Almost 7 million adult Americans have had a stroke. There is a growing need for more effective treatment options as add-ons to conventional therapies. This article summarizes the published literature for pharmacologic agents used for the enhancement of motor and speech recovery after stroke. Amphetamine, levodopa, selective serotonin reuptake inhibitors, and piracetam were the most commonly used drugs. Pharmacologic augmentation of stroke motor and speech recovery seems promising but systematic, adequately powered, randomized, and double-blind clinical trials are needed. At this point, the use of these pharmacologic agents is not supported by class I evidence.
Key points
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Stroke is a common and serious condition.
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The main focus of the article is pharmacologic agents used for motor and speech recovery after stroke.
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Amphetamine, levodopa, selective serotonin reuptake inhibitors, and piracetam were the most commonly used drugs in enhancing motor and speech recovery after stroke.
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Adding drug therapy to conventional rehabilitation seems beneficial in poststroke motor and speech recovery.
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Adequately powered, randomized, double-blind clinical trials are needed to explore pharmacologic enhancement of stroke recovery.
Introduction
Approximately 6.8 million Americans more than 20 years of age have had a stroke. On average, every 40 seconds, someone in the United States has a stroke. Motor and speech deficits are common results of stroke. Fifty percent of patients have some hemiparesis after stroke and 19% have aphasia. Although physical, occupational, and speech therapies are the most widely used treatment in the rehabilitation of stroke survivors, their therapeutic effects are generally modest. There is a growing need for more effective treatment options as add-ons to conventional therapy. For several decades, pharmacologic agents have been used as potential approaches for enhancing motor and speech recovery.
This article summarizes published literature in motor ( Table 1 ) and speech ( Table 2 ) recovery after stroke. The clinical trials investigating primarily recovery from poststroke depression, poststroke spasticity, cognitive impairment, activities of daily living (ADLs), neuropathic pain, and seizures have not been included. However, if the improvements in these deficits were reported secondarily to motor or speech recovery, they are mentioned. Experimental studies with animals and healthy controls, and case reports, were not included either because of the large number of clinical trials in the past.
| Reference | Type of Stroke | Type of Drug Used | Number of Patients (Active/Placebo) | Time Postinjury at Enrollment | Treatment Protocol | Motor Outcome Assessment | Final Follow-up After Enrollment |
|---|---|---|---|---|---|---|---|
| Hazama et al, 1980 | Ischemic/hemorrhagic | Citicoline | 55/56/54 a | >3 mo | High-dose citicoline (1 g/d/8 w), or low-dose citicoline (250 mg/d/8 w) + functional rehabilitation program | Hemiplegia Function Test | 8 wk |
| Crisostomo et al, 1988 | Ischemic | D-AMP | 8 (4/4) | <10 d | Single dose of 10 mg of D-AMP + 45 min PT | FM | 3 d |
| Ueda et al, 1994 | Ischemic/hemorrhagic | Citicoline | 248 (124/124) | 4 wk–1 y | 1 g/d/8 wk + specific rehabilitation | Hemiplegia Function Test | 8 wk |
| Walker-Batson et al, 1995 | Ischemic | D-AMP | 6 (5/5) | 10–30 d | 10 doses of 10 mg D-AMP at 3–4 d interval + 1 h PT | FM | 4 wk |
| Reding et al, 1995 | Ischemic | D-AMP | 21 (9/12) | 7–45 d | 10 mg/d D-AMP for 14 d then 5 mg/d for 3 d + standard inpatient rehabilitation | FM | 4 wk |
| Dam et al, 1996 | Ischemic | MPT and FLU | 46 (14/16/14) b | 1–6 mo | 150 mg/d MPT, 20 mg/d FLU for 3 mo + 1–2 h/d of PT, 2 h of OT, and 1 h of ST if needed 5 d/w | Graded Neurologic Scale | 3 mo |
| Grade et al, 1998 | Ischemic/hemorrhagic | MPH | 21 (10/11) | 14–21 d | 3 w of MPH was started at 5 mg and increased gradually to 30 mg for 3 w + standard inpatient rehabilitation | FM | 3 wk |
| Pariente et al, 2001 | Ischemic | FLU | 8 (8/8) | 14 d | 1 dose of 20 mg FLU | NHPT, finger tapping | 1 d |
| Scheidtmann et al, 2001 | Ischemic/hemorrhagic | l -Dopa | 53 (26/27) | 3 wk–6 mo | 100 mg/d of l -dopa for 3 mo + PT | RMA | 6 wk |
| Sonde et al, 2001 | Ischemic/hemorrhagic | D-AMP | 31 (12/19) | 5–10 d | 10 doses of 10 mg D-AMP at 3–4 d interval + 30 min PT | FM | 3 mo |
| Martinsson & Wahlgren, 2003 | Ischemic | D-AMP | 45 (30/15) | <3 d | 2.5-5-10 mg of D-AMP for 5 consecutive days | Lindmark Scale | 3 mo |
| Treig et al, 2003 | Ischemic | D-AMP | 24 (12/12) | <6 wk | 10 doses with 10 mg D-AMP every 4th day in 36 d combined with 45 min of PT (5 times/wk) | RMA | 1 y |
| Nadeau et al, 2004 | Ischemic/hemorrhagic | DON | 20 (10/10) | >1 y | 6 wk 10 mg/d DON + 10 times of 6 h CIT of upper limb (at last 2 wk) | BBT, WMFT, FM, MAL, finger tapping | 6 mo |
| Floel et al, 2005 | Ischemic | l -Dopa | 9 (9/9) | >12 mo | Single dose of 100 mg of L-dopa + motor memory training | TMS-evoked thumb movements | 1 d |
| Tardy et al, 2006 | Ischemic/hemorrhagic | MPH | 8 (8/8) | 17 d | Single dose of 20 mg MPH | Hand grip strength, finger tapping and speed during a target pursuit task, fMRI | 1 d |
| Gladstone et al, 2006 | Ischemic/hemorrhagic | D-AMP | 71 (34/37) | 5–10 d | 10 sessions of D-AMP | FM | 3 mo |
| Sonde & Lokk, 2007 | Ischemic/hemorrhagic | D-AMP and l -dopa | 25 (7/4/7/7) c | 5–10 d | 10 sessions with 20 mg of D-AMP, 100 mg of l -dopa, or 10 mg of D-AMP + 50 mg of l -dopa or placebo | FM | 3 mo |
| Sprigg et al, 2007 | Ischemic | D-AMP | 33 (17/16) | 3–30 d | 5 mg initially, then 10 mg D-AMP for 10 subsequent doses with 3-d or 4-d separations + inpatient rehabilitation | FM | 3 mo |
| Zittel et al, 2007 | Ischemic/hemorrhagic | RBX | 10 (10/10) | >6 mo | Single dose of 6 mg of RBX + 1 h of PT | Tapping speed, grip strength, NHPT, and TMS MEPs | 1 d |
| Restemeyer et al, 2007 | Ischemic | l -Dopa | 10 (10/10) | >6 mo | Single dose of 100 mg L-dopa + 1 h of PT | NHPT, grip strength, and ARAT and TMS cortical excitability | Right after PT |
| Zittel et al, 2008 | Ischemic/hemorrhagic | CIT | 8 (8/8) | >6 mo | Single dose of CIT + 1 h of PT | NHPT, hand grip strength | 2 h |
| Iranmanesh & Vakilian, 2008 | Hemorrhagic | Citicoline | 32 (16/16) | <6 h | 250 mg/d citicoline for 14 d | Muscular strength | 3 mo |
| Acler et al, 2009 | Ischemic/hemorrhagic | CIT | 20 (10/10) | <10 d | 10 mg/d CIT for 4 mo + PT | Lindmark Scale | 4 mo |
| Cramer et al, 2009 | Ischemic/hemorrhagic | RPR | 33 (17/16) | 1–12 mo | 9 w of RPR (0.25–4 mg/d, titrated daily) + 90 min PT | Gait velocity, gait endurance, FM | 3 mo |
| Wang et al, 2011 | Ischemic/hemorrhagic | RBX | 11 (11/11) | 1–12 mo | Single dose of 6 mg RBX | ARAT, hand grip strength, finger tapping, rapid tapping, and fMRI | 1 d |
| Chollet et al, 2011 | Ischemic | FLU | 113 (57/56) | 5–10 d | 20 mg/d FLU for 3 mo + PT | FM | 3 mo |
| Kakuda et al, 2011 | Ischemic/hemorrhagic | l -Dopa | 5 (5/0) | >12 mo | 100 mg/d l -dopa for 7 wk + rTMS and OT | FM, WMFT | 4 wk |
| Schuster et al, 2011 | Ischemic | D-AMP | 16 (7/9) | <2 mo | 10 times 10 mg D-AMP over 5 wk + standard inpatient rehabilitation | Chedoke-McMaster Stroke Assessment | 1 y |
| Mohammadianinejad et al, 2014 | Ischemic | Lithium | 66 (32/34) | <2 d | 300 mg twice daily for 1 mo + inpatient therapy | FM | 1 mo |
a 55/56/54 is high dose, low dose, and placebo respectively.
b 14/16/14 is maprotiline, fluoxetine, and placebo respectively.
c 7/4/7/7 is 20 mg of D-AMP, 100 mg of l -dopa, 10 mg of d -amphetamine, plus 50 mg of l -dopa or placebo respectively.
| Reference | Type of Stroke | Type of Drug Used | Number of Patients (Active/Placebo) | Time Postinjury | Treatment Protocol | Language Outcome Assessment | Final Follow-up |
|---|---|---|---|---|---|---|---|
| Walker-Batson et al, 1992 | Ischemic | D-AMP | 6 (6/0) | 10–30 d | 10 doses of 10 mg D-AMP at 3–4 d interval + 60 min ST | PICA | 1 y |
| Enderby et al, 1994 | Ischemic | Piracetam | 67 (30/37) | 6–9 wk after | 12 wk 4.8 g/d piracetam + standard inpatient rehabilitation | Aachen Aphasia Test | 24 wk |
| De Deyn et al, 1997 | Ischemic | Piracetam | 373 (180/193) | <12 h | Piracetam 12 g in bolus intravenously within 12 h after stroke onset, followed by piracetam 12 g/d IV until fourth d. Thereafter 12 g/d until 4 w, then 4.8 g/d for 8 wk | Frenchay Aphasia Screening Test | 12 wk |
| Bragoni et al, 2000 | Ischemic/hemorrhagic | BR | 11 (11/0) | >1 y | Phase 1: placebo plus domperidon (30 mg tid) + ST (2 individual sessions weekly) (day 90). Phase 2: BR (started at 2.5 mg up to 30 mg tid, for a 4-wk period) plus domperidon, and ST (day 150). Phase 4: BR (30 mg tid) plus domperidon | Standardized Italian language test, token test, visual naming test | 9 mo |
| Kessler et al, 2000 | Ischemic | Piracetam | 24 (12/12) | 14 d | 6 wk of 2400 mg piracetam twice daily + 5 times/w 60 min ST | Aachen Aphasia Test | 6 wk |
| Szelies et al, 2001 | Ischemic | Piracetam | 24 | 14 d | 6 wk of 2400 mg piracetam twice daily + 5 times/w 60 min ST | Aphasia Test | 6 wk |
| Walker-Batson et al, 2001 | Ischemic | D-AMP | 21 (12/9) | 16–45 d | 10 doses of 10 mg D-AMP at 3–4 d intervals + 1 h ST | PICA | 6 mo |
| Berthier et al, 2003 | Ischemic/hemorrhagic | Donepezil | 10 (10/0) | >6 mo | 5 mg/d donepezil for first 4 wk, followed by 10 mg/d for 12 wk + ST | WAB and PALPA | 20 wk |
| Laska et al, 2005 | Ischemic/hemorrhagic | Moclobemide | 66 (34/31) | 3 wk | Started with 300 mg moclobemide and escalated to 600 mg in 1 mo for 6 mo + routine inpatient rehabilitation | Reinvang Grunntest for afasi + ANELT | 6 mo |
| Berthier et al, 2006 | Ischemic/hemorrhagic | Donepezil | 26 (13/13) | >1 y | 5 mg/d donepezil for first 4 wk, followed by 10 mg/d for 12 wk + ST | WAB, CAL, and PALPA | 20 wk |
| Ashtary et al, 2006 | Ischemic/hemorrhagic | BR | 38 (19/19) | Acute (undefined) | Bromocriptine in 2.5-mg/d increments for 4 w to 10 mg/d for a total of 4 mo | Persian Language Test | 16 wk |
| Seniów et al, 2009 | Ischemic/hemorrhagic | l -Dopa | 39 (20/19) | 2–8 wk | 100 mg/d l -dopa + ST 5 times/wk for 3 wk | BDAE | 3 wk |
| Berthier et al, 2009 | Ischemic/hemorrhagic | Memantine | 27 (14/13) | 1 y | 20 mg/d memantine only for 16 w, followed by memantine + CIAT (weeks 16–18), memantine alone again (weeks 18–20), and washout (weeks 20–24), and then an open-label extension phase of memantine (weeks 24–48) | WAB and CAL | 48 wk |
| Gungor et al, 2011 | Ischemic | Piracetam | 30 (15/15) | 2–32 d | 4.8 g piracetam/d for 6 mo | GAT | 24 wk |
| Breitenstein et al, 2015 | Ischemic/hemorrhagic | l -Dopa | 10 (10/10) | >1 y | 100/25 mg of l -dopa/carbidopa or placebo daily + 4 h of ST for 2 wk | Naming Performance and Verbal Communication | 6 mo |
Details about adverse events are not included because this is not the scope of the article. Only serious adverse events related to the drug are mentioned. Engelter provides more specific information about adverse events.
Introduction
Approximately 6.8 million Americans more than 20 years of age have had a stroke. On average, every 40 seconds, someone in the United States has a stroke. Motor and speech deficits are common results of stroke. Fifty percent of patients have some hemiparesis after stroke and 19% have aphasia. Although physical, occupational, and speech therapies are the most widely used treatment in the rehabilitation of stroke survivors, their therapeutic effects are generally modest. There is a growing need for more effective treatment options as add-ons to conventional therapy. For several decades, pharmacologic agents have been used as potential approaches for enhancing motor and speech recovery.
This article summarizes published literature in motor ( Table 1 ) and speech ( Table 2 ) recovery after stroke. The clinical trials investigating primarily recovery from poststroke depression, poststroke spasticity, cognitive impairment, activities of daily living (ADLs), neuropathic pain, and seizures have not been included. However, if the improvements in these deficits were reported secondarily to motor or speech recovery, they are mentioned. Experimental studies with animals and healthy controls, and case reports, were not included either because of the large number of clinical trials in the past.
| Reference | Type of Stroke | Type of Drug Used | Number of Patients (Active/Placebo) | Time Postinjury at Enrollment | Treatment Protocol | Motor Outcome Assessment | Final Follow-up After Enrollment |
|---|---|---|---|---|---|---|---|
| Hazama et al, 1980 | Ischemic/hemorrhagic | Citicoline | 55/56/54 a | >3 mo | High-dose citicoline (1 g/d/8 w), or low-dose citicoline (250 mg/d/8 w) + functional rehabilitation program | Hemiplegia Function Test | 8 wk |
| Crisostomo et al, 1988 | Ischemic | D-AMP | 8 (4/4) | <10 d | Single dose of 10 mg of D-AMP + 45 min PT | FM | 3 d |
| Ueda et al, 1994 | Ischemic/hemorrhagic | Citicoline | 248 (124/124) | 4 wk–1 y | 1 g/d/8 wk + specific rehabilitation | Hemiplegia Function Test | 8 wk |
| Walker-Batson et al, 1995 | Ischemic | D-AMP | 6 (5/5) | 10–30 d | 10 doses of 10 mg D-AMP at 3–4 d interval + 1 h PT | FM | 4 wk |
| Reding et al, 1995 | Ischemic | D-AMP | 21 (9/12) | 7–45 d | 10 mg/d D-AMP for 14 d then 5 mg/d for 3 d + standard inpatient rehabilitation | FM | 4 wk |
| Dam et al, 1996 | Ischemic | MPT and FLU | 46 (14/16/14) b | 1–6 mo | 150 mg/d MPT, 20 mg/d FLU for 3 mo + 1–2 h/d of PT, 2 h of OT, and 1 h of ST if needed 5 d/w | Graded Neurologic Scale | 3 mo |
| Grade et al, 1998 | Ischemic/hemorrhagic | MPH | 21 (10/11) | 14–21 d | 3 w of MPH was started at 5 mg and increased gradually to 30 mg for 3 w + standard inpatient rehabilitation | FM | 3 wk |
| Pariente et al, 2001 | Ischemic | FLU | 8 (8/8) | 14 d | 1 dose of 20 mg FLU | NHPT, finger tapping | 1 d |
| Scheidtmann et al, 2001 | Ischemic/hemorrhagic | l -Dopa | 53 (26/27) | 3 wk–6 mo | 100 mg/d of l -dopa for 3 mo + PT | RMA | 6 wk |
| Sonde et al, 2001 | Ischemic/hemorrhagic | D-AMP | 31 (12/19) | 5–10 d | 10 doses of 10 mg D-AMP at 3–4 d interval + 30 min PT | FM | 3 mo |
| Martinsson & Wahlgren, 2003 | Ischemic | D-AMP | 45 (30/15) | <3 d | 2.5-5-10 mg of D-AMP for 5 consecutive days | Lindmark Scale | 3 mo |
| Treig et al, 2003 | Ischemic | D-AMP | 24 (12/12) | <6 wk | 10 doses with 10 mg D-AMP every 4th day in 36 d combined with 45 min of PT (5 times/wk) | RMA | 1 y |
| Nadeau et al, 2004 | Ischemic/hemorrhagic | DON | 20 (10/10) | >1 y | 6 wk 10 mg/d DON + 10 times of 6 h CIT of upper limb (at last 2 wk) | BBT, WMFT, FM, MAL, finger tapping | 6 mo |
| Floel et al, 2005 | Ischemic | l -Dopa | 9 (9/9) | >12 mo | Single dose of 100 mg of L-dopa + motor memory training | TMS-evoked thumb movements | 1 d |
| Tardy et al, 2006 | Ischemic/hemorrhagic | MPH | 8 (8/8) | 17 d | Single dose of 20 mg MPH | Hand grip strength, finger tapping and speed during a target pursuit task, fMRI | 1 d |
| Gladstone et al, 2006 | Ischemic/hemorrhagic | D-AMP | 71 (34/37) | 5–10 d | 10 sessions of D-AMP | FM | 3 mo |
| Sonde & Lokk, 2007 | Ischemic/hemorrhagic | D-AMP and l -dopa | 25 (7/4/7/7) c | 5–10 d | 10 sessions with 20 mg of D-AMP, 100 mg of l -dopa, or 10 mg of D-AMP + 50 mg of l -dopa or placebo | FM | 3 mo |
| Sprigg et al, 2007 | Ischemic | D-AMP | 33 (17/16) | 3–30 d | 5 mg initially, then 10 mg D-AMP for 10 subsequent doses with 3-d or 4-d separations + inpatient rehabilitation | FM | 3 mo |
| Zittel et al, 2007 | Ischemic/hemorrhagic | RBX | 10 (10/10) | >6 mo | Single dose of 6 mg of RBX + 1 h of PT | Tapping speed, grip strength, NHPT, and TMS MEPs | 1 d |
| Restemeyer et al, 2007 | Ischemic | l -Dopa | 10 (10/10) | >6 mo | Single dose of 100 mg L-dopa + 1 h of PT | NHPT, grip strength, and ARAT and TMS cortical excitability | Right after PT |
| Zittel et al, 2008 | Ischemic/hemorrhagic | CIT | 8 (8/8) | >6 mo | Single dose of CIT + 1 h of PT | NHPT, hand grip strength | 2 h |
| Iranmanesh & Vakilian, 2008 | Hemorrhagic | Citicoline | 32 (16/16) | <6 h | 250 mg/d citicoline for 14 d | Muscular strength | 3 mo |
| Acler et al, 2009 | Ischemic/hemorrhagic | CIT | 20 (10/10) | <10 d | 10 mg/d CIT for 4 mo + PT | Lindmark Scale | 4 mo |
| Cramer et al, 2009 | Ischemic/hemorrhagic | RPR | 33 (17/16) | 1–12 mo | 9 w of RPR (0.25–4 mg/d, titrated daily) + 90 min PT | Gait velocity, gait endurance, FM | 3 mo |
| Wang et al, 2011 | Ischemic/hemorrhagic | RBX | 11 (11/11) | 1–12 mo | Single dose of 6 mg RBX | ARAT, hand grip strength, finger tapping, rapid tapping, and fMRI | 1 d |
| Chollet et al, 2011 | Ischemic | FLU | 113 (57/56) | 5–10 d | 20 mg/d FLU for 3 mo + PT | FM | 3 mo |
| Kakuda et al, 2011 | Ischemic/hemorrhagic | l -Dopa | 5 (5/0) | >12 mo | 100 mg/d l -dopa for 7 wk + rTMS and OT | FM, WMFT | 4 wk |
| Schuster et al, 2011 | Ischemic | D-AMP | 16 (7/9) | <2 mo | 10 times 10 mg D-AMP over 5 wk + standard inpatient rehabilitation | Chedoke-McMaster Stroke Assessment | 1 y |
| Mohammadianinejad et al, 2014 | Ischemic | Lithium | 66 (32/34) | <2 d | 300 mg twice daily for 1 mo + inpatient therapy | FM | 1 mo |
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