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Intrathecal and Oral Baclofen Use in Adults With Spinal Cord Injury: A Systematic Review of Efficacy in Spasticity Reduction, Functional Changes, Dosing, and Adverse Events

      Abstract

      Objective

      To examine the efficacy, dosing, and safety profiles of intrathecal and oral baclofen in treating spasticity after spinal cord injury (SCI).

      Data Sources

      PubMed and Cochrane Databases were searched from 1970-2018 with keywords baclofen, spinal cord injury, and efficacy.

      Study Selection

      The database search yielded 588 sources and 10 additional relevant publications. After removal of duplicates, 398 publications were screened.

      Data Extraction

      Data were extracted using the following population, intervention, comparator, outcomes, and study designs criteria: studies including adult patients with SCI with spasticity; the intervention could be oral or intrathecal administration of baclofen; selection was inclusive for control groups, surgical management, rehabilitation, and alternative pharmaceutical agents; outcomes were efficacy, dosing, and adverse events. Randomized controlled trials, observational studies, and case reports were included. Meta-analyses and systematic reviews were excluded.

      Data Synthesis

      A total of 98 studies were included with 1943 patients. Only 4 randomized, double-blinded, and placebo-controlled trials were reported. Thirty-nine studies examined changes in the Modified Ashworth Scale (MAS; 34 studies) and Penn Spasm scores (Penn Spasm Frequency; 19 studies), with average reductions of 1.7±1.3 and 1.6±1.4 in individuals with SCI, respectively. Of these data, a total of 6 of the 34 studies (MAS) and 2 of the 19 studies (Penn Spasm Frequency) analyzed oral baclofen. Forty-three studies addressed adverse events with muscle weakness and fatigue frequently reported.

      Conclusions

      Baclofen is the most commonly-prescribed antispasmodic after SCI. Surprisingly, there remains a significant lack of large, placebo-controlled, double-blinded clinical trials, with most efficacy data arising from small studies examining treatment across different etiologies. In the studies reviewed, baclofen effectively improved spasticity outcome measures, with increased efficacy through intrathecal administration. Few studies assessed how reduced neural excitability affected residual motor function and activities of daily living. A host of adverse events were reported that may negatively affect quality of life. Comparative randomized controlled trials of baclofen and alternative treatments are warranted because these have demonstrated promise in relieving spasticity with reduced adverse events and without negatively affecting residual motor function.

      Keywords

      List of abbreviations:

      ADL (activities of daily living), AIS (American Spinal Injury Association Impairment Scale), GABA (gamma-aminobutyric acid), MAS (Modified Ashworth Scale), mMRC (modified Medical Research Council), SCI (spinal cord injury)
      Spinal cord injury (SCI) has an annual incidence of 15-83 per million globally,
      • Sekhon LH
      • Fehlings MG
      Epidemiology, demographics, and pathophysiology of acute spinal cord injury.
      ,
      • Singh A
      • Tetreault L
      • Kalsi-Ryan S
      • Nouri A
      • Fehlings MG
      Global prevalence and incidence of traumatic spinal cord injury.
      with spasticity affecting ∼70% of these individuals.
      • Biering-Sorensen F
      • Nielsen JB
      • Klinge K
      Spasticity-assessment: a review.
      • Pandyan AD
      • Gregoric M
      • Barnes MP
      • et al.
      Spasticity: clinical perceptions, neurological realities and meaningful measurement.
      • Maynard FM
      • Karunas RS
      • Waring 3rd, WP
      Epidemiology of spasticity following traumatic spinal cord injury.
      Spasticity is a movement disorder characterized by involuntary muscle activity such as spasms, clonus, impaired muscle coactivation patterns and increased velocity-dependent resistance to passive stretch.
      • Sherrington CS
      Decerebrate rigidity, and reflex coordination of movements.
      • Skold C
      • Levi R
      • Seiger A
      Spasticity after traumatic spinal cord injury: nature, severity, and location.
      • Dietz V
      Spastic movement disorder.
      Further, spasticity and the disruption of normal movement, speech, and balance often impairs function and ability to carry out activities of daily living (ADL).
      • McKay WB
      • Sweatman WM
      • Field-Fote EC
      The experience of spasticity after spinal cord injury: perceived characteristics and impact on daily life.
      • Levi R
      • Hultling C
      • Seiger A
      The Stockholm Spinal Cord Injury Study. 3. Health-related issues of the Swedish Annual Level-of-Living Survey in SCI subjects and controls.
      • Andresen SR
      • Biering-Sorensen F
      • Hagen EM
      • Nielsen JF
      • Bach FW
      • Finnerup NB
      Pain, spasticity and quality of life in individuals with traumatic spinal cord injury in Denmark.
      • Little JW
      • Micklesen P
      • Umlauf R
      • Britell C
      Lower extremity manifestations of spasticity in chronic spinal cord injury.
      • Tibbett J
      • Widerstrom-Noga EG
      • Thomas CK
      • Field-Fote EC
      Impact of spasticity on transfers and activities of daily living in individuals with spinal cord injury.
      In a 2018 patient-reported effect of spasticity survey, participants described stiffness associated with spasticity as the most detrimental aspect to normal function with pain in the legs reported in 57% of those with SCI.
      • McKay WB
      • Sweatman WM
      • Field-Fote EC
      The experience of spasticity after spinal cord injury: perceived characteristics and impact on daily life.
      ,
      • Andresen SR
      • Biering-Sorensen F
      • Hagen EM
      • Nielsen JF
      • Bach FW
      • Finnerup NB
      Pain, spasticity and quality of life in individuals with traumatic spinal cord injury in Denmark.
      Approximately 40% of individuals in the Stockholm Spinal Cord Injury Study report problematic spasticity negatively affecting ADL,
      • Levi R
      • Hultling C
      • Seiger A
      The Stockholm Spinal Cord Injury Study. 3. Health-related issues of the Swedish Annual Level-of-Living Survey in SCI subjects and controls.
      especially transfers. Despite the significant effect of spasticity on quality of life, there are few objective measures that correlate with perceived detriment and suffering.
      Spasticity after SCI develops chronically as neurons and neural circuits below the injury adapt to decreased descending inputs and movement-related sensory input. Within the spinal cord, several reflex pathways can affect sensorimotor output and changes in the excitability of these pathways occur because of decreased supraspinal modulation and plastic changes within the spinal cord itself.
      • Mailis A
      • Ashby P
      Alterations in group Ia projections to motoneurons following spinal lesions in humans.
      • Faist M
      • Mazevet D
      • Dietz V
      • Pierrot-Deseilligny E
      A quantitative assessment of presynaptic inhibition of Ia afferents in spastics. Differences in hemiplegics and paraplegics.
      • Aymard C
      • Katz R
      • Lafitte C
      • et al.
      Presynaptic inhibition and homosynaptic depression: a comparison between lower and upper limbs in normal human subjects and patients with hemiplegia.
      • Crone C
      • Nielsen J
      • Petersen N
      • Ballegaard M
      • Hultborn H
      Disynaptic reciprocal inhibition of ankle extensors in spastic patients.
      • Crone C
      • Nielsen J
      Central control of disynaptic reciprocal inhibition in humans.
      • Crone C
      • Petersen NT
      • Nielsen JE
      • Hansen NL
      • Nielsen JB
      Reciprocal inhibition and corticospinal transmission in the arm and leg in patients with autosomal dominant pure spastic paraparesis (ADPSP).
      • Calancie B
      • Broton JG
      • Klose KJ
      • Traad M
      • Difini J
      • Ayyar DR.
      Evidence that alterations in presynaptic inhibition contribute to segmental hypo- and hyperexcitability after spinal cord injury in man.
      • Schindler-Ivens S
      • Shields RK.
      Low frequency depression of H-reflexes in humans with acute and chronic spinal-cord injury.
      • Roby-Brami A
      • Bussel B.
      Long-latency spinal reflex in man after flexor reflex afferent stimulation.
      • D'Amico JM
      • Condliffe EG
      • Martins KJ
      • Bennett DJ
      • Gorassini MA.
      Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity.
      At the neuronal level, the loss of descending modulation by serotonin and noradrenaline leads to both increases in the intrinsic excitability of the motor neurons themselves and disinhibition of sensory input to the motor neurons, leading to prolongation of the excitatory postsynaptic potentials.
      • D'Amico JM
      • Condliffe EG
      • Martins KJ
      • Bennett DJ
      • Gorassini MA.
      Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity.
      Together, these changes contribute to an imbalance in excitatory and inhibitory inputs to the motor neurons whereby brief, innocuous sensory stimuli can trigger long-lasting involuntary muscle activity (spasms).
      • D'Amico JM
      • Condliffe EG
      • Martins KJ
      • Bennett DJ
      • Gorassini MA.
      Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity.
      The most common clinical measures of spasticity are the Modified Ashworth Scale (MAS) and the Penn Spasm Frequency self-assessment. However, these clinical tools fail to entirely capture the different movement components contributing to the broader term of “spasticity,” do not correlate with neurophysiological measures of hyperexcitability,
      • Sinkjaer T
      • Toft E
      • Larsen K
      • Andreassen S
      • Hansen HJ.
      Non-reflex and reflex mediated ankle joint stiffness in multiple sclerosis patients with spasticity.
      ,
      • Schindler-Ivens SM
      • Shields RK.
      Comparison of linear regression and probit analysis for detecting H-reflex threshold in individuals with and without spinal cord injury.
      and have poor interrater reliability.
      • Mutlu A
      • Livanelioglu A
      • Gunel MK.
      Reliability of Ashworth and Modified Ashworth Scales in children with spastic cerebral palsy.
      • Bohannon RW
      • Smith MB.
      Interrater reliability of a Modified Ashworth Scale of muscle spasticity.
      • Fleuren JF
      • Voerman GE
      • Erren-Wolters CV
      • et al.
      Stop using the Ashworth Scale for the assessment of spasticity.
      Briefly, the MAS score assesses on a scale of 0-4 the resistance of a relaxed, single joint as it is moved throughout its full available range of motion (table 1).
      • Bohannon RW
      • Smith MB.
      Interrater reliability of a Modified Ashworth Scale of muscle spasticity.
      ,
      • Ashworth B
      Preliminary trial of carisoprodol in multiple sclerosis.
      The Penn Spasm Frequency is a self-report noting both the severity and frequency of spasms (see table 1).
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      It is clear that both measurements assess different aspects of spasticity, accounting for the lack of correlation between the 2 scores within the same individual.
      • Baunsgaard CB
      • Nissen UV
      • Christensen KB
      Biering-Sorensen F. Modified Ashworth Scale and spasm frequency score in spinal cord injury: reliability and correlation.
      Moreover, there is a need to develop more optimal techniques for the evaluation of spasticity in individuals with SCI. Other measures include the Tardieu Scale score, which assesses resistance to fast and slow passive mobility,
      • Haugh AB
      • Pandyan AD
      • Johnson GR.
      A systematic review of the Tardieu Scale for the measurement of spasticity.
      and the Modified Tardieu Scale, which measures velocity of passive range of motion at measured joint angles.
      • Akpinar P
      • Atici A
      • Ozkan FU
      • et al.
      Reliability of the Modified Ashworth Scale and Modified Tardieu Scale in patients with spinal cord injuries.
      Table 1Spasticity rating scales
      Modified Ashworth ScalePenn Spasm Frequency Scale
      0: No increase in muscle tone0: No spasms
      1: Slight increase in muscle tone, manifested by a catch or by minimal resistance at the end of the ROM when the affected part(s) is moved in flexion or extension1: Mild spasms induced by stimulation
      1+: Slight increase in muscle tone, manifested by a catch followed by minimal resistance throughout the remainder (less than half) of the ROM2: Full spasms occurring less than once per hour
      2: More marked increase in tone through most of the ROM, but affected part(s) easily moved3: Spasms occurring more than once per hour
      3: Considerable increase muscle in tone; passive movement difficult4: Spasms occurring more than 10 times/h
      4: Affected part(s) rigid in flexion or extension
      Abbreviation: ROM, range of motion.
      Baclofen is prescribed to treat spasticity, and its use is extensively reported for SCI, stroke, cerebral palsy, and multiple sclerosis.
      • Andresen SR
      • Biering-Sorensen F
      • Hagen EM
      • Nielsen JF
      • Bach FW
      • Finnerup NB
      Pain, spasticity and quality of life in individuals with traumatic spinal cord injury in Denmark.
      ,
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      ,
      • Sammaraiee Y
      • Yardley M
      • Keenan L
      • Buchanan K
      • Stevenson V
      • Farrell R
      Intrathecal baclofen for multiple sclerosis related spasticity: a twenty year experience.
      ,
      • Penn RD.
      Intrathecal baclofen for spasticity of spinal origin: seven years of experience.
      Given its structure as a derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), baclofen acts as an agonist to metabotropic GABA-B receptors throughout the central nervous system to reduce the presynaptic release of excitatory neurotransmitters.
      • Calancie B
      • Broton JG
      • Klose KJ
      • Traad M
      • Difini J
      • Ayyar DR.
      Evidence that alterations in presynaptic inhibition contribute to segmental hypo- and hyperexcitability after spinal cord injury in man.
      ,
      • Curtis DR
      • Gynther BD
      • Lacey G
      • Beattie DT.
      Baclofen: reduction of presynaptic calcium influx in the cat spinal cord in vivo.
      • Shimizu T
      • Hino T
      • Komori T
      • Hirai S.
      Loss of the muscle silent period evoked by transcranial magnetic stimulation of the motor cortex in patients with cervical cord lesions.
      • Kumru H
      • Kofler M.
      Effect of spinal cord injury and of intrathecal baclofen on brainstem reflexes.
      Baclofen for SCI can be administered orally or intrathecally with implantation of a metered pump. However, oral administration may be ineffective in up to 25% of patients with SCI because of baclofen's poor blood-brain barrier penetration, requiring more direct delivery via intrathecal route.
      • Ochs G
      • Struppler A
      • Meyerson BA
      • et al.
      Intrathecal baclofen for long-term treatment of spasticity: a multi-centre study.
      Intrathecal baclofen, introduced in the 1980s, is considered for severe spasticity, offering localized distribution to the thecal sac and lower rates of toxicity from systemic dissemination.
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      ,
      • Balsara K
      • Jea A
      • Raskin JS.
      Neurosurgical management of spastic conditions of the upper extremity.
      • Ertzgaard P
      • Campo C
      • Calabrese A.
      Efficacy and safety of oral baclofen in the management of spasticity: a rationale for intrathecal baclofen.
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      While substantial literature supports the use of baclofen as an effective spasmolytic, most studies analyze its use across multiple indications that may not fully appreciate mechanistic differences between pathologies and coexisting goals of recovery. For example, baclofen for spasticity after SCI reduces symptoms but also inhibits movement and functional restoration.
      • Wainberg M
      • Barbeau H
      • Gauthier S.
      Quantitative assessment of the effect of cyproheptadine on spastic paretic gait: a preliminary study.
      • Angeli C
      • Ochsner J
      • Harkema S.
      Effects of chronic baclofen use on active movement in an individual with a spinal cord injury.
      • Barbeau H
      • Norman KE.
      The effect of noradrenergic drugs on the recovery of walking after spinal cord injury.
      • Norman KE
      • Pepin A
      • Barbeau H.
      Effects of drugs on walking after spinal cord injury.
      In this systematic review, we comprehensively investigate the efficacy in spasticity reduction, changes in function, dosing, and adverse events associated with baclofen use in the treatment of spasticity after SCI. Efficacy has been considered as reductions in spasticity scores (modified Ashworth scores, Penn Spasm scores). Recovery of motor function (motor scores, voluntary movement, standing, walking) was not often reported as an outcome; however, changes in composite scores such as the Barthel Index are reported. These scores include ADL and/or ease for caregiving as well as performance during some motor tasks.
      • Hobart JC
      • Thompson AJ.
      The five item Barthel Index.
      ,
      • Sinoff G
      • Ore L.
      The Barthel Activities of Daily Living Index: self-reporting versus actual performance in the old-old (>or = 75 years).
      Where available, we report level of injury and severity of injury according to the American Spinal Injury Association Impairment Scale (AIS) criteria. Quantification of efficacy, dosing, and adverse events is reported across all studies.

      Methods

      Data extraction

      We framed the search around a Participants, Intervention, Comparison, Outcomes, Study Designs model to define the population receiving baclofen for SCI, and the study design performed to yield a comprehensive and reproducible topic search (fig 1). All studies including at least 1 patient with SCI were included in the analysis regardless of number of patients in the study with other pathologies including multiple sclerosis, stroke, cerebral palsy, and hereditary spastic paresis.
      Fig 1
      Fig 1Preferred Reporting Items for Systematic Reviews and Meta-analyses flowchart describing search and selection process of articles selected for this systematic review.

      Participants, intervention, comparison, outcomes, study designs outline

      Participants were adult patients aged ≥18 years using baclofen via oral or intrathecal administration for muscle spasticity secondary to SCI (acute or chronic). To include and analyze all uses of baclofen in SCI reported in the literature, studies with at least 1 patient with SCI were included, regardless of amount or focus of other pathology resulting in spasticity or additional pharmaceutical used.
      Intervention was baclofen via oral or intrathecal administration for muscle spasticity, pain, or functional improvement.
      Comparison between baclofen use in other pathologies (ie, multiple sclerosis, stroke, cerebral palsy), oral vs intrathecal baclofen use, with or without rehabilitation, alternative pharmaceutical agents, perioperative care regimens, or no comparison group were included in the present analysis.
      Outcomes were efficacy of spasticity reduction and functional improvement using metrics such as MAS, Penn Spasm Frequency, Tardieu Scale, Fugl-Meyer, dosing of oral or intrathecal baclofen, expected or unexpected adverse events related to baclofen use, and effects on function associated with baclofen use. Clinically meaningful differences were reviewed if implicated and included in studies but not required for inclusion.
      Study design was inclusive of prospective, retrospective, case reports, case series, observational studies, comparative studies, and randomized controlled trials.

      Search criteria

      We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (2009) to construct the framework of the systematic review and conducted the search on November 30, 2018, using PubMed and Cochrane Databases from 1970-2018 (see fig 1).
      • Moher D
      • Liberati A
      • Tetzlaff J
      • Altman DG
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      Additional articles used in the references were incorporated from the references of those articles identified in the searches. We used Keyword and Medical Subject Headings of the National Library of Medicine terms for predictive outcomes to include the following terms, with numbered iterations for the 2 databases as follows:
      Eligibility criteria: Current publication in English language: (1) PubMed: Baclofen AND Spinal Cord Injury: 510 articles; 91 included; (2) Ovid: Baclofen AND Spinal Cord Injury OR spinal cord injuries: 290 articles; 7 included.
      See supplemental table S1 (available online only at http://www.archives-pmr.org/) for detailed list of studies included in the review.

      Risk of bias evaluation

      Assessment of conflict of interest, funding for study and study design were assessed according to QUADAS criteria.

      Exclusion criteria

      Systematic reviews and meta-analyses were excluded. Exclusion criteria also included studies with nonhuman participants, pediatric population, language other than English, and those studies without full text. Combination protocols such as coadministration of morphine for treatment of spasticity were excluded. Also, studies that analyzed biomarkers with use of baclofen without clinical assessments were excluded.

      Data evaluation

      We followed the QUADAS tool to evaluate risk bias and result applicability of the studies according to 2003 guidelines. A total of 13 questions on the QUADAS survey that cover patient selection, index test, reference standard, and timing were addressed for each study and incorporated into the final analysis (supplemental table S2, available online only at http://www.archivespmr.org/).

      Results

      A total of 98 studies were included in the final analysis, and 26 of those were case reports (see supplemental table S1). There were limited studies (19/98) that were uniquely focused on participants with SCI only (fig 2). The pooled sample size for all studies was 1923 patients with SCI (see fig 2). Of these, injury level was reported in only 37% of individuals, with 393 cervical- and 321 thoracic-level injuries reported. Where reported (27% of individuals), the distribution of AIS scores included 137 patients with AIS A, 73 with AIS B, 74 with AIS C, and 56 with AIS D injuries. Chronicity of injury ranged from 1 month to 57 years for 632 patients with SCI (33% of total). When reported, the majority of participants with SCI were between 20 and 40 years old. A total of 1412 individual demographic and AIS injury characteristics were not reported (73% of total). Thirty-six studies addressed the efficacy of baclofen in reducing clinical measures of spasticity (MAS score, 591 individuals with SCI; Penn Spasm Frequency scores, 275 individuals with SCI). Seven studies reported reduced yet unspecified spasm scores after baclofen administration. A total of 8 studies including 128 participants with SCI were found to specifically discuss ability to walk or assessed function with established metrics in the study cohort. Most studies addressed adverse events or dosing; 48 studies specifically addressed adverse events associated with baclofen use, 18 of which were associated with oral dosing of baclofen only. A total of 50 studies examined intrathecal dosing (total of 621 individuals with SCI), and 26 studies examined oral baclofen dosing (total of 604 individuals with SCI), representing ∼64% of the individuals with SCI studied across all reported studies. Of 98 studies, only 6 randomized controlled trials
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      ,
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      ,
      • Yan X
      • Lan J
      • Liu Y
      • Miao J.
      Efficacy and safety of botulinum toxin type A in spasticity caused by spinal cord injury: a randomized, controlled trial.
      • Kumru H
      • Benito-Penalva J
      • Kofler M
      • Vidal J.
      Analgesic effect of intrathecal baclofen bolus on neuropathic pain in spinal cord injury patients.
      • Luo D
      • Wu G
      • Ji Y
      • et al.
      The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury.
      • Nance PW
      • Huff FJ
      • Martinez-Arizala A
      • et al.
      Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.
      were identified to evaluate baclofen efficacy in participants with SCI; 4 of these studies were randomized, double-blinded, and placebo-controlled, while 1 study was a comparative trial (baclofen vs botulinum toxin vs physical therapy alone)
      • Yan X
      • Lan J
      • Liu Y
      • Miao J.
      Efficacy and safety of botulinum toxin type A in spasticity caused by spinal cord injury: a randomized, controlled trial.
      that was randomized and double-blinded. The remaining study was a randomized, comparative trial (baclofen vs tolperisone),
      • Luo D
      • Wu G
      • Ji Y
      • et al.
      The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury.
      and blinding was not indicated in the research design. Four studies examined efficacy of intrathecal
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      ,
      • Penn RD.
      Intrathecal baclofen for spasticity of spinal origin: seven years of experience.
      ,
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      ,
      • Kumru H
      • Benito-Penalva J
      • Kofler M
      • Vidal J.
      Analgesic effect of intrathecal baclofen bolus on neuropathic pain in spinal cord injury patients.
      baclofen use, and in 2 of these studies the use of a saline injection as a placebo was only implemented during the screening process and therefore only to examine the acute effects of intrathecal baclofen administration.
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      The long-term effects of intrathecal baclofen on spasticity was not placebo-controlled in these 2 studies.
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      ,
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      Fig 2
      Fig 2Proportion of total studies (N=98) reporting on efficacy, adverse events, dosing, and motor function following baclofen use in individuals with spasticity after SCI. Horizontal box plot illustrates median and IQR for no. of individuals with SCI across all studies when reported.

      Dosing

      Dosing of baclofen was reported in 67 studies, representing the greatest portion of all studies included in this review (∼64 %). Most studies reported dosing ranges across participants with different pathologies. Other studies reported mean doses for participant cohorts across a study timeline or specific therapeutic doses for individual participants during observation and follow-up.

      Oral baclofen dosing

      Of the 67 studies, 26 studies reported oral baclofen dosing (n=604 individuals with SCI of 1205 total individuals reported) (fig 3). Eleven of these studies reported minimum and maximum dose information. The minimum oral dose of baclofen was 15 mg daily, with the maximum oral dose 266 mg daily. Lastly, where the average of stable doses were reported, the mean oral dose was ∼73 mg daily (n=223 individuals, ∼89% SCI).
      Fig 3
      Fig 3Baclofen dosing. (A) Intrathecal and (B) oral baclofen dosing reported across all publications. Line plots illustrate maximum (filled circles) and minimum (open circles) doses when reported. Underlying box plot illustrates no. of individuals reported across each publication. Box plots illustrate average minimum, maximum, and average baclofen doses across all publications.

      Intrathecal baclofen dosing

      Of the 67 studies, 50 studies reported intrathecal baclofen dosing (n=621 individuals with SCI of 1340 total individuals reported) (see fig 3). Minimum and maximum dose information was provided for 26 studies. To summarize, the minimum intrathecal dose reported was 60 μg over 24 hours, with the maximum dose 1668 μg over 24 hours. From the studies that reported the average or stable dose for individuals using intrathecal baclofen, the average was ∼308 μg daily (n=731 individuals, ∼35% SCI).

      Efficacy

      Efficacy was defined as the effectiveness of baclofen in reducing clinical measures of spasticity. The reported outcome measures are the MAS score and the Penn Spasm Frequency score (see table 1). The effects of baclofen on these clinical outcome measures were reported in 36 studies (∼38 % of total), and of these studies, only 18 studies specifically assessed the efficacy of baclofen use in individuals with spasticity after SCI. These studies represented 598 participants with SCI over the last 31 years and 365 participants with other neurologic impairments.

      Changes in MAS

      Seventeen studies reported on the efficacy of baclofen in reducing MAS in the population with SCI specifically (n=350 individuals) (fig 4A). Of these, 6 studies reported a reduction of 1.0±1.7 in MAS with oral baclofen use (n=260 individuals with SCI) (see fig 4A), and 11 studies reported a reduction of 2.1±1.0 in MAS with intrathecal baclofen use (n=90 individuals with SCI) (fig 4A), demonstrating increased efficacy through intrathecal administration of baclofen.
      Fig 4
      Fig 4Efficacy of baclofen. Changes in (A) Modified Ashworth scores and (B) Penn Spasm frequency scores following oral (filled circles) and intrathecal (open circles) baclofen administration. SCI-only reported values are indicated in the line plots. Averages are illustrated in the box plots. Combined average reports values obtained across individuals of different pathologies (SCI, MS, CP). No. of individuals with SCI is shown on the right axes of all plots.
      Abbreviations: CP, cerebral palsy; MS, multiple sclerosis.

      Change in Penn Spasm Frequency score

      Penn Spasm scores assessing frequency and severity of spasms were reported in 20 studies (∼19% of total). From these 20 studies, 275 of 464 participants were diagnosed with SCI, with spasticity arising from different etiologies comprising the remainder of the participants. Of the 20 studies, 9 studies reported findings specific to patients with SCI (see fig 4B). Of these SCI-specific values, 2 studies reported a reduction of 0.63±0. 85 with oral baclofen use (n=47 individuals with SCI). Like changes in MAS reported above, a larger reduction in Penn Spasm scores was reported with intrathecal baclofen administration (−1.9±1.5, n=83 individuals with SCI).

      Efficacy outcomes from studies examining multiple pathologies

      In the studies that reported combined averages across multiple pathologies, only the efficacy of intrathecal baclofen was evaluated. In these studies, baclofen effectively reduced the MAS by 2.0±0.9, with participants with SCI representing ∼53% of the individuals in this data set (n=241 SCI of 458 total individuals reported). Baclofen effectively reduced the Penn Spasm score by 2.0±1.3, with individuals with SCI representing ∼50% of the individuals in this data set (n=145 SCI of 288 total individuals reported). These results are similar to those reported in the SCI-specific literature detailed above.

      Function

      A total of 6 studies discuss the effects of baclofen on residual functional capacity, representing 5.7% of studies on baclofen use in SCI. In these studies it is difficult to differentiate the direct effects of baclofen on residual motor function vs the indirect effects mediated through a reduction in spasticity. Spasticity itself directly impairs muscle function, gait, and ADL. Specifically, spasticity in the lower limbs of individuals with incomplete SCI results in a loss of voluntary flexor muscle activity, while extensor spasms contribute strongly to loss of gait function.
      • Bravo-Esteban E
      • Taylor J
      • Abian-Vicen J
      • et al.
      Impact of specific symptoms of spasticity on voluntary lower limb muscle function, gait and daily activities during subacute and chronic spinal cord injury.
      In a more recent cross-sectional survey, 78% of participants reported that spasticity had some effect on their daily lives.
      • McKay WB
      • Sweatman WM
      • Field-Fote EC
      The experience of spasticity after spinal cord injury: perceived characteristics and impact on daily life.
      Stiffness affected daily living by interfering with exercise, grooming, dressing, and hygiene tasks, whereas involuntary muscle spasms and clonus were only weakly correlated to effects on daily living.
      • McKay WB
      • Sweatman WM
      • Field-Fote EC
      The experience of spasticity after spinal cord injury: perceived characteristics and impact on daily life.
      In this study, antispasticity medications were ineffective in 58% of respondents.
      • McKay WB
      • Sweatman WM
      • Field-Fote EC
      The experience of spasticity after spinal cord injury: perceived characteristics and impact on daily life.
      In the studies described below, motor function was assessed using mean changes in 10-m and 6-minute walk tests, functional improvement scores, or measures such as ability to carry out ADL or instrumental ADL.

      Improvements in walking

      One study of 3 participants reports improvements in spatiotemporal gait parameters in 2 individuals after baclofen administration,
      • Kitade I
      • Arishima H
      • Kikuta KI.
      Effect of the intrathecal baclofen screening test on the spatiotemporal gait motion parameters of patients with cervical spinal cord injuries who exhibited diffuse spasticity: a report of three cases.
      specifically a ∼13-second reduction in walking time, a reduction in the total step count (∼7 steps), and an increase in step length of ∼3.5 cm during the 10-m walking test.
      • Kitade I
      • Arishima H
      • Kikuta KI.
      Effect of the intrathecal baclofen screening test on the spatiotemporal gait motion parameters of patients with cervical spinal cord injuries who exhibited diffuse spasticity: a report of three cases.
      No marked improvements were noted in ADL.
      • Kitade I
      • Arishima H
      • Kikuta KI.
      Effect of the intrathecal baclofen screening test on the spatiotemporal gait motion parameters of patients with cervical spinal cord injuries who exhibited diffuse spasticity: a report of three cases.
      Another study of 12 individuals with incomplete SCI and varying degrees of walking abilities examined the effects of baclofen, cyproheptadine, and clonidine on walking function.
      • Norman KE
      • Pepin A
      • Barbeau H.
      Effects of drugs on walking after spinal cord injury.
      Overall, drug effects were more significant in those who could not walk overground.
      • Norman KE
      • Pepin A
      • Barbeau H.
      Effects of drugs on walking after spinal cord injury.
      More specifically, oral baclofen did not improve walking ability despite reducing spasticity, and in some individuals treadmill speed of walking actually increased during the washout period after baclofen administration.
      • Norman KE
      • Pepin A
      • Barbeau H.
      Effects of drugs on walking after spinal cord injury.
      After completion of this study, 7 individuals continued drug treatment, with only 1 individual continuing baclofen therapy in combination with cyproheptadine.
      • Norman KE
      • Pepin A
      • Barbeau H.
      Effects of drugs on walking after spinal cord injury.
      In line with previous findings, a 2016 study noted no functional improvements in walking or ambulation for 6 individuals receiving intrathecal baclofen with mean doses of 600 µg per day.
      • Clearfield JS
      • Nelson ME
      • McGuire J
      • Rein LE
      • Tarima S.
      Intrathecal baclofen dosing regimens: a retrospective chart review.

      Improvements in ADL and ease of caregiving

      One study involving 12 participants reported an increase in the FIM of 25.4 (from 50.9 to 76.3) after 6 months of intrathecal baclofen administration.
      • Azouvi P
      • Mane M
      • Thiebaut JB
      • Denys P
      • Remy-Neris O
      • Bussel B.
      Intrathecal baclofen administration for control of severe spinal spasticity: functional improvement and long-term follow-up.
      The functional improvement measure contains 18 items, each rated 1-7, where 7 involves 100% independence, assessing ability to carry out ADL in several domains to determine disability and likely necessity of care dependence.
      • Chumney D
      • Nollinger K
      • Shesko K
      • Skop K
      • Spencer M
      • Newton RA.
      Ability of Functional Independence Measure to accurately predict functional outcome of stroke-specific population: systematic review.
      In this study, motor functional independence measure walking score also increased from 3.6±0.9 to 5.8±0.2 after 6 months.
      • Azouvi P
      • Mane M
      • Thiebaut JB
      • Denys P
      • Remy-Neris O
      • Bussel B.
      Intrathecal baclofen administration for control of severe spinal spasticity: functional improvement and long-term follow-up.
      In a separate study, an improvement of 23.25 in the Barthel Index scale after 6 weeks of oral baclofen use for 75 patients with mean age of 36 years was reported.
      • Luo D
      • Wu G
      • Ji Y
      • et al.
      The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury.
      Improvements in instrumental ADL scores for 1 participant in a report of 2 participants noted improvements in dressing, bathing, clipping toenails, and transfer measures such as moving without supervision and driving.
      • Becker WJ
      • Harris CJ
      • Long ML
      • Ablett DP
      • Klein GM
      • DeForge DA.
      Long-term intrathecal baclofen therapy in patients with intractable spasticity.

      Adverse events

      A total of 43 studies (∼41 % of all studies) discussed expected or unexpected adverse events associated with baclofen. Of the 43 studies, 15 were associated with oral dosing of baclofen only. The most common complication was muscle weakness reported in 15 studies and at least 107 individuals with SCI (56 oral), followed by fatigue, which was reported in 20 studies with at least 69 individuals with SCI (12 oral). Other frequently reported adverse events were nausea (∼18 participants [6 oral]), dizziness (∼16 participants [9 oral]), altered mental status or hallucination (∼13 participants), overdose (∼15 participants [1 oral]), erectile dysfunction (∼13 participants), withdrawal (∼9 participants), hypotension (∼13 participants [1 oral]), infection (∼5 participants), respiratory depression (∼5 participants), and bloating and constipation (∼6 participants) (Fig 5).
      Fig 5
      Fig 5Adverse events reported after oral and intrathecal baclofen administration. Bar chart (left axis) illustrates no. of individuals reporting adverse events, with the no. of publications reported on the right axis (line plot).

      Randomized controlled trials

      While several studies have reported on baclofen's efficacy in managing spasticity, only 6 of these studies were randomized controlled trials conducted in patients with SCI.
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      ,
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      ,
      • Yan X
      • Lan J
      • Liu Y
      • Miao J.
      Efficacy and safety of botulinum toxin type A in spasticity caused by spinal cord injury: a randomized, controlled trial.
      • Kumru H
      • Benito-Penalva J
      • Kofler M
      • Vidal J.
      Analgesic effect of intrathecal baclofen bolus on neuropathic pain in spinal cord injury patients.
      • Luo D
      • Wu G
      • Ji Y
      • et al.
      The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury.
      • Nance PW
      • Huff FJ
      • Martinez-Arizala A
      • et al.
      Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.
      Of these trials, 3 studies examined the efficacy of intrathecal baclofen administration,
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      ,
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      ,
      • Kumru H
      • Benito-Penalva J
      • Kofler M
      • Vidal J.
      Analgesic effect of intrathecal baclofen bolus on neuropathic pain in spinal cord injury patients.
      with another 2 comparative studies
      • Yan X
      • Lan J
      • Liu Y
      • Miao J.
      Efficacy and safety of botulinum toxin type A in spasticity caused by spinal cord injury: a randomized, controlled trial.
      ,
      • Luo D
      • Wu G
      • Ji Y
      • et al.
      The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury.
      examining the efficacy of oral baclofen and 1 study examining the efficacy of the baclofen isomer (arbaclofen placarbil).
      • Nance PW
      • Huff FJ
      • Martinez-Arizala A
      • et al.
      Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.

      Intrathecal baclofen trials

      In 1993, Coffey et al conducted one of the largest and most robust trials in which 93 patients (59 SCI, 31 multiple sclerosis, 3 other pathologies) were enrolled in a randomized, double-blind, placebo-controlled trial comparing the acute effects of test injections of varying doses of baclofen (50, 75, or 100µg) or placebo to determine whether individuals qualified for implantation of an intrathecal baclofen pump. During these screening assessments, no patients responded to the placebo injection; however, in 94.6% of participants, baclofen injections reduced MAS and spasm scores by at least 2 points.
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      Of these patients who passed the screening assessments, 75 individuals (47 SCI, 27 MS, 1 other) underwent pump implantation to examine long-term administration of intrathecal baclofen; however, this portion of the trial was not placebo-controlled. During the 19-month follow-up period, long-term intrathecal administration of baclofen reduced the MAS score by an average of 2.1 for patients with SCI, with a concomitant average reduction in muscle spasm score of 2.2.
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      This reduction remained stable over time.
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      The effective daily dose of intrathecal baclofen increased over the duration of the study from 187 to 405 μg/d on average, with doses typically higher in individuals with SCI (increased from 196μg/d to 462μg/d, on average).
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      Drug-related adverse effects were observed in 3 patients in the screening trial and 8 patients in the chronic therapy phase of the trial.
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      These included hypo- and hypertension, seizure, depression, drowsiness, temporary weakness, and respiratory depression. Thirty-one device-related complications occurred across 28 individuals, requiring a secondary surgical or invasive procedure (did not report diagnosis group allocation).
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      This study did not report effects on motor function or ADL outcomes. In 1989, Penn et al performed a randomized double-blinded, crossover study of intrathecal baclofen use in 20 patients, 10 of whom had SCI and the other 10 were patients with multiple sclerosis.
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      All enrolled patients had previously failed maximum oral dosage of baclofen. During the blinded placebo-controlled crossover portion of the study, MAS score decreased by 2.8 points, and the spasm score decreased by 2.9 points across the entire study group after baclofen but not saline infusion.
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      In all 10 individuals with SCI, intrathecal baclofen decreased both MAS and spasm scores by an average of 2.7±1.3 and 2.8±1.1, respectively.
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      During long-term follow-up of these individuals in an open trial of intrathecal baclofen (∼19 months, not placebo-controlled), the reductions in MAS and spasm scores were maintained.
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      Dosing of intrathecal baclofen varied considerably across patients, ranging from 62-749 μg/d.
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      Device-related complications such as dislodgement, pump failure, and pain at the implantation site were reported; however, no drug-related adverse events such as confusion or drowsiness were noted.
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      Lastly, it was reported that during maintenance treatment, many patients reported improvements in ADL such as self-care, transferring, sleeping, and urinary continence.
      • Penn RD
      • Savoy SM
      • Corcos D
      • et al.
      Intrathecal baclofen for severe spinal spasticity.
      In a 2018 study, Kumru et al performed a randomized, double-blinded, placebo-controlled trial examining the acute effects of a single bolus of intrathecal baclofen vs saline on neuropathic pain unrelated to spasticity in 11 individuals with SCI. Although not a primary outcome, MAS was significantly reduced in the intrathecal baclofen group (pre: 2.0±1.3 vs post: 0.0±0.1) but not in the placebo group.
      • Kumru H
      • Benito-Penalva J
      • Kofler M
      • Vidal J.
      Analgesic effect of intrathecal baclofen bolus on neuropathic pain in spinal cord injury patients.

      Oral baclofen trials

      To date, 3 randomized controlled trials have examined the efficacy of oral baclofen administration. In one of the largest studies to date, 336 patients with SCI were randomized to 3 different treatment groups: physical therapy alone, physical therapy with botulinum toxin type A, or physical therapy with baclofen in a 1:1:1 ratio.
      • Yan X
      • Lan J
      • Liu Y
      • Miao J.
      Efficacy and safety of botulinum toxin type A in spasticity caused by spinal cord injury: a randomized, controlled trial.
      Outcome measures included MAS scores, Barthel Index, disability assessments, and modified Medical Research Council (mMRC) scores. MAS scores were significantly improved in the baclofen and botulinum toxin type A groups at the 2-week time point and beyond.
      • Yan X
      • Lan J
      • Liu Y
      • Miao J.
      Efficacy and safety of botulinum toxin type A in spasticity caused by spinal cord injury: a randomized, controlled trial.
      It took 4 weeks for spasticity to significantly improve in the physical therapy group; however, at the 6-week time point, there were no significant differences in improvements of MAS scores between the baclofen and physical therapy only groups.
      • Yan X
      • Lan J
      • Liu Y
      • Miao J.
      Efficacy and safety of botulinum toxin type A in spasticity caused by spinal cord injury: a randomized, controlled trial.
      The Barthel Index functional outcome scores were increased within 2 weeks after baclofen administration compared with physical therapy alone.
      • Yan X
      • Lan J
      • Liu Y
      • Miao J.
      Efficacy and safety of botulinum toxin type A in spasticity caused by spinal cord injury: a randomized, controlled trial.
      Again, improvements in the Barthel Index occurred only at the 6-week time point in the physical therapy only group. The Barthel Index assesses independence across 10 different activities, with a total assigned score from 0 (total dependence) to 100 (complete independence).
      • Hobart JC
      • Thompson AJ.
      The five item Barthel Index.
      ,
      • Sinoff G
      • Ore L.
      The Barthel Activities of Daily Living Index: self-reporting versus actual performance in the old-old (>or = 75 years).
      Because this index is a combined measure of independence across ease of caregiving, ADL, and motor tasks (eg, ambulation, stair climbing), it is difficult to determine which specific tasks were improved with baclofen administration. In line with these findings, improvements in disability assessment scores and mMRC scores occurred earlier (2-week and 4-week time points, respectively). While baclofen was associated with improvements in mMRC scores, those receiving physical therapy alone failed to demonstrate an improvement in these scores.
      • Yan X
      • Lan J
      • Liu Y
      • Miao J.
      Efficacy and safety of botulinum toxin type A in spasticity caused by spinal cord injury: a randomized, controlled trial.
      Adverse effects of oral baclofen administration were noted and included asthenia and sleepiness.
      • Yan X
      • Lan J
      • Liu Y
      • Miao J.
      Efficacy and safety of botulinum toxin type A in spasticity caused by spinal cord injury: a randomized, controlled trial.
      Luo et al conducted a randomized, comparative trial of oral baclofen (n=75) vs oral tolperisone (n=75) in patients with spasticity due to SCI.
      • Luo D
      • Wu G
      • Ji Y
      • et al.
      The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury.
      In the baclofen group, MAS score decreased by 1.79 points (3.34±0.05 to 1.55±0.05), with improvements in muscle strength (mMRC scale; 1.31±0.05 to 2.79±0.03) and functional outcomes measured by the Barthel index (36.05±1.41 to 59.31±1.32).
      • Luo D
      • Wu G
      • Ji Y
      • et al.
      The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury.
      Similar improvements in spasticity and muscle strength were obtained after oral administration of tolperisone after 6 weeks; however, a greater improvement in the Barthel Index was observed (38.53±1.41 to 73.35±1.32).
      • Luo D
      • Wu G
      • Ji Y
      • et al.
      The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury.
      Adverse events were reported with increased incidence after baclofen administration compared with tolperisone (36 vs 14 adverse events), with asthenia cited as the most frequently reported adverse effect.
      • Luo D
      • Wu G
      • Ji Y
      • et al.
      The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury.
      In 2011, Nance et al conducted a multiple-dose, randomized, double-blinded placebo-controlled trial examining the efficacy of arbaclofen placarbil, a prodrug of the R-isomer of baclofen that allows for an extended-release oral formulation. Thirty-seven individuals with spasticity due to SCI were enrolled. Ten individuals were randomized to the 10-mg arbaclofen placarbil/placebo group, 13 patients to the 20-mg arbaclofen placarbil/placebo group, and 14 patients to the 30-mg arbaclofen placarbil/placebo group.
      • Nance PW
      • Huff FJ
      • Martinez-Arizala A
      • et al.
      Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.
      Compared with placebo, the 20- and 30-mg arbaclofen placarbil doses significantly reduced MAS scores and patient-reported weekly average spasticity severity measures.
      • Nance PW
      • Huff FJ
      • Martinez-Arizala A
      • et al.
      Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.
      No differences were noted in secondary outcome measures of muscle strength, night-time awakening due to muscle spasms, pain severity, or sleep quality.
      • Nance PW
      • Huff FJ
      • Martinez-Arizala A
      • et al.
      Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.
      At least 1 treatment-related adverse event was reported in 75.7% of individuals receiving arbaclofen placarbil and in 48.6% of individuals receiving placebo.
      • Nance PW
      • Huff FJ
      • Martinez-Arizala A
      • et al.
      Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.
      Across all groups, the most commonly reported adverse events were urinary tract infection, pain, insomnia, and nasopharyngitis, with pain and insomnia uniquely associated with administration of arbaclofen placarbil.
      • Nance PW
      • Huff FJ
      • Martinez-Arizala A
      • et al.
      Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.
      Additionally, dizziness was an adverse event with a high incidence (14.3%) in the high-dose (30mg) arbaclofen placarbil group only.
      • Nance PW
      • Huff FJ
      • Martinez-Arizala A
      • et al.
      Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.
      Adverse events typically associated with baclofen use were infrequent after administration of arbaclofen placarbil.
      • Nance PW
      • Huff FJ
      • Martinez-Arizala A
      • et al.
      Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.

      Discussion

      The present review of 98 studies is a comprehensive review of baclofen use specific to SCI and demonstrates (1) there is a lack of pivotal trials with robust study method to examine efficacy of baclofen administration in the population with SCI; (2) efficacy as defined by reduction in MAS and Penn Spasm score were consistently reported after both oral (short-term) and intrathecal (short- and long-term) administration; (3) there is limited evidence for functional motor improvement with oral or intrathecal administration; and (4) the most prevalent reports are related to drug-related adverse events and dosing. Most trials examined baclofen use across different pathologic indications, including SCI, multiple sclerosis, and stroke. Only 6 randomized controlled trials investigated the effects of baclofen on MAS score and spasm measures with variation in specificity for SCI, route of administration, and dosing. While baclofen is widely used clinically to control spasticity after SCI, the lack of robust quantitative efficacy measures and the limited number of randomized, double blinded, placebo-controlled clinical trials should be considered and addressed. Additionally, a host of adverse events are associated with its use that may significantly affect quality of life, affect residual motor function, and lead to additional invasive operations.
      • Coffey JR
      • Cahill D
      • Steers W
      • et al.
      Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
      ,
      • Nance PW
      • Huff FJ
      • Martinez-Arizala A
      • et al.
      Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.
      ,
      • Coffey RJ
      • Edgar TS
      • Francisco GE
      • et al.
      Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially life-threatening syndrome.
      Given the heterogeneity of SCI presentation, minimal clinically important differences are challenging to determine for patients with SCI.
      • Wu X
      • Liu J
      • Tanadini LG
      • et al.
      Challenges for defining minimal clinically important difference (MCID) after spinal cord injury.
      However, minimal clinically important differences may at least be considered greater than the minimal detectable difference to determine clinical improvement.
      • Wu X
      • Liu J
      • Tanadini LG
      • et al.
      Challenges for defining minimal clinically important difference (MCID) after spinal cord injury.
      For more quantitative functional tests such as the 10-m walk test, the minimal detectable difference has been determined to be 0.06-0.13 minutes
      • Musselman KE
      • Yang JF.
      Walking tasks encountered by urban-dwelling adults and persons with incomplete spinal cord injuries.
      ,
      • Lam T
      • Noonan VK
      • Eng JJ
      • Team SR.
      A systematic review of functional ambulation outcome measures in spinal cord injury.
      or 45.8 m for the 6-minute walk test.
      • Lam T
      • Noonan VK
      • Eng JJ
      • Team SR.
      A systematic review of functional ambulation outcome measures in spinal cord injury.
      Semiquantitative ordinal rating scales such as the MAS or Penn Spasm Scale may be more difficult to determine a universal clinical improvement for patients with SCI. The MAS score is often used clinically to evaluate clinical outcome of intervention or decide treatment in patients with spasticity.
      • Ashworth B
      Preliminary trial of carisoprodol in multiple sclerosis.
      ,
      • Alibiglou L
      • Rymer WZ
      • Harvey RL
      • Mirbagheri MM.
      The relation between Ashworth scores and neuromechanical measurements of spasticity following stroke.
      ,
      • Kawano O
      • Masuda M
      • Takao T
      • et al.
      The dosage and administration of long-term intrathecal baclofen therapy for severe spasticity of spinal origin.
      Developed in 1964, the MAS was originally created for evaluation of patients with multiple sclerosis.
      • Ashworth B
      Preliminary trial of carisoprodol in multiple sclerosis.
      Based on an analysis of patients with stroke, the Rehabilitation Institute of Chicago has reported 1 point in the MAS scale suggests a clinically meaningful improvement.

      Rehab measure: Ashworth Scale/Modified Ashworth Scale. Available at: https://www.sralab.org/rehabilitation-measures/ashworth-scale-modified-ashworth-scale. Accessed August 2021.

      Because of questionable interrater reliability and validity, concerns of variability and accuracy exist in reporting methods of Ashworth scores.
      • Mutlu A
      • Livanelioglu A
      • Gunel MK.
      Reliability of Ashworth and Modified Ashworth Scales in children with spastic cerebral palsy.
      ,
      • Fleuren JF
      • Voerman GE
      • Erren-Wolters CV
      • et al.
      Stop using the Ashworth Scale for the assessment of spasticity.
      Alibiglou et al compared quantitative neuromechanical assessments of reflex stiffness for patients with spasticity from stroke and found no correlation between muscle stiffness and torque with Ashworth score.
      • Alibiglou L
      • Rymer WZ
      • Harvey RL
      • Mirbagheri MM.
      The relation between Ashworth scores and neuromechanical measurements of spasticity following stroke.
      Fleuren et al also demonstrate no association between flexion electromyographic activity parameters and MAS score. Another study contradicts the reliability of the MAS on evaluation of spasticity that showed poor and moderate interrater reliability from the intraclass correlations coefficient. Further, they recommend interpreting scores with great caution and advise to stop using MAS score for spasticity assessments.
      • Mutlu A
      • Livanelioglu A
      • Gunel MK.
      Reliability of Ashworth and Modified Ashworth Scales in children with spastic cerebral palsy.
      ,
      • Fleuren JF
      • Voerman GE
      • Erren-Wolters CV
      • et al.
      Stop using the Ashworth Scale for the assessment of spasticity.
      It is unclear if even significant improvements in MAS score equate to functional improvements or enhanced quality of life in this patient population.
      Despite the high prevalence of baclofen as a first-line treatment for spasticity after SCI,
      • Chang E
      • Ghosh N
      • Yanni D
      • Lee S
      • Alexandru D
      • Mozaffar T.
      A review of spasticity treatments: pharmacological and interventional approaches.
      more studies are needed to systematically examine whether baclofen remains the most promising treatment in individuals with SCI. Specifically, the mechanisms driving the development of spasticity after SCI are not likely to be the same across different pathologies. Therefore, it is surprising that most studies group together patients across different pathologies. Second, the reliability, validity, and responsiveness of the tools available to assess the efficacy of baclofen on spasticity and function remains unexplored if not inconclusive. Promising results have been demonstrated in studies comparing baclofen use with other pharmacologic and nonpharmacologic treatments.
      • Norman KE
      • Pepin A
      • Barbeau H.
      Effects of drugs on walking after spinal cord injury.
      ,
      • Luo D
      • Wu G
      • Ji Y
      • et al.
      The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury.
      While baclofen may work centrally to reduce spastic activity, it may mask clinical motor examination and inhibit voluntary movement recovery.
      • Angeli C
      • Ochsner J
      • Harkema S.
      Effects of chronic baclofen use on active movement in an individual with a spinal cord injury.
      ,
      • Theriault ER
      • Huang V
      • Whiteneck G
      • Dijkers MP
      • Harel NY.
      Antispasmodic medications may be associated with reduced recovery during inpatient rehabilitation after traumatic spinal cord injury.
      Additionally, inclusion of quality of life metrics may benefit the current analysis as other outcome measures that indicate severity of burden associated with drug-related adverse events.

      Pharmacologic alternatives

      Like baclofen, most pharmacologic treatments are associated with their own adverse event profiles; however, some studies have indicated that while baclofen has detrimental effects on motor function, other drugs may improve function. Specifically, in 78 individuals with SCI, tizanidine (and clonidine), a noradrenergic α2 receptor agonist, effectively reduced MAS scores compared with placebo, with no change in residual walking function and ADL.
      • Wainberg M
      • Barbeau H
      • Gauthier S.
      Quantitative assessment of the effect of cyproheptadine on spastic paretic gait: a preliminary study.
      ,
      • Barbeau H
      • Norman KE.
      The effect of noradrenergic drugs on the recovery of walking after spinal cord injury.
      ,
      • Norman KE
      • Pepin A
      • Barbeau H.
      Effects of drugs on walking after spinal cord injury.
      ,
      • Nance PW.
      A comparison of clonidine, cyproheptadine and baclofen in spastic spinal cord injured patients.
      • Wainberg M
      • Barbeau H
      • Gauthier S.
      The effects of cyproheptadine on locomotion and on spasticity in patients with spinal cord injuries.
      • Nance PW
      • Bugaresti J
      • Shellenberger K
      • Sheremata W
      • Martinez-Arizala A.
      Efficacy and safety of tizanidine in the treatment of spasticity in patients with spinal cord injury. North American Tizanidine Study Group.
      Tizanidine may be used cautiously in patients with kidney or hepatic dysfunction given its kidney clearance and risk of hepatotoxicity, requiring monitoring of creatinine and aminotransferase levels.
      • Newman PM
      • Nogues M
      • Newman PK
      • Weightman D
      • Hudgson P.
      Tizanidine in the treatment of spasticity.
      Additionally, tizanidine is known to prolong the QT interval and may interact with other commonly prescribed medications in this patient population with similar QT-prolonging effects such as fluoroquinolones.
      • Kaddar N
      • Vigneault P
      • Pilote S
      • Patoine D
      • Simard C
      • Drolet B.
      Tizanidine (Zanaflex): a muscle relaxant that may prolong the QT interval by blocking IKr.
      In 25 participants with SCI, the off-label administration of cyproheptadine, a nonspecific serotonergic (5HT2) and noradrenergic (α1) receptor blocker, was as effective as baclofen and clonidine in reducing excessive muscle activity.
      • Nance PW.
      A comparison of clonidine, cyproheptadine and baclofen in spastic spinal cord injured patients.
      Cyproheptadine at low doses improved residual walking function in individuals with incomplete SCI.
      • Wainberg M
      • Barbeau H
      • Gauthier S.
      The effects of cyproheptadine on locomotion and on spasticity in patients with spinal cord injuries.
      Other pharmacologic treatments used to treat spasticity after SCI by targeting the GABAergic system (similar to baclofen) include diazepam
      • Polc P
      • Mohler H
      • Haefely W.
      The effect of diazepam on spinal cord activities: possible sites and mechanisms of action.
      ,
      • Sieghart W.
      Pharmacology of benzodiazepine receptors: an update.
      and gabapentin
      • Taylor CP.
      Emerging perspectives on the mechanism of action of gabapentin.
      ,
      • Sills GJ.
      The mechanisms of action of gabapentin and pregabalin.
      ; however, no quantitative evidence supports substantial clinical effects. Botulinum toxin injections also provide localized relief from spasticity symptoms by blocking the release of acetylcholine at the neuromuscular junction with repeated injections required because of the waning effects after 2-4 months.
      • Das TK
      • Park DM.
      Botulinum toxin in treating spasticity.
      • Das TK
      • Park DM.
      Effect of treatment with botulinum toxin on spasticity.
      • Simpson LL.
      Identification of the major steps in botulinum toxin action.
      • Fortuna R
      • Horisberger M
      • Vaz MA
      • Herzog W.
      Do skeletal muscle properties recover following repeat onabotulinum toxin A injections?.
      However, this comes at the cost of further reducing muscle strength and an increase in the amount of noncontractile muscle tissue.
      • Fortuna R
      • Horisberger M
      • Vaz MA
      • Herzog W.
      Do skeletal muscle properties recover following repeat onabotulinum toxin A injections?.
      Despite potential pharmacologic alternatives to baclofen, depression of central nervous system excitability cannot be avoided. Therefore, treatment of spasticity through or in combination with nonpharmacologic methods may remain a more suitable alternative when possible.

      Nonpharmacologic alternatives

      Nonpharmacologic alternatives to treating spasticity after SCI vary based on residual motor capacity of the individual. The first line of physical therapy treatment applicable for most individuals aims to maintain joint range of motion through stretching exercises and passive movements.
      • Bovend'Eerdt TJ
      • Newman M
      • Barker K
      • Dawes H
      • Minelli C
      • Wade DT.
      The effects of stretching in spasticity: a systematic review.
      • Harvey LA
      • Herbert RD
      • Glinsky J
      • Moseley AM
      • Bowden J.
      Effects of 6 months of regular passive movements on ankle joint mobility in people with spinal cord injury: a randomized controlled trial.
      • Odeen I
      • Knutsson E.
      Evaluation of the effects of muscle stretch and weight load in patients with spastic paraplegia.
      • Rayegani SM
      • Shojaee H
      • Sedighipour L
      • Soroush MR
      • Baghbani M
      • Amirani OB.
      The effect of electrical passive cycling on spasticity in war veterans with spinal cord injury.
      These techniques have effectively reduced measurements of spasticity; however, results are inconsistent regarding improvements in motor function because of reduced spasticity. While the above techniques may be considered “passive,” alternatives involving voluntary contractions of the muscle for individuals with residual motor capacity have shown promise in treating spasticity. Locomotor training reduces ankle clonus, flexor, and extensor spasms as well as cocontraction while improving strength, walking speed, and self-reported mobility.
      • Gorassini MA
      • Norton JA
      • Nevett-Duchcherer J
      • Roy FD
      • Yang JF.
      Changes in locomotor muscle activity after treadmill training in subjects with incomplete spinal cord injury.
      • Adams MM
      • Hicks AL.
      Comparison of the effects of body-weight-supported treadmill training and tilt-table standing on spasticity in individuals with chronic spinal cord injury.
      • Manella KJ
      • Field-Fote EC.
      Modulatory effects of locomotor training on extensor spasticity in individuals with motor-incomplete spinal cord injury.
      Resistance training is another intervention that may reduce spasticity without the adverse events associated with pharmacologic agents.
      • Jayaraman A
      • Thompson CK
      • Rymer WZ
      • Hornby TG.
      Short-term maximal-intensity resistance training increases volitional function and strength in chronic incomplete spinal cord injury: a pilot study.
      ,

      Hsieh JTC, Wolfe DL, McIntyre A, et al. Spasticity following spinal cord injury. 2012. Available at: https://scireproject.com/wp-content/uploads/2022/04/spasticity_V7.pdf. Accessed August 25, 2022.

      Electrical stimulation of the nervous system has also been used to manage spasticity with no detriment to motor function. Peripheral nerve stimulation of different intensities has been demonstrated to reduce spasticity
      • Marsolais EB
      • Kobetic R.
      Development of a practical electrical stimulation system for restoring gait in the paralyzed patient.
      • van der Salm A
      • Veltink PH
      • Ijzerman MJ
      • Groothuis-Oudshoorn KC
      • Nene AV
      • Hermens HJ.
      Comparison of electric stimulation methods for reduction of triceps surae spasticity in spinal cord injury.
      • Carty A
      • McCormack K
      • Coughlan GF
      • Crowe L
      • Caulfield B.
      Alterations in body composition and spasticity following subtetanic neuromuscular electrical stimulation training in spinal cord injury.
      and sometimes to a similar extent as baclofen, even at intensities of stimulation that do not produce muscle contractions (transcutaneous electrical nerve stimulations at 100Hz).
      • Aydin G
      • Tomruk S
      • Keles I
      • Demir SO
      • Orkun S.
      Transcutaneous electrical nerve stimulation versus baclofen in spasticity: clinical and electrophysiologic comparison.
      More sophisticated stimulation techniques that are not common practice in the clinic have also demonstrated promise in reducing spasticity after SCI. Noninvasive brain stimulation paradigms using transcranial magnetic stimulation delivered at different frequencies has effectively reduced spasticity measures and in some cases increased neurophysiological measurements of excitability in the short-term.
      • Kumru H
      • Murillo N
      • Samso JV
      • et al.
      Reduction of spasticity with repetitive transcranial magnetic stimulation in patients with spinal cord injury.
      • Nardone R
      • De Blasi P
      • Holler Y
      • et al.
      Repetitive transcranial magnetic stimulation transiently reduces punding in Parkinson's disease: a preliminary study.
      • Nardone R
      • Brigo F
      • Versace V
      • et al.
      Cortical afferent inhibition abnormalities reveal cholinergic dysfunction in Parkinson's disease: a reappraisal.
      Spinal cord stimulation, transcutaneously and through implanted epidural electrodes similarly improved spasticity measures while improving residual motor function; however, results have been variable.
      • Nagel SJ
      • Wilson S
      • Johnson MD
      • et al.
      Spinal cord stimulation for spasticity: historical approaches, current status, and future directions.
      It has been suggested that this variability in response is because of placement of the electrodes and implemented stimulation parameters.
      • Mesbah S
      • Ball T
      • Angeli C
      • et al.
      Predictors of volitional motor recovery with epidural stimulation in individuals with chronic spinal cord injury.
      In more recent work, stimulation from 50-100 Hz, delivered through implanted electrodes, improved passive stretch resistance and reduced the use of antispastic medication.
      • Pinter MM
      • Gerstenbrand F
      • Dimitrijevic MR.
      Epidural electrical stimulation of posterior structures of the human lumbosacral cord: 3. Control of spasticity.
      More so, noninvasive transcutaneous stimulation of the spinal cord at 50 Hz reduced MAS, clonus, and spasms, with clinically meaningful improvements lasting up to 2 hours post intervention.
      • Hofstoetter US
      • Freundl B
      • Danner SM
      • et al.
      Transcutaneous spinal cord stimulation induces temporary attenuation of spasticity in individuals with spinal cord injury.
      ,
      • Hofstoetter US
      • McKay WB
      • Tansey KE
      • Mayr W
      • Kern H
      • Minassian K.
      Modification of spasticity by transcutaneous spinal cord stimulation in individuals with incomplete spinal cord injury.
      More promising, the applicability of transcutaneous spinal cord stimulation as a home-based therapy was explored with progressive improvements in therapeutic effects.
      • Hofstoetter US
      • Freundl B
      • Danner SM
      • et al.
      Transcutaneous spinal cord stimulation induces temporary attenuation of spasticity in individuals with spinal cord injury.
      Walking function was also examined in this study, with variation in changes in the timed 10-m walk test across individuals
      • Hofstoetter US
      • Freundl B
      • Danner SM
      • et al.
      Transcutaneous spinal cord stimulation induces temporary attenuation of spasticity in individuals with spinal cord injury.
      ; however, the stimulation parameters used for the management of spasticity (50Hz) are not the same as those implemented for recovery of locomotion (typically ∼30Hz). Finally, most of the above studies focused on improvements in spasticity and effects on residual motor function in individuals with incomplete SCI; therefore, further examination of the potential applicability of these techniques to manage spasticity in individuals with severe SCI are warranted.

      Study limitations

      Limitations in the present review stem from the variability in study design, clinical assessments, and diagnostic indications across studies on baclofen use for spasticity in traumatic SCI. Heterogeneity of investigation designs (eg, retrospective, prospective, case series) with differing durations of treatment and modes of administration (intrathecal or oral) and a limited randomized controlled trial cohort may confound generalizability of the current findings. Additionally, many studies compare baclofen use across different pathologies and indications such as SCI and stroke that further reduces generalizability of claims made. Common assessments used in measurement of spasticity, including the Modified Ashworth score and Penn Spasm score have interrater reliability concerns that also confound validity of measurements in spasm and interfere with structured study comparisons of results and conclusions in a review or meta-analysis.

      Conclusions

      Current literature would benefit from improved study methods evaluating the clinical efficacy of baclofen in patients with SCI. Moderate improvements in spasticity is evident with baclofen; however, negative effects on residual motor function are not adequately addressed in the literature. Future prospective, double blinded, randomized controlled trials are necessary in patients with SCI and should compare baclofen with alternative treatment methods.

      Appendix. Supplementary materials

      References

        • Sekhon LH
        • Fehlings MG
        Epidemiology, demographics, and pathophysiology of acute spinal cord injury.
        Spine (Phila Pa 1976). 2001; 26: S2-12
        • Singh A
        • Tetreault L
        • Kalsi-Ryan S
        • Nouri A
        • Fehlings MG
        Global prevalence and incidence of traumatic spinal cord injury.
        Clin Epidemiol. 2014; 6: 309-331
        • Biering-Sorensen F
        • Nielsen JB
        • Klinge K
        Spasticity-assessment: a review.
        Spinal Cord. 2006; 44: 708-722
        • Pandyan AD
        • Gregoric M
        • Barnes MP
        • et al.
        Spasticity: clinical perceptions, neurological realities and meaningful measurement.
        Disabil Rehabil. 2005; 27: 2-6
        • Maynard FM
        • Karunas RS
        • Waring 3rd, WP
        Epidemiology of spasticity following traumatic spinal cord injury.
        Arch Phys Med Rehabil. 1990; 71: 566-569
        • Sherrington CS
        Decerebrate rigidity, and reflex coordination of movements.
        J Physiol. 1898; 22: 319-332
        • Skold C
        • Levi R
        • Seiger A
        Spasticity after traumatic spinal cord injury: nature, severity, and location.
        Arch Phys Med Rehabil. 1999; 80: 1548-1557
        • Dietz V
        Spastic movement disorder.
        Spinal Cord. 2000; 38: 389-393
        • McKay WB
        • Sweatman WM
        • Field-Fote EC
        The experience of spasticity after spinal cord injury: perceived characteristics and impact on daily life.
        Spinal Cord. 2018; 56: 478-486
        • Levi R
        • Hultling C
        • Seiger A
        The Stockholm Spinal Cord Injury Study. 3. Health-related issues of the Swedish Annual Level-of-Living Survey in SCI subjects and controls.
        Paraplegia. 1995; 33: 726-730
        • Andresen SR
        • Biering-Sorensen F
        • Hagen EM
        • Nielsen JF
        • Bach FW
        • Finnerup NB
        Pain, spasticity and quality of life in individuals with traumatic spinal cord injury in Denmark.
        Spinal Cord. 2016; 54: 973-979
        • Little JW
        • Micklesen P
        • Umlauf R
        • Britell C
        Lower extremity manifestations of spasticity in chronic spinal cord injury.
        Am J Phys Med Rehabil. 1989; 68: 32-36
        • Tibbett J
        • Widerstrom-Noga EG
        • Thomas CK
        • Field-Fote EC
        Impact of spasticity on transfers and activities of daily living in individuals with spinal cord injury.
        J Spinal Cord Med. 2019; 42: 318-327
        • Mailis A
        • Ashby P
        Alterations in group Ia projections to motoneurons following spinal lesions in humans.
        J Neurophysiol. 1990; 64: 637-647
        • Faist M
        • Mazevet D
        • Dietz V
        • Pierrot-Deseilligny E
        A quantitative assessment of presynaptic inhibition of Ia afferents in spastics. Differences in hemiplegics and paraplegics.
        Brain. 1994; 117: 1449-1455
        • Aymard C
        • Katz R
        • Lafitte C
        • et al.
        Presynaptic inhibition and homosynaptic depression: a comparison between lower and upper limbs in normal human subjects and patients with hemiplegia.
        Brain. 2000; 123: 1688-1702
        • Crone C
        • Nielsen J
        • Petersen N
        • Ballegaard M
        • Hultborn H
        Disynaptic reciprocal inhibition of ankle extensors in spastic patients.
        Brain. 1994; 117: 1161-1168
        • Crone C
        • Nielsen J
        Central control of disynaptic reciprocal inhibition in humans.
        Acta Physiol Scand. 1994; 152: 351-363
        • Crone C
        • Petersen NT
        • Nielsen JE
        • Hansen NL
        • Nielsen JB
        Reciprocal inhibition and corticospinal transmission in the arm and leg in patients with autosomal dominant pure spastic paraparesis (ADPSP).
        Brain. 2004; 127: 2693-2702
        • Calancie B
        • Broton JG
        • Klose KJ
        • Traad M
        • Difini J
        • Ayyar DR.
        Evidence that alterations in presynaptic inhibition contribute to segmental hypo- and hyperexcitability after spinal cord injury in man.
        Electroencephalogr Clin Neurophysiol. 1993; 89: 177-186
        • Schindler-Ivens S
        • Shields RK.
        Low frequency depression of H-reflexes in humans with acute and chronic spinal-cord injury.
        Exp Brain Res. 2000; 133: 233-241
        • Roby-Brami A
        • Bussel B.
        Long-latency spinal reflex in man after flexor reflex afferent stimulation.
        Brain. 1987; 110: 707-725
        • D'Amico JM
        • Condliffe EG
        • Martins KJ
        • Bennett DJ
        • Gorassini MA.
        Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity.
        Front Integr Neurosci. 2014; 8: 36
        • Sinkjaer T
        • Toft E
        • Larsen K
        • Andreassen S
        • Hansen HJ.
        Non-reflex and reflex mediated ankle joint stiffness in multiple sclerosis patients with spasticity.
        Muscle Nerve. 1993; 16: 69-76
        • Schindler-Ivens SM
        • Shields RK.
        Comparison of linear regression and probit analysis for detecting H-reflex threshold in individuals with and without spinal cord injury.
        Electromyogr Clin Neurophysiol. 2004; 44: 153-159
        • Mutlu A
        • Livanelioglu A
        • Gunel MK.
        Reliability of Ashworth and Modified Ashworth Scales in children with spastic cerebral palsy.
        BMC Musculoskelet Disord. 2008; 9: 44
        • Bohannon RW
        • Smith MB.
        Interrater reliability of a Modified Ashworth Scale of muscle spasticity.
        Phys Ther. 1987; 67: 206-207
        • Fleuren JF
        • Voerman GE
        • Erren-Wolters CV
        • et al.
        Stop using the Ashworth Scale for the assessment of spasticity.
        J Neurol Neurosurg Psychiatry. 2010; 81: 46-52
        • Ashworth B
        Preliminary trial of carisoprodol in multiple sclerosis.
        Practitioner. 1964; 192: 540-542
        • Penn RD
        • Savoy SM
        • Corcos D
        • et al.
        Intrathecal baclofen for severe spinal spasticity.
        N Engl J Med. 1989; 320: 1517-1521
        • Baunsgaard CB
        • Nissen UV
        • Christensen KB
        Biering-Sorensen F. Modified Ashworth Scale and spasm frequency score in spinal cord injury: reliability and correlation.
        Spinal Cord. 2016; 54: 702-708
        • Haugh AB
        • Pandyan AD
        • Johnson GR.
        A systematic review of the Tardieu Scale for the measurement of spasticity.
        Disabil Rehabil. 2006; 28: 899-907
        • Akpinar P
        • Atici A
        • Ozkan FU
        • et al.
        Reliability of the Modified Ashworth Scale and Modified Tardieu Scale in patients with spinal cord injuries.
        Spinal Cord. 2017; 55: 944-949
        • Sammaraiee Y
        • Yardley M
        • Keenan L
        • Buchanan K
        • Stevenson V
        • Farrell R
        Intrathecal baclofen for multiple sclerosis related spasticity: a twenty year experience.
        Mult Scler Relat Disord. 2018; 27: 95-100
        • Penn RD.
        Intrathecal baclofen for spasticity of spinal origin: seven years of experience.
        J Neurosurg. 1992; 77: 236-240
        • Curtis DR
        • Gynther BD
        • Lacey G
        • Beattie DT.
        Baclofen: reduction of presynaptic calcium influx in the cat spinal cord in vivo.
        Exp Brain Res. 1997; 113: 520-533
        • Shimizu T
        • Hino T
        • Komori T
        • Hirai S.
        Loss of the muscle silent period evoked by transcranial magnetic stimulation of the motor cortex in patients with cervical cord lesions.
        Neurosci Lett. 2000; 286: 199-202
        • Kumru H
        • Kofler M.
        Effect of spinal cord injury and of intrathecal baclofen on brainstem reflexes.
        Clin Neurophysiol. 2012; 123: 45-53
        • Ochs G
        • Struppler A
        • Meyerson BA
        • et al.
        Intrathecal baclofen for long-term treatment of spasticity: a multi-centre study.
        J Neurol Neurosurg Psychiatry. 1989; 52: 933-939
        • Balsara K
        • Jea A
        • Raskin JS.
        Neurosurgical management of spastic conditions of the upper extremity.
        Hand Clin. 2018; 34: 547-554
        • Ertzgaard P
        • Campo C
        • Calabrese A.
        Efficacy and safety of oral baclofen in the management of spasticity: a rationale for intrathecal baclofen.
        J Rehabil Med. 2017; 49: 193-203
        • Coffey JR
        • Cahill D
        • Steers W
        • et al.
        Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study.
        J Neurosurg. 1993; 78: 226-232
        • Wainberg M
        • Barbeau H
        • Gauthier S.
        Quantitative assessment of the effect of cyproheptadine on spastic paretic gait: a preliminary study.
        J Neurol. 1986; 233: 311-314
        • Angeli C
        • Ochsner J
        • Harkema S.
        Effects of chronic baclofen use on active movement in an individual with a spinal cord injury.
        Spinal Cord. 2012; 50: 925-927
        • Barbeau H
        • Norman KE.
        The effect of noradrenergic drugs on the recovery of walking after spinal cord injury.
        Spinal Cord. 2003; 41: 137-143
        • Norman KE
        • Pepin A
        • Barbeau H.
        Effects of drugs on walking after spinal cord injury.
        Spinal Cord. 1998; 36: 699-715
        • Hobart JC
        • Thompson AJ.
        The five item Barthel Index.
        J Neurol Neurosurg Psychiatry. 2001; 71: 225-230
        • Sinoff G
        • Ore L.
        The Barthel Activities of Daily Living Index: self-reporting versus actual performance in the old-old (>or = 75 years).
        J Am Geriatr Soc. 1997; 45: 832-836
        • Moher D
        • Liberati A
        • Tetzlaff J
        • Altman DG
        • PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        J Clin Epidemiol. 2009; 62: 1006-1012
        • Yan X
        • Lan J
        • Liu Y
        • Miao J.
        Efficacy and safety of botulinum toxin type A in spasticity caused by spinal cord injury: a randomized, controlled trial.
        Med Sci Monit. 2018; 24: 8160-8171
        • Kumru H
        • Benito-Penalva J
        • Kofler M
        • Vidal J.
        Analgesic effect of intrathecal baclofen bolus on neuropathic pain in spinal cord injury patients.
        Brain Res Bull. 2018; 140: 205-211
        • Luo D
        • Wu G
        • Ji Y
        • et al.
        The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury.
        Saudi Pharm J. 2017; 25: 655-659
        • Nance PW
        • Huff FJ
        • Martinez-Arizala A
        • et al.
        Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.
        Spinal Cord. 2011; 49: 974-980
        • Bravo-Esteban E
        • Taylor J
        • Abian-Vicen J
        • et al.
        Impact of specific symptoms of spasticity on voluntary lower limb muscle function, gait and daily activities during subacute and chronic spinal cord injury.
        NeuroRehabilitation. 2013; 33: 531-543
        • Kitade I
        • Arishima H
        • Kikuta KI.
        Effect of the intrathecal baclofen screening test on the spatiotemporal gait motion parameters of patients with cervical spinal cord injuries who exhibited diffuse spasticity: a report of three cases.
        NMC Case Rep J. 2014; 1: 20-23
        • Clearfield JS
        • Nelson ME
        • McGuire J
        • Rein LE
        • Tarima S.
        Intrathecal baclofen dosing regimens: a retrospective chart review.
        Neuromodulation. 2016; 19: 642-649
        • Azouvi P
        • Mane M
        • Thiebaut JB
        • Denys P
        • Remy-Neris O
        • Bussel B.
        Intrathecal baclofen administration for control of severe spinal spasticity: functional improvement and long-term follow-up.
        Arch Phys Med Rehabil. 1996; 77: 35-39
        • Chumney D
        • Nollinger K
        • Shesko K
        • Skop K
        • Spencer M
        • Newton RA.
        Ability of Functional Independence Measure to accurately predict functional outcome of stroke-specific population: systematic review.
        J Rehabil Res Dev. 2010; 47: 17-29
        • Becker WJ
        • Harris CJ
        • Long ML
        • Ablett DP
        • Klein GM
        • DeForge DA.
        Long-term intrathecal baclofen therapy in patients with intractable spasticity.
        Can J Neurol Sci. 1995; 22: 208-217
        • Coffey RJ
        • Edgar TS
        • Francisco GE
        • et al.
        Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially life-threatening syndrome.
        Arch Phys Med Rehabil. 2002; 83: 735-741
        • Wu X
        • Liu J
        • Tanadini LG
        • et al.
        Challenges for defining minimal clinically important difference (MCID) after spinal cord injury.
        Spinal Cord. 2015; 53: 84-91
        • Musselman KE
        • Yang JF.
        Walking tasks encountered by urban-dwelling adults and persons with incomplete spinal cord injuries.
        J Rehabil Med. 2007; 39: 567-574
        • Lam T
        • Noonan VK
        • Eng JJ
        • Team SR.
        A systematic review of functional ambulation outcome measures in spinal cord injury.
        Spinal Cord. 2008; 46: 246-254
        • Alibiglou L
        • Rymer WZ
        • Harvey RL
        • Mirbagheri MM.
        The relation between Ashworth scores and neuromechanical measurements of spasticity following stroke.
        J Neuroeng Rehabil. 2008; 5: 18
        • Kawano O
        • Masuda M
        • Takao T
        • et al.
        The dosage and administration of long-term intrathecal baclofen therapy for severe spasticity of spinal origin.
        Spinal Cord. 2018; 56: 996-999
      1. Rehab measure: Ashworth Scale/Modified Ashworth Scale. Available at: https://www.sralab.org/rehabilitation-measures/ashworth-scale-modified-ashworth-scale. Accessed August 2021.

        • Chang E
        • Ghosh N
        • Yanni D
        • Lee S
        • Alexandru D
        • Mozaffar T.
        A review of spasticity treatments: pharmacological and interventional approaches.
        Crit Rev Phys Rehabil Med. 2013; 25: 11-22
        • Theriault ER
        • Huang V
        • Whiteneck G
        • Dijkers MP
        • Harel NY.
        Antispasmodic medications may be associated with reduced recovery during inpatient rehabilitation after traumatic spinal cord injury.
        J Spinal Cord Med. 2018; 41: 63-71
        • Nance PW.
        A comparison of clonidine, cyproheptadine and baclofen in spastic spinal cord injured patients.
        J Am Paraplegia Soc. 1994; 17: 150-156
        • Wainberg M
        • Barbeau H
        • Gauthier S.
        The effects of cyproheptadine on locomotion and on spasticity in patients with spinal cord injuries.
        J Neurol Neurosurg Psychiatry. 1990; 53: 754-763
        • Nance PW
        • Bugaresti J
        • Shellenberger K
        • Sheremata W
        • Martinez-Arizala A.
        Efficacy and safety of tizanidine in the treatment of spasticity in patients with spinal cord injury. North American Tizanidine Study Group.
        Neurology. 1994; 44 ([discussion: S51-2]): S44-S51
        • Newman PM
        • Nogues M
        • Newman PK
        • Weightman D
        • Hudgson P.
        Tizanidine in the treatment of spasticity.
        Eur J Clin Pharmacol. 1982; 23: 31-35
        • Kaddar N
        • Vigneault P
        • Pilote S
        • Patoine D
        • Simard C
        • Drolet B.
        Tizanidine (Zanaflex): a muscle relaxant that may prolong the QT interval by blocking IKr.
        J Cardiovasc Pharmacol Ther. 2012; 17: 102-109
        • Polc P
        • Mohler H
        • Haefely W.
        The effect of diazepam on spinal cord activities: possible sites and mechanisms of action.
        Naunyn Schmiedebergs Arch Pharmacol. 1974; 284: 319-337
        • Sieghart W.
        Pharmacology of benzodiazepine receptors: an update.
        J Psychiatry Neurosci. 1994; 19: 24-29
        • Taylor CP.
        Emerging perspectives on the mechanism of action of gabapentin.
        Neurology. 1994; 44 (-6 [discussion: S31-2]): S10
        • Sills GJ.
        The mechanisms of action of gabapentin and pregabalin.
        Curr Opin Pharmacol. 2006; 6: 108-113
        • Das TK
        • Park DM.
        Botulinum toxin in treating spasticity.
        Br J Clin Pract. 1989; 43: 401-403
        • Das TK
        • Park DM.
        Effect of treatment with botulinum toxin on spasticity.
        Postgrad Med J. 1989; 65: 208-210
        • Simpson LL.
        Identification of the major steps in botulinum toxin action.
        Annu Rev Pharmacol Toxicol. 2004; 44: 167-193
        • Fortuna R
        • Horisberger M
        • Vaz MA
        • Herzog W.
        Do skeletal muscle properties recover following repeat onabotulinum toxin A injections?.
        J Biomech. 2013; 46: 2426-2433
        • Bovend'Eerdt TJ
        • Newman M
        • Barker K
        • Dawes H
        • Minelli C
        • Wade DT.
        The effects of stretching in spasticity: a systematic review.
        Arch Phys Med Rehabil. 2008; 89: 1395-1406
        • Harvey LA
        • Herbert RD
        • Glinsky J
        • Moseley AM
        • Bowden J.
        Effects of 6 months of regular passive movements on ankle joint mobility in people with spinal cord injury: a randomized controlled trial.
        Spinal Cord. 2009; 47: 62-66
        • Odeen I
        • Knutsson E.
        Evaluation of the effects of muscle stretch and weight load in patients with spastic paraplegia.
        Scand J Rehabil Med. 1981; 13: 117-121
        • Rayegani SM
        • Shojaee H
        • Sedighipour L
        • Soroush MR
        • Baghbani M
        • Amirani OB.
        The effect of electrical passive cycling on spasticity in war veterans with spinal cord injury.
        Front Neurol. 2011; 2: 39
        • Gorassini MA
        • Norton JA
        • Nevett-Duchcherer J
        • Roy FD
        • Yang JF.
        Changes in locomotor muscle activity after treadmill training in subjects with incomplete spinal cord injury.
        J Neurophysiol. 2009; 101: 969-979
        • Adams MM
        • Hicks AL.
        Comparison of the effects of body-weight-supported treadmill training and tilt-table standing on spasticity in individuals with chronic spinal cord injury.
        J Spinal Cord Med. 2011; 34: 488-494
        • Manella KJ
        • Field-Fote EC.
        Modulatory effects of locomotor training on extensor spasticity in individuals with motor-incomplete spinal cord injury.
        Restor Neurol Neurosci. 2013; 31: 633-646
        • Jayaraman A
        • Thompson CK
        • Rymer WZ
        • Hornby TG.
        Short-term maximal-intensity resistance training increases volitional function and strength in chronic incomplete spinal cord injury: a pilot study.
        J Neurol Phys Ther. 2013; 37: 112-117
      2. Hsieh JTC, Wolfe DL, McIntyre A, et al. Spasticity following spinal cord injury. 2012. Available at: https://scireproject.com/wp-content/uploads/2022/04/spasticity_V7.pdf. Accessed August 25, 2022.

        • Marsolais EB
        • Kobetic R.
        Development of a practical electrical stimulation system for restoring gait in the paralyzed patient.
        Clin Orthop Relat Res. 1988; : 64-74
        • van der Salm A
        • Veltink PH
        • Ijzerman MJ
        • Groothuis-Oudshoorn KC
        • Nene AV
        • Hermens HJ.
        Comparison of electric stimulation methods for reduction of triceps surae spasticity in spinal cord injury.
        Arch Phys Med Rehabil. 2006; 87: 222-228
        • Carty A
        • McCormack K
        • Coughlan GF
        • Crowe L
        • Caulfield B.
        Alterations in body composition and spasticity following subtetanic neuromuscular electrical stimulation training in spinal cord injury.
        J Rehabil Res Dev. 2013; 50: 193-202
        • Aydin G
        • Tomruk S
        • Keles I
        • Demir SO
        • Orkun S.
        Transcutaneous electrical nerve stimulation versus baclofen in spasticity: clinical and electrophysiologic comparison.
        Am J Phys Med Rehabil. 2005; 84: 584-592
        • Kumru H
        • Murillo N
        • Samso JV
        • et al.
        Reduction of spasticity with repetitive transcranial magnetic stimulation in patients with spinal cord injury.
        Neurorehabil Neural Repair. 2010; 24: 435-441
        • Nardone R
        • De Blasi P
        • Holler Y
        • et al.
        Repetitive transcranial magnetic stimulation transiently reduces punding in Parkinson's disease: a preliminary study.
        J Neural Transm (Vienna). 2014; 121: 267-274
        • Nardone R
        • Brigo F
        • Versace V
        • et al.
        Cortical afferent inhibition abnormalities reveal cholinergic dysfunction in Parkinson's disease: a reappraisal.
        J Neural Transm (Vienna). 2017; 124: 1417-1429
        • Nagel SJ
        • Wilson S
        • Johnson MD
        • et al.
        Spinal cord stimulation for spasticity: historical approaches, current status, and future directions.
        Neuromodulation. 2017; 20: 307-321
        • Mesbah S
        • Ball T
        • Angeli C
        • et al.
        Predictors of volitional motor recovery with epidural stimulation in individuals with chronic spinal cord injury.
        Brain. 2021; 144: 420-433
        • Pinter MM
        • Gerstenbrand F
        • Dimitrijevic MR.
        Epidural electrical stimulation of posterior structures of the human lumbosacral cord: 3. Control of spasticity.
        Spinal Cord. 2000; 38: 524-531
        • Hofstoetter US
        • Freundl B
        • Danner SM
        • et al.
        Transcutaneous spinal cord stimulation induces temporary attenuation of spasticity in individuals with spinal cord injury.
        J Neurotrauma. 2020; 37: 481-493
        • Hofstoetter US
        • McKay WB
        • Tansey KE
        • Mayr W
        • Kern H
        • Minassian K.
        Modification of spasticity by transcutaneous spinal cord stimulation in individuals with incomplete spinal cord injury.
        J Spinal Cord Med. 2014; 37: 202-211