral cor- ticularly the effects of noradrenergic agents on motor re-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 covery after injury to the cerebral cortex, are highly Determining whether the detrimental effects of drugs dependent on the animal’s experience (eg, drug adminis- anticipated from laboratory studies also occur in humans tration must be coupled with training). is difficult but important, because many of these medica- The first study of the effects of amphetamine on re- tions are commonly given to patients recovering from stroke. coveryafterstrokeinhumanswascarefullydesignedtosimu- In a retrospective cohort study, the level of motor recov- late the paradigm used in the laboratory. A detailed review ery of patients who had a stroke and who received, either of clinical studies has been published.7 Eight patients with alone or in combination, the antihypertensives clonidine stable motor deficits were randomized to receive a single or prazosin, dopamine receptor antagonists, benzodiaz- dose of amphetamine or a placebo within 10 days of ische- epines, or phenytoin (drugs that were anticipated to im- mic stroke, with drug administration tightly coupled with pair recovery based on the results of laboratory studies) was . The following day, the amphetamine- compared with the level of recovery of a similar group of treated group had a significant improvement in motor per- patients who were not given any of these medications. Pa- formance (PϽ.05, Wilcoxon rank-sum test), whereas there tients who received the drugs had poorer levels of recov- was little change in the placebo-treated group. A second ery than did the control patients. Multivariate regression double-blind, placebo-controlled trial involving 12 patients analysis indicated a significant effect (P=.025) of “drug found no treatment effect, but it differed in several ways from group” even after correcting for the contributions of other the previous study. A different dosing regimen was used, variables, including the initial severity of the deficit. A simi- interventions began more than 1 month after the stroke, lar effect was found in a separate cohort of patients with and the administration of the drug or placebo was not tightly anterior circulation ischemic stroke, who were enrolled as linkedwithphysicaltherapy.Inathirddouble-blind,placebo- control patients in a short-term interventional stroke trial. controlled trial, a short course of treatment began between Almost 40% received 1 or a combination of drugs hypoth- 15 and 30 days after the stroke, with each dose of amphet- esized to impair recovery during the first 30 days after stroke. amine or placebo given in tight conjunction with physical As with the previous study, stepwise multivariate analyses therapy.Patientstreatedwithamphetaminehadsignificantly indicated a negative effect on outcome in the drug group, greater improvements in motor scores compared with independent of the degree of the initial motor impairment, placebo-treated patients (PϽ.05, Mann-Whitney U test), comorbidconditions,andotherpatientcharacteristics.How- and that benefit persisted for as long as 10 months after the ever, because both studies involved retrospective analyses, intervention ceased. In combination with the principles whether the reason for the administration of a given drug learned from the laboratory, these 3 clinical studies suggest or the drug itself influenced recovery cannot be determined. that drug dosage, timing, and the tight coupling of drug Furthermore, the effects of specific “detrimental” drugs, dos- therapy with physical therapy may be critical determinants age, and timing could not be analyzed. of whether the treatment is efficacious. Physicians caring for patients recovering from stroke Limited prospective studies of other drugs that were should become aware of the potential negative effect of hoped to enhance poststroke recovery have been conducted drugs commonly prescribed to treat other conditions. recently. One controlled study of the effect of methylphe- Whenever possible, these drugs should be avoided. As nidate on poststroke neurologic impairments found no ef- the basic neurobiological factors underlying recovery be- fect of the drug on physical performance despite significant come better understood, drugs targeted at enhancing the effectsoncardiovascularfunction.However,variablesshown recovery process may become part of the standard treat- to be important from laboratory studies and suggested from ment of patients who have had a stroke. the results of the aforementioned clinical trials of amphet- amine were not considered in the study design. Trazodone, a drug that impairs recovery from hemiplegia in the rat, was Accepted for publication August 28, 1997. found to reduce disability in patients who are depressed af- Corresponding author: Larry B. Goldstein, MD, Box ter a stroke. Other studies have found a beneficial effect of 3651, Duke University Medical Center, Durham, NC 27710 fluoxetine (PՅ.05, Mann-Whitney U test) and no signifi- (e-mail: [email protected]). cant effect of the norepinephrine reuptake blockers mapro- tiline and hydrochloride. Therefore, unlike amphetamine, the effects of antidepressants on functional REFERENCES recovery in humans seem to be different from the effects 1. Feeney DM, Sutton RL. Pharmacotherapy for recovery of function after brain in- predicted based on the results of the laboratory studies jury. Crit Rev Neurobiol. 1987;3:135-197. (Table). These disparate results may have occurred because 2. Feeney DM, Weisend MP, Kline AE. Noradrenergic pharmacotherapy, intracere- the drugs were only given in a single dose in the laboratory bral infusion and adrenal transplantation promote functional recovery after cor- tical damage. J Neural Transplant Plast. 1993;4:199-213. studies and were given soon after the injury. Again, dos- 3. Goldstein LB. Basic and clinical studies of pharmacologic effects on recovery ing and timing may be important variables. Preliminary un- from brain injury. J Neural Transplant Plast. 1993;4:175-192. controlled studies suggested that the administration of bro- 4. Goldstein LB, Bullman S. Effects of dorsal noradrenergic bundle lesions on re- covery after sensorimotor cortex injury. Pharmacol Biochem Behav. 1997;58: mocriptine mesylate, a dopamine agonist, improved fluency 1151-1157. in certain patients with aphasia. However, 2 small controlled 5. Schallert T, Jones TA, Weaver MS, Shapiro LE, Crippens D, Fulton R. Pharma- cologic and anatomic considerations in recovery of function. Phys Med Rehabil. studies found no differences. These disappointing results 1992;6:375-393. may have been due to a variety of factors. One study of the 6. Wallace A, Montan˜ez S, Lorio M, Hernandez TD. Vigabatrin, unlike some other effects of amphetamine on recovery from aphasia resulting , does not hinder recovery of function. Epilepsia. 1996;37(suppl 5):27. Abstract. from stroke has been completed. Although the results seem 7. Goldstein LB. Influence of common drugs and related factors on stroke out- promising, the study was uncontrolled. come. Curr Opin Neurol. 1997;10:52-57.

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