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Intrathecal Baclofen for Reducing Spasticity

Programmable pumps can be surgically implanted for the treatment of spasticity in SCI. The most commonly delivered drug is intrathecal baclofen (ITB). Many of the studies looking at intrathecal baclofen use for spasticity combine multiple causes of spasticity (SCI, multiple sclerosis and cerebral palsy) which makes the results difficult to interpret for SCI specifically. Several of the studies in this section include studies where fewer than 50% of the patients have SCI. While these individual studies may not meet the formal SCIRE criteria, their importance for inclusion emerged by representing a larger number of patients with spinal cord injuries when grouped together.

Outcome measures for intrathecal baclofen include direct spasticity measures such as the Ashworth and MAS and spasm frequency scales, and indirect measures such as functional outcome measures, complication rates and quality of life as well as cost-benefit analyses.

While oral baclofen can be useful in the treatment of spasticity, the use of high doses can lead to adverse effects, most commonly over sedation. Delivering baclofen directly into the cerebral spinal fluid allows a higher concentration of baclofen administration to the spinal cord with fewer systemic side effects. ITB is most effective in treating lower extremity spasticity and less so for upper extremity spasticity. However, the location of the intrathecal catheter tip can be adjusted at the time of surgical implantation depending on the clinical presentation with higher tip locations (cephalad at T6, compared to T10-L2) being used in patients with higher injuries (Burns & Meythaler 2001). The pump can be programmed to provide a steady dose of intrathecal baclofen throughout the day or programmed to include boluses at certain times of the day. ITB is usually only considered after one year post-SCI.

Potential complications from intrathecal baclofen treatment include overdose, withdrawal and surgical complications. Disruption or malfunction of the catheter-pump system is a common cause of withdrawal and can result in an acute life-threatening baclofen withdrawal syndrome. The signs and symptoms of acute intrathecal baclofen withdrawal include increased spasticity, itching, fever, altered mental status, rhaobdomyolysis, seizures, reversible cardiomyopathy, and death.

Table 13 Intrathecal Baclofen for Reducing Spasticity

Author Year

Country
Research Design

Score
Total Sample Size

MethodsOutcome
Ordia et al. 1996

USA

Phase 1–RCT

Phase 2-Pre-Post

PEDro=6

N=66

 

Population: MS, SCI (n=27), Other causes of spinal spasticity.

Intervention: Phase 1-Patients were randomized to receive normal saline or test dose intrathecal baclofen. Phase 2-Intrathecal baclofen pump implantation. Some individuals (n=10) were studied for costs study comparing 1 yr pre-and post pump implantation.

Outcome Measures: Ashworth scores (AS), Spasm Frequency Scale (SFS), Drug tolerance, Treatment complications, Cost-benefit analysis.

1.     Test dose: All 66 individuals responded positively to test bolus dose and none of the 9 randomized individuals responded to placebo.

2.     Long-term: A decrease in AS and improvement in decreased from 4.3 pre-operatively to 1.4 (p<0.0005) at last follow-up, SFS improved from 3.6 to 0.5 (p<0.0005) at last follow-up.

3.     An average reduction in 2.7 hospitalization days per individual was found for a cost savings of $2500 per day institutional costs (or $6700 per patient) with the cost of the treatment paid back in <2.5 yr.

Nance et al. 1995

Canada

Phase 1–RCT

Phase 2–Pre-Post

PEDro=9

N=7

Population: Injury etiology: SCI=5, MS=2; Level of injury: C5-T8; Level of severity: Frankel grade: A-B.

Intervention: Phase 1-A daily bolus of placebo or baclofen (12.5 to 100 mcg titrated dose). Phase 2-Intrathecal baclofen pump implantation.

Outcome Measures: Ashworth Scale (AS), Spasm Frequency Scale (SFS), Pendulum test, Hospital Cost Analysis, Bladder and respiratory function, Adverse events.

1.     Test dose: Intrathecal baclofen 50 mcg decreased the average AS.

2.     Long-term: A decrease in AS mean=1.8 (p<0.005) and SFS mean=0.8 (p<0.005) and an improved leg swing in pendulum test. No change in bladder or respiratory function. Improvements in ADLs noted.

3.     n=6 were included in the cost analysis. Overall savings of $153,120 were calculated based on a reduction in hospital related spasticity treatment following pump implantation.

4.     Follow-up ranged from 24 to 41 mo.

Coffey et al. 1993

USA

Phase 1–RCT

Phase 2-Pre-Post

PEDro=8

N=75

Population: Injury etiology: SCI=59, MS/Other spinal pathology=16.

Intervention: Phase 1-Randomized trial test injection baclofen versus placebo with up-titration from 50 mcg to 100 mcg. Phase 2-Intrathecal baclofen pump implantation.

Outcome Measures: Ashworth Scale (AS), Spasm Frequency Scale (SFS).

1.     Test dose: 88 individuals (94.6%) responded to the test dose with a decrease in AS and SFS. No individuals responded to placebo.

2.     Long-term: For the SCI group, the AS and sfs decreased post-pump.

3.     Patients were followed for 5-41 mo (mean 19 mo).

Kravitz et al. 1992

USA

RCT Crossover

PEDro=7

N=6

Population: Spastic Individuals (n=6): Mean age=38.33±5.34yr; Gender: males=4, females=2; Etiology: SCI=4, Multiple Sclerosis=2; Level of injury: C=3, T=1; Time since injury=NR; AIS scale: NR.

Intervention: This RCT crossover consisted of two conditions with no washout period; 1) baclofen, and 2) saline (placebo). A subcutaneous baclofen pump system was implanted into the lumbar subarachnoid space of all participants. Participants received infusion over two nights. Saline or baclofen was infused on alternating nights. Subjects were monitored over two consecutive nights using a polysomnography. Electromyography (EMG) recordings of the tibialis anterior, hamstrings, quadriceps and triceps surae were conducted.

Outcome Measures: EMG Activity Index (EMG events/hr).

1.     There was a significant interaction effect between treatment and time of EMG activity (i.e., before arousal, without arousal, and after arousal) (p=0.037).

2.     The main effects of the treatment and time were not significant (p=0.06; p=0.22, respectively).

3.     Pairwise comparisons revealed a significant reduction in EMG activity when on baclofen after arousal (p=0.019). However, there was no significant between-group difference without arousal or before arousal (p>0.05).

 

 

Hugenholtz et al. 1992

Canada

RCT Crossover

PEDro=6

N=6

 

 

Population: Injury etiology: MS=2, SCI=4.

Intervention: Crossover trial of intrathecal baclofen or saline over the course of 11 days followed by a 30-day trial of daily intrathecal baclofen bolus injections.

Outcome Measures: Effects of spasticity on life questionnaire, Modified Ashworth Scale (MAS), Spasm Frequency Score (SFS), Reflex score, Passive range of motion (ROM), Muscle strength testing, A timed dressing evaluation, the Smith Hand Function evaluation, Urodynamic studies, Neurophysiologic studies.

 

Crossover phase

1.      Baclofen had a significant effect on lower limb tone and reflexes, trunk and leg spasms, questionnaire scores and passive ROM in upper and lower limb joints (p<0.05).

2.      A clinically significant placebo effect was observed for reduced tone, spasms and reflexes in 1 subject.

30-day bolus phase:

3.      Subjects sustained the clinically significant effects of baclofen on tone, spasms and lower limb passive ROM. However, the magnitude of the effect decreased after 30 days. The effects on passive ROM in upper limb joints and lower limb reflexes were lost after 30 days (p<0.05).

4.      Scores in the Smith Hand Function Evaluation & Dressing Test Evaluation did not change. Urodynamic results (bladder volume) improved in 2 subjects.

Loubser et al. 1991

USA

Phase 1 – RCT

Phase 2 – Pre-Post

N=9

Population: Gender: males=9, females=0; Injury etiology: traumatic SCI=9; Level of injury: C2-T12.

Intervention: Test dose: 5-day infusion of varying doses of baclofen and a single 12 hr placebo infusion over a 5-day period to determine optimum intrathecal baclofen dosage. Long-term: Intrathecal baclofen pump implantation.

Outcome Measures: Ashworth scale (AS), Neurological reflex scale, Evaluation of functional abilities, Evaluation of personal independence, Global Assessment Scale (GAS).

1.     Test dose: A decrease was seen in optimal reflex score (t=7.69, p<0.001) and the AS with baclofen grade (t=6.05, p<0.001), between placebo and optimal reflex score a change was noted (t=3.68, p=0.01) and Ashworth grade (t=6.0, p<0.001) and between placebo and control Ashworth grade (t=2.95, p=0.02). At optimum intrathecal baclofen dosage, 8/9 individuals benefited in functional evaluations.

2.     Long-term: Only 7 subjects participated. The AS and mean reflex score decreased from 3.79±0.69 to 2.00±0.96 (t=12.9, p=0.001). The mean reflex score decreased from 3.85±0.62 to 2.18±0.43 (t=6.76, p=0.001).

3.     Follow-up ranged from 3-22 mo.

Penn et al. 1989

USA

Phase 1–RCT

Phase 2-Pre-Post

PEDro=9

N=20

Population: Injury etiology: MS=10, SCI=10; Level of injury: C5-T9.

Intervention: Phase 1-A 3-day infusion of saline or intrathecal baclofen (100 mcg/mm) via programmable pump. Phase 2–An open label long-term observation of intrathecal baclofen.

Outcome Measures: Ashworth scale (AS), Spasm Frequency Scale (SFS), Laboratory analysis of motor control (EMG), Individual impression.

1.     Test dose: In both the SCI and MS groups, the period of baclofen administration could be identified from the saline administration period by the improvement in AS and SFS (<0.01). Overall (all subjects combined), the AS decreased from 4.0±1.0 to 1.2±0.4 (p=0.0001) and the SFS decreased from 3.3±1.2 to 0.4±0.8 (p=0.0005).

2.     Long-term: For all individuals combined, the AS and SFS decreased.

3.     Follow-up ranged from 10-33 mo (average 19).

Stetkarova et al. 2015

Czech Republic

Post-Test

N=39

Population: Age range: 21-56 yr; Gender: males=24, females=15; Injury etiology: chronic SCI=24, multiple sclerosis=15.

Intervention: Intrathecal baclofen pump implantation.

Outcome Measures: Complications of intrathecal baclofen pumps including frequency and severity of intrathecal baclofen withdrawal syndrome, Modified Ashworth Scale (MAS).

1.       A total of 54 pumps were implanted in 39 individuals 24/54 pumps had complications and 14 (26%) of these complications were due to catheter problems. Other causes of complications included pump explantation (2 individuals), infection (4 individuals), CSF leakage (2 individuals), seroma (1 patient), skin dehiscence (1 patient).

2.       Eight individuals developed baclofen withdrawal syndrome on a total daily dose of ITB in the range of 90-420 µg/day (average of 189 µg/day). Seven of these individuals had withdrawal syndrome due to catheter complications.

3.       All but one individual with baclofen withdrawal symptoms developed increased MAS scores up to 3-4.

Calabro et al. 2014

Italy

Pre-Post

N=20

Population: Mean age: 34.9 yr; Gender: males=20, females=0; Injury etiology: traumatic SCI=10, spinal cord vascular lesion=3, degenerative diseases=6, syringomyelia =1; Mean time since injury: 6.1 yr.

Intervention: Individuals were administered intrathecal baclofen in the subarachnoid space up to level T8. Outcomes were assessed before pump implantation and 2mo after.

Outcome Measures: International index of erectile function (IIEF) to measure sexual function before and after pump implantation, Modified Ashworth Scale (MAS), Spasm frequency scale (SFS), Visual analog scale (VAS), Hamilton depression rating scale (HDRS), Diagnostic impotence questionnaire (DIQ).

1.     There was a significant decrease in IIEF median scores from before implantation to after implantation.

2.      There was a correlation between lower IIEF scores and higher intrathecal baclofen doses.

3.      MAS, SFS, VAS and HDRS improved significantly 2 mo after implantation (p<0.0001).

Heetla et al. 2010

Netherlands

Pre-Post

N=4

Population: Age range: 20-49 yr; Injury etiology: SCI, MS, CP; Level of injury: T6-T10.

Intervention: Pulsatile bolus infusion of intrathecal baclofen on a daily dose.

Outcome Measures: Modified Ashworth Scale (MAS).

1.       Switching from continuous to pulsatile bolus infusion resulted in a decrease of the daily intrathecal baclofen
dose.2.       The clinical effect could be kept stable, without introducing adverse events.
Korenkov et al. 2002

Germany

Pre-Post

N=12

Population: Gender: males=12, females=0; Injury etiology: SCI=12.

Intervention: Intrathecal baclofen pump implantation.

Outcome Measures: Ashworth Scale (AS), Spasm Frequency Score (SFS).

1.     Significant post-operative reduction of muscle tone and SFS (p<0.05). AS decreased from 4.2 to 2.2 in the lower limbs and from 2.2 to 1.0 in the UE.

2.     Decrease in AS.

3.     Self-care, nursing care, PT, transfers, sitting tolerance, muscle pain and sleeplessness were all reported as improved but no measures were reported.

Denys et al. 1998

France

Pre-Post

N=9

Population: Gender: males=9, females=0; Injury etiology: MS=4, SCI=5; Level of injury: C4-T11=9; Level of severity: AIS A-C.

Intervention: Intrathecal baclofen pump implantation.

Outcome Measures: Genitosexual function self-report questionnaire.

1.      No decrease in libido.

2.      The ability of subjects to achieve reflexogenic (9/9) or psychogenic erections (3/9) was maintained but 8/9 subjects reported impaired erection after intrathecal baclofen.

3.      5/9 subjects reported decreased penile rigidity with 3/9 unable to achieve intercourse after intrathecal baclofen.

4.      6/9 subjects reported decreased erection duration. 2/9 reported increased erection duration.

5.      3/3 subjects with ejaculatory function pre-pump reported loss of ejaculatory function (2/3) or more difficult ejaculation (1/3) post-pump.

6.      At follow-up, impaired erection was reported by nine individuals, and rigidity reduction was reported in 5 individuals.

7.      In five individuals, maximum erection duration was decreased. 4/5 reported duration of less than 5 min. Two individuals reported an increase in maximum erection duration when using baclofen.

8.      Three individuals could reach ejaculation without stimulation. Two individuals lost the ability to ejaculate during treatment; however, it returned when treatment was discontinued.

9.      Mean follow-up was 44mo.

Azouvi et al. 1996

France

Pre-Post

N=18

Population: Injury etiology: MS=6, SCI=12; Level of injury: C5-T11; Level of severity: Frankel A-D.

Intervention: Intrathecal baclofen pump implantation.

Outcome Measures: Ashworth Scale (AS), Spasm Frequency Score (SFS), Functional Independence Measure (FIM).

1.     Improvement in AS, SFS and at 6 mo, AS was improved Z=-3.79 (p<0.001), SFS was improved Z=-3.78 (p<0.001). With FIM, the most dramatic improvements were seen in the 12 individuals with thoracic or low cervical lesions (FIM evolved from 50.9±9.7 to 76.3±14.5, Z=-3.06, p<0.01). The following items gained ≥2 FIM scores: bathing, dressing lower body, and the 3 items related to transfers.

2.     Follow-up ranged from 9-72 mo (average 37.4)

Abel & Smith 1994

USA

Pre-Post

N=23

Population: Injury etiology: MS=6, SCI=17; Level of injury: C4-T12; Level of severity: AIS: A-D.

Intervention: Intrathecal baclofen pump implantation.

Outcome Measures: Ashworth Scale (AS) and Spasm Frequency Score (SFS).

1.     Test dose: Decrease in AS and SFS.

2.     Long-term: Decrease in AS

3.     Follow-up ranged from 2-34 mo with average 16mo.

Ochs et al. 1989

Germany

Pre-Post

N=28

Population: Injury etiology: MS=18, SCI=10.

Intervention: Intrathecal baclofen pump implantation.

Outcome Measures: Ashworth Scale (AS) and Spasm Frequency Scale (SFS), Electrophysiological data.

1.     Improvement in AS and SFS. Intrathecal baclofen influenced electrophysiological data.

2.     Follow-up up to 2 yr.

Parke et al. 1989

USA

Pre-Post

N=8

Population: Injury etiology: MS=4, SCI=4.

Intervention: Intrathecal baclofen pump implantation.

Outcome Measures: Ashworth Scale (AS), Muscle strength and modified PECS scale.

1.     No statistical results were reported although all subjects showed an improvement in AS. Muscle strength did not change. Improvements were also noted in the PECS scores.

2.     Follow-up was at least 6 mo.

Kawano et al. 2018

Japan

Case Series

N=34

 

Population: Spasticity of Spinal Origin (n=34): Etiology: SCI=29, Hereditary Spastic Paraplegia=3, Multiple Sclerosis=1, HTLV-1 associated myelopathy=1; Mean age=NR; Gender=NR; Level of injury=NR; Mean time since injury=NR; AIS scale=NR.

Intervention: Individuals with spasticity of spinal origin were treated with surgical implantation of baclofen pump. Changes in spasticity and baclofen dose were recorded. Outcome measures were assessed before and after surgical implantation, as well as at follow up (M=6 yr, 11 mo).

Outcome Measures: Ashworth score

1.     Baclofen dose remained consistent over a long period of time for the majority of individuals. Few individuals had large fluctuations in dose.

2.     There were significant decreases in Ashworth score after surgery and at follow up compared to before surgery.

Heetla et al. 2009

Netherlands

Case Series

N=37

Population: Gender: males=19, females=18; Injury etiology: traumatic SCI=10, MS=14, miscellaneous=13.

Intervention: Prior history of use with intrathecal baclofen therapy, alter infusion mode.

Outcome Measures: Ashworth Scale (AS), Dose titration, Co-medication, Drug-related side effects.

1.      Baclofen dose increased in the first 18 mo after implantation (p<0.05), and then stabilized around a mean dose of 350 mcg per day.

2.      Eight individuals (22%) developed tolerance, defined as a dose increase of >100 mcg per yr.

3.      Altering the infusion mode from simple to complex continuous (n=6) had no effect on the development of tolerance.

4.      Pulsatile bolus infusion (n=1) and a drug holiday (n=2) were both effective in reducing the daily baclofen dose.

5.      Pump-related complications occurred once per 10.5 yr of intrathecal baclofen treatment.

6.      Drug-related side effects (mild) had an annual risk of 13.8%.

Boviatsis et al. 2005

Greece

Case Series

NInitial=22,

NFinal=21

Population: Injury etiology: MS=15, SCI=7; Level of injury: C4-T11=22.

Intervention: Intrathecal Baclofen pump implantation. Subjects were implanted with an infusion pump delivering a continuous flow at a fixed rate of bolus intrathecal baclofen.

Outcome Measures: Barthel Index (BI), Ashworth Scale (AS), Penn Spasm Frequency Scale (PSFS), Self-assessment pain scale.

1.     The SCI group demonstrated a lower AS (4.57 to 2.57, p=0.0134) and a decrease in PSFS (3.71 to 1.28, p=0.00006) post pump insertion.

2.     All individuals reported improved function after surgery with an increase in BI increased as a result of the treatment in the SCI group (from 17.1 before to 50.7 after treatment, p=0.0073). Dressing and transfers were 2 activities that improved significantly (p=0.0465 and p=0.0016, respectively). The degree of improvement was different according to level of lesion.

3.     The self-assessment pain scale revealed a limited improvement in pain (p=0.0941).

4.     Follow-up ranged from 9-55 mo (median 35 mo).

Plassat et al. 2004

France

Case Series

NInitial=41,

NFinal=37

Population: Injury etiology: SCI=17, MS and cerebral spasticity=24.

Intervention: intrathecal baclofen pump placement.

Outcome Measures: Visual analog scale (VAS), Satisfaction score Locomotion, Pain, Sleep, Ashworth Scale (AS).

1.     At final assessment average VAS satisfaction with the pump was 7.4.

2.     Ambulation status was unchanged in 85%. Improvements were noted in pain and sleep and AS decreased.

3.     Follow-up average 4 yr.

Zahavi et al. 2004

Netherlands

Case Series

NInitial=38,

NFinal=21

Population: Injury etiology: SCI=6, MS and other spinal spasticity=22.

Intervention: Intrathecal baclofen pump implantation.

Outcome Measures: Ashworth Scale (AS), Spasm Frequency Score (SFS), Extended Disability Status Score (EDSS), Ambulation Index (AI), Injury Severity Score (ISS), Sickness Impact Profile (SIP), Hopkins symptom check list.

1.     Improvement in AS from baseline 2.82 to final assessment 0.91 (p<0.05) and SFS from baseline 1.79 to final assessment 0.67 (p<0.05).

2.     Worsening in EDSS, AI and ISS (all p<0.05) compared with baseline (in progressive and non-progressive groups of individual disabilities). Worsening in level of disability (EDSS and ISS p<0.05) and the psychosocial aspect of the perceived health status scale (SIP) (p<0.05) were seen when compared from baseline and at 26 wk.

3.     Follow-up ranged from 66 to 108 mo with a mean of 84.9 mo.

Avellino & Loeser 2000

USA

Case series

N=62

Population: Mean age: 38.6 yr; Gender: males=35, females=27; Injury etiology: SCI=38, MS=17, other spinal=7, traumatic brain injury=5, cerebral palsy=4; Level of injury: C=20, T=8.

Intervention: Retrospective chart review was conducted on individuals implanted with intrathecal baclofen treatment for spasticity were retrospectively reviewed.

Outcome Measures: Ashworth Score (AS), Spasm Frequency Score (SFS), Dosage, Complications.

1.     Significant improvement at follow up (average 33.6 mo) was seen in the final AS and the SFS for individuals with SCI (p<0.001).

2.     Individuals with SCI were administered an average dosage of about 500 mcgday.

3.     36% of individuals with SCI presented with complications.

4.     Catheter failure was the most common complication.

Penn et al. 1992

USA

Case Series

N=66

Population: Injury etiology: MS=34, SCI=32.

Intervention: Intrathecal baclofen pump implantation.

Outcome Measures: Ashworth Scale (AS) and Spasm Frequency Scale (SFS).

1.     Test dose: 64/66 individuals responded to a test dose of intrathecal baclofen with a decrease in either AS or SFS.

2.     Long-term: 84% treated adequately for spasticity.

3.     Follow-up average 30 mo (up to 81 mo).

Broseta et al. 1990

Spain

Case Series

N=19

Population: Injury etiology: MS, cerebral spasticity, SCI=5; Level of injury: T3-L1.

Intervention: Implantation of programmable pump.

Outcome Measures: Ashworth Scale (AS), Spasm Frequency Scale (SFS), Reflex assessment, Cystomanometry and perineal electromyography for assessment of neurological bladder dysfunction, Electrophysiological H/M ratio, Total dose.

1.     Reduction in AS and SFS improvement in hyperreflexia, objective improvements in transfer activities and skilled acts, improved comfort, reduced H/M ratio and improved bladder function.

2.     Mean follow-up 11 mo.

Gunnarsson and Samuelsson 2015

Sweden

Observational

N=14

Population: Mean age: 51.0 yr; Gender: males=8, females=6; Injury etiology: SCI=8, cerebral palsy=2, multiple sclerosis=4.

Intervention: All individuals received intrathecal baclofen (ITB) treatment for a mean of 5.9 yr. Using an interview guide, open ended interviews concerning individuals’ experiences with ITB treatment were conducted. Experiences were divided into 5 main categories: procedures before treatment, effect of ITB on daily life and activities of daily living (ADL), continuous follow-up, expected and unexpected consequences of ITB and overall satisfaction with ITB.

Outcome Measures: Interview responses.

1.     Overall individuals were satisfied with intrathecal baclofen treatment and all would choose to have a pump implanted again.

2.     Patients expressed a need for more information reqarding steps in the treatment process and treatment expectations.

Borrini et al. 2014

France

Observational

N=158

Population: Mean age: 45.7 yr; Gender: males=56, females=102; Injury etiology: SCI=67, multiple sclerosis=45, brain injury=33, familial spastic paraparesis=7, other=6.

Intervention: Individuals undergoing intrathecal baclofen therapy were implanted with spinal catheter tips in their lower thoracic region (T10-12). Data was analyzed from January 1 to December 31 2010, individuals were classified as surgical if they received an implant during 2010.

Outcome Measures: Frequency and type of adverse event (AE): device-related AE, surgical-related AE, and drug-related AE.

 

1.     128 individuals underwent implantation before 2010 (non-surgical), and 30 during 2010 (surgical) of which 20 were new implants and 10 were replacements.

2.     The total number of AEs was 38 of which 18 were defined as serious.

3.     28 individuals had at least one AE, 8 individuals had two AEs and 1 individual had three AEs.

4.     53% were surgical-related, 29% were device-related and 18% were drug-related.

5.     Overall incidence rate of AEs per mo was 0.023: 0.012 for surgical-related AEs, 0.007 for device-related AEs and 0.004 for drug-related AEs.

6.     The incidence rate of serious AEs per mo was 0.011.

7.     58% of AEs occurred during the first mo following surgery.

Discussion

Spasticity

There were six studies employing an RCT design to evaluate the effects of intrathecal baclofen in SCI. Although these studies are small and combine different etiologies of spasticity, they do provide a limited body of level 1 evidence to support the use of intrathecal baclofen test doses to decrease spasticity in SCI as measured by Ashworth scale and spasm frequency score (Penn et al. 1989; Loubser et al. 1991; Coffey et al. 1993; Nance et al. 1995; Ordia et al. 1996, Hugenholtz et al. 1992).

Only one study (Kravitz et. al. 1992) examined the effects of intrathecal baclofen on the neurophysiological effects on mucle. They looked at EMG activity in six subjects in a double-blind placebo control crossover design. All six subjects had spinal cord injury. They noted a significant reduction in nocturnal EMG activity while on intrathecal baclofen. This was a small study and the study did not look at any correlation with spasticity or daily activity outcomes.

It is unlikely that RCTs will be undertaken to examine the long-term effectiveness of intrathecal baclofen given the effectiveness of test doses. However, several level 4 studies support the long term use of intrathecal baclofen to decrease spasticity with the most frequently used outcome measures being the Ashworth scale and spasm frequency scales (Heetla et al. 2009; Ochs et al. 1989; Penn et al. 1989; Broseta et al. 1990; Loubser et al. 1991; Penn et al. 1992; Coffey et al. 1993; Abel & Smith 1994; Nance et al. 1995; Ordia et al. 1996; Korenkov et al. 2002; Plassat et al. 2004; Boviatsis et al. 2005; Avellino Loeser 2000; Heetla et al. 2010 and Kawano et. al. 2018). Most recently Kawano conducted a retrospective chart review on 34 individuals with spasticity due to various spinal cord disorders. All the subjects were recieving long-term baclofen. 29 of the 34 subjects had spinal cord injury. The data collected showed an average reduction in the ashworth’s score of 1.92 and an average dose of intrathecal baclofen. The average followup time period was greater than 6 years and the average dose fo baclofen was 230.5 ucg per day. This review supported low complication rates and a stable dose of intrathecal baclofen in most of the patients. This study did not included any references to function or quality of life. The effects of intrathecal baclofen are more pronounced in the lower extremities than the upper extremities (Korenkov et al. 2002).

The systematic review by McIntyre et al. (2014) summarizes the evidence from a pooled subject sample size of 162 patients. All eight of the studies included in the review provided level 4 evidence that ITB decreases spasticity with a decrease in MAS from 3.1 to 4.5 at baseline to 1.0 to 2.0 at follow-up. Over time, there was an increase in the range of average daily dosing in these subjects from 57 to 187 mcg/day at baseline to 219 to 536 mcg/day at follow-up. Follow-up periods ranged from five to 41 months.

Table 14 Summary of Intrathecal Baclofen RCTs for Reducing Spasticity–Spasticity Outcomes

Author Year
Total Sample Size
MethodsOutcome
Ordia et al. 1996

NInitial=66,

NFinal=57

(SCI=27)

 

Test dose: n=9 individuals were randomized to receive normal saline or test dose intrathecal Baclofen. Subsequent test doses were not open label.

Long-term: Intrathecal baclofen pump implantation.

Test dose: All 66 individuals responded positively to test bolus dose and none of the 9 randomized individuals responded to placebo.

Long-term: A significant decrease in Ashworth score and spasm frequency scale at last follow-up

Nance et al. 1995

NInitial=7

NFinal=6

(SCI=5)

 

Test dose: A daily bolus of placebo or baclofen (12.5 to 100mcg titrated dose).

Long-term: Intrathecal baclofen pump implantation.

Test dose: Intrathecal baclofen 50 mcg decreased the average Ashworth score.

Long-term: A significant decrease in Ashworth score and spasm frequency score and an improved leg swing in pendulum test.

Coffey et al. 1993

N=75

(SCI=59)

Test dose: Randomized trial test injection baclofen versus placebo with up-titration from 50 mcg to 100 mcg.

Long-term: Intrathecal baclofen pump implantation.

Test dose: 88 individuals (94.6%) responded to the test dose with a decrease in Ashworth and spasm scale. No individuals responded to placebo.

Long-term: For the SCI group, the Ashworth score and spasm score decreased post-pump.

 

 

Hugenholtz et al. 1992

N=6

(SCI=4)

 

 

Test dose: Randomized trial test injection baclofen versus placebo over 11 days.

Long-term: 30-day trial of daily intrathecal baclofen bolus injections.

 

Test dose: Baclofen had a significant effect on lower limb tone and reflexes, trunk and leg spasms, questionnaire scores and passive range of motion in upper and lower limb joints (p<0.05). A clinically significant placebo effect was observed for reduced tone, spasms and reflexes in 1 subject.

Long-term: Subjects sustained the clinically significant effects of baclofen on tone, spasms and lower limb passive range of motion. However, the magnitude of the effect decreased after 30 days. The effects on passive range of motion in upper limb joints and lower limb reflexes were lost after 30 days (p<0.05).

Loubser et al. 1991

N=9

(SCI=9)

Test dose: 5-day infusion of varying doses of baclofen and a single 12-hr placebo infusion over a 5 day period to determine optimum intrathecal baclofen dosage.

Long-term: Intrathecal baclofen pump implantation.

Test dose: At optimum intrathecal baclofen dosage, 8/9 individuals benefited in functional evaluations.

Long-term: Only 7 subjects participated. The Ashworth score and mean reflex score decreased.

 

Penn et al. 1989

N=20

(SCI=10)

Test dose: A 3-day infusion of saline or intrathecal baclofen (100 mcg/ml) via programmable pump.

Long-term: An open label long-term observation of intrathecal baclofen.

Test dose & Long-term: Overall (all subjects combined), significant decreases for the Ashworth score and the spasm frequency scale decreased as a result of intrathecal baclofen.

Table 15 Systematic Reviews of Intrathecal Baclofen for Spasticity

Authors Year

Country

Date included in the review

Score

Total Sample Size

Method

Level of evidence

Questions

Conclusions
McIntyre et al.

2014

Canada

Review of published articles up to and including February 2012

AMSTAR=7

N=8

 

Method: Comprehensive literature search of English RCT, prospective-controlled trials, cohort studies, case control studies, pre-post studies, post-test, case series, observational studies, clinical consensus and case reports.

Databases: Pub Med, EMBASE, CINAHL.

Level of evidence: Level 1: RCTs with PEDro ≥6; Level 2: RCTs with PEDro<6, Prospective-controlled trials and cohort studies; Level 3: case control studies; Level 4: pre-post studies, post-test and case series. Level 5: observational studies, clinical consensus and case reports.

Questions/measures/hypothesis:

Review the effectiveness of continuous spinal intrathecal baclofen in the treatment of spasticity more than 6 mo post SCI.

1.     No RCTs and 8 non-RCTs met inclusion criteria for a pooled subject sample of 162 individuals.

2.     All of the included studies provided level 4 evidence that ITB decreases spasticity with a decrease in MAS from 3.1-4.5 at baseline to 1.0 to 2.0 at follow-up.

3.     There was an increase in the range of average daily dosing from 57 to 187 mcg/day at baseline to 219 to 536 mcg/day at follow-up.

4.     Several complications were reported, especially due to catheters.

5.     Follow-up periods ranged from 5 to 41 mo.

Functional Outcome

The effects of intrathecal baclofen on functional outcomes are much harder to summarize. Most studies are observational, pre-post studies with small numbers of SCI patients grouped in combination with several other diagnoses (most often MS). In addition, there is a lack of standardized outcome measures used to study functional outcomes. Finally, the majority of studies are not stratified by SCI level or ASIA impairment scale (AIS).

There are several observational studies looking at the short-term and long-term complication rates seen with intrathecal baclofen. Overall, complication rates are low and can be categorized as medication related or pump related. However, complications can be severe and include death (Heetla et al. 2009; Loubser et al. 1991; Penn et al. 1992; Coffey et al. 1993; Abel & Smith 1994; Nance et al. 1995; Azouvi et al. 1996; Ordia et al. 1996; Stempien & Tsai 2000; Korenkov et al. 2002; Plassat et al. 2004; Avellino & Loeser 2000; Heetla et al. 2010).

Borrini et al. (2014) conducted a prospective study of adverse events in a mixed group of patients with SCI (42%), multiple sclerosis (28%) and other diagnoses resulting in spasticity. Among 128 patients with pre-existing pumps and 30 patients undergoing new pump implantation, they found an overall incidence rate of event of 0.023 adverse events per month. The majority of adverse events (58%) occurred within the first month post surgery (new implantation or pump replacement). Furthermore, in a retrospective review of 130 patients with SCI (38%) and multiple sclerosis (62%), Draulans et al. (2013) found an adverse event rate of 0.011 events per month with the majority (75%) of complications related to catheter problems. Finally, Stetkarova et al. (2015) reported a complication rate of 0.01 per month with an acute withdrawal rate of 0.004 per month.

Tolerance to intrathecal baclofen has also been observed (Ochs et al. 1989; Coffey et al. 1993; Abel & Smith 1994; Ordia et al. 1996; Heetla et al. 2009). Intrathecal baclofen has been shown to decrease sexual function as measured by self-reported penile rigidity, duration of erection and ejaculation. The effect of intrathecal baclofen on ejaculation appears to be reversible based on a small number of cases (Denys et al. 1998).

In a recent pre-post study, Calabro et al. (2014) demonstrated a decrease in erectile function in men following intrathecal baclofen pump implantation, especially at higher dosages.

Overall, there is level 4 evidence to suggest that functional outcomes as measured by scales such as Barthel index scale and FIM improve with intrathecal baclofen (Parke et al. 1989; Broseta et al. 1990; Nance et al. 1995; Azouvi et al. 1996; Ordia et al. 1996; Plassat et al. 2004; Boviatsis et al. 2005). However, it is notable that Zahavi et al. (2004) reports a small statistically significant deterioration in disability as measured by the expanded disability status scale, ambulation index and incapacity status scale. The article notes that this may not be a clinically significant deterioration (Zahavi et al. 2004). Loubser reports the potential for decreased functional outcomes especially with respect to ambulatory status in patients who may depend on their spasticity for ambulation (Loubser et al. 1991).

Finally, in a recent qualitative study by Gunnarsson and Samuelsson (2015), patients reported an overall satisfaction with intrathecal baclofen treatment and all 14 patients stated that they would undergo pump implantation again.

Table 16 Summary of Intrathecal Baclofen Observational Studies for Reducing Spasticity–Functional Outcomes

Author Year

Total Sample Size

MethodsOutcome
Boviatsis et al. 2005

N=22

(SCI=7)

Intervention: Intrathecal baclofen pump implantation. Subjects were implanted with an infusion pump delivering a continuous flow at a fixed rate of bolus intrathecal baclofen.All individuals reported improved function after surgery but the degree of improvement was different according to level of lesion.
Azouvi et al. 1996

N=18

(SCI=12)

Intervention: Intrathecal baclofen pump implantation.Improvement in FIM at 6 mo ≥2 FIM scores: bathing, dressing lower body, and the 3 items related to transfers. Most improvement in 12 individuals with thoracic or low cervical lesions.
Plassat et al. 2004

N=41

(SCI=17)

Intervention: Intrathecal baclofen pump placement.Improvements were noted in pain and sleep and Ashworth score decreased.
Zahavi et al. 2004

N=38

(SCI=6)

Intervention: Intrathecal baclofen pump implantation.

 

Worsening in EDSS, AI and ISS and the psychosocial aspect of the perceived health status scale (SIP) were seen when compared from baseline and at 26 wk.
Korenkov et al. 2002

N=12

(SCI=12)

Intervention: Intrathecal baclofen pump implantation.Self-care, nursing care, PT, transfers, sitting tolerance, muscle pain and sleeplessness were all reported as improved but no measures were reported.
Loubser et al. 1991

N=9

(SCI=9)

Test dose: 5-day infusion of varying doses of baclofen and a single 12 hr placebo infusion over a 5-day period to determine optimum intrathecal baclofen dosage.

Long-term: Intrathecal baclofen pump implantation.

At optimum intrathecal baclofen dosage, 8/9 individuals benefited in functional evaluations.

 

Broseta et al. 1990

N=19

(SCI=5)

Intervention: Implantation of programmable pump.

 

Objective improvements in transfer activities and skilled acts, improved comfort, reduced H/M ratio and improved bladder function
Parke et al. 1989

N=8

(SCI=4)

Intervention: Intrathecal baclofen pump implantation.Improvements were noted in the PECS scores.

Cost-Effectiveness

There has been one prospective study that performed a cost analysis for intrathecal baclofen pumps but this study did not meet SCIRE criteria for inclusion (i.e., <50% SCI subjects). However, without other cost analysis studies involving SCI patients, findings by Postma (1999) are presented here since intrathecal baclofen cost effectiveness is an important consideration. Postma (1999) studied 33 subjects with MS and SCI and found subjects who received a pump had higher direct medical costs than subjects who did not receive a pump. However, Postma (1999) concluded that the improvement in quality of life in subjects who received a pump more than justified the direct costs associated with the pump.

A more recent review of ITB cost analysis, which was funded by a pump manufacturer, Medtronic, noted significant cost benefit, proportionate to the duration of pump use (Saulino et al. 2015). Again, this review did not meet the SCIRE criteria for inclusion (i.e., <50% SCI patients). To illustrate the potential cost savings of ITB treatment, Saulino et al. (2015) reported that by seven years post pump implant, the average cumulative savings was more than USD $22,000 per patient.

There are two level 1b studies examining cost-effectiveness with the usage of intrathecal baclofen (Nance et al. 1995; Ordia et al. 1996). Ordia et al. (1996) did not specify whether SCI or MS subjects were studied for cost-effectiveness, but the authors did report gross cost savings with intrathecal baclofen due to an overall reduction in hospital days post pump implantation (Ordia et al. 1996).

Nance et al. (1995) also combines MS and SCI subjects. In contrast to Ordia et al. (1996) who examined overall hospital days, Nance et al. (1995) examined only hospital days related to spasticity and found a net savings in costs related to pump implantation.

Table 17 Summary Intrathecal Baclofen for Reducing Spasticity – Cost Analysis

Author Year

Total Sample Size

MethodsOutcome
Ordia et al. 1996

NInitial=66,

NFinal=57

(SCI=27)

 

Long-term: Intrathecal baclofen pump implantation. Ten individuals were studied for costs study comparing 1yr pre-and post pump implantation.An average reduction in 2.7 hospitalization days per individual was found for a cost savings of $2500 per day institutional costs (or $6700 per patient) with the cost of the treatment paid back in <2.5 yr.
Nance et al. 1995

NInitial=7,

NFinal=6

(SCI=5)

 

Long-term: Intrathecal baclofen pump implantation.

 

 

N=6 were included in the cost analysis. Overall savings of $153,120 were calculated based on a reduction in hospital related spasticity treatment following pump implantation.

Intrathecal Baclofen Withdrawal and Overdose

With sudden withdrawal of intrathecal baclofen, there is a risk of an acute life-threatening baclofen withdrawal syndrome. The signs and symptoms of acute intrathecal baclofen withdrawal include increased spasticity, itching, fever, altered mental status, rhaobdomyolysis, seizures and death.

Withdrawal can occur with human errors in pump programming, errors in pump refills (wrong concentrations or dosages) and with mechanical failures in pumps and/or catheters. Of note, Miracle et al. (2011) reviewed varying types of imaging as an approach to the evaluation of intrathecal pump and catheter systems in the event of withdrawal symptoms. Patients with intrathecal baclofen pumps need to be educated regarding the pump alarm sounds and the signs and symptoms of baclofen withdrawal so that they can seek early assessment and treatment. The differential diagnosis for baclofen withdrawal includes autonomic dysreflexia, neuromalignant syndrome and malignant hyperthermia (Coffey 2002).

Initial treatment for intrathecal baclofen withdrawal is the reestablishment of intrathecal baclofen treatment as soon as possible. If this is not possible, then oral baclofen, dantrolene and intravenous benzodiazepines are used to help manage the withdrawal syndrome (Coffey 2002).

Acute baclofen withdrawal syndrome shares many characteristics with serotonergic syndrome. Meythaler (2003) added cyproheptadine, a serotonin antagonist, to the management of acute intrathecal baclofen withdrawal in four subjects and found improvements in signs and symptoms of withdrawal.

Intrathecal baclofen overdose is less common and is most often due to errors at the time of pump refills or programming errors (Watve 2011). Symptoms include hypotonia, hypotension, somnolence, seizures and respiratory depression. Acute overdose is managed with cessation of baclofen treatment, supportive treatment and withdrawal of cerebrospinal fluid (and subsequent reduction of circulating ITB). Once ITB treatment has been stopped and the overdose symptoms have been treated, patients need to be monitored closely for the development of of ITB withdrawal. Treatment with ITB should be resumed as early as possible.

Table 18 Treatment of intrathecal baclofen withdrawal and overdose

Author Year

Country
Research Design

Score
Total Sample Size

MethodsOutcome
Crawley et al. 2004

UK

Pre-Post

N=11

Population: N/R.

Intervention: Low dose radioisotope procedure was used to investigate catheter failure in individuals with SCI with implanted drug delivery systems and uncontrolled spasm.

Outcome Measures: Pump functioning.

1.     5 of 11 individuals had normal pump function; while 6 had a blocked catheter, 4 of which had a proximal block.

2.     The isotope test was able to indicate the need for surgery and inspection of the equipment in 6 individuals, while avoiding surgery for 5.

Meythaler et al. 2003

USA

Case Series

N=4

Population: Age range: 32-49 yr; Gender: males=3, females=1; Injury etiology: SCI=3, cerebral palsy=1.

Intervention: Individuals with intrathecal baclofen withdrawal were treated with 4 to 8mg of oral cyproheptadine every 6-8 hr in addition to oral diazepam every 6-12 hr, oral baclofen every 6 hr and/or ITB boluses.

Outcome Measures: Signs and symptoms of intrathecal baclofen withdrawal.

1.     Addition of 4 mg of cyproheptadine treatment resulted in a relief of itching and signs of baclofen withdrawal.

 

Coffey et al. 2002

USA

Case Series

N=6

Population: Injury etiology: SCI=4, cerebral palsy=1, MS=1; Level of injury: C=3, T=1.

Intervention: Charts were reviewed of individuals with severe ITB withdrawal.

Outcome Measures: Withdrawal symptoms.

1.     Most subjects (4/6) reported withdrawal symptoms by the 1st day of ITB cessation.

2.     Treatment for withdrawal included oral baclofen, valium and enteral diazepam.

3.     Misdiagnosis or late diagnosis resulted in the death of all individuals with SCI, while both individuas without SCI recovered.

Table 19 Systematic Reviews of Inthrathecal Baclofen Withdrawl and Overdose

Author Year

Country

Date included in the review

Score

Total Sample Size

Method

Level of evidence

Questions

Conclusions
Watve et al.

2011

United Kingdom

Review of published articles between 1989-2010

AMSTAR=9

N=36

Method: Comprehensive literature search of articles on acute intrathecal baclofen therapy (ITB) overdose and ITB withdrawal. Articles were restricted to English and subjects >18 yr of age.

Databases: MEDLINE, EMBASE, PUBMED, COCHRANE.

Level of evidence: Case series, Case reports.

Question: Consolidation of available evidence and development of treatment pathways for acute ITB overdose and withdrawal states.

1.      13 studies on ITB overdose and 23 studies on ITB withdrawal were identified.

2.    Cause and management of ITB overdose:

a.    Overdose was closely associated with filling procedures or is iatrogenic in 26/29 ipatients (refilling of the pump (n=14), intrathecal bolus (n=6), dose titration (n=2)).

3.    Cause and management of ITB withdrawal:

a.    Patients experience withdrawal symptoms close to their refill dates. 40% are catheter related, other causes are infected pump removal, empty reservoir volume, end of battery life and iatrogenic programming errors.

Conclusions

There is level 1a evidence (from six small-sample RCTs; Ordia et al. 1996; Nance et al. 1995; Coffey et al. 1993; Hugenholtz et al. 1992; Loubster et al. 1991; Penn et al. 1989) that bolus or test dose intrathecal baclofen decreases spasticity.

There is level 4 evidence (from several studies; see Table 13) that support the use of long-term intrathecal baclofen to decrease spasticity.

There is conflicting level 4 evidence (from several studies; see Table 15) that intrathecal baclofen may improve functional outcomes.

There is level 1b evidence (from two RCTs; Ordia et al. 1996; Nance et al. 1995) that intrathecal baclofen is a cost-effective intervention for treating post SCI spasticity.

There is level 4 evidence (from several studies; see Table 13) that complication rates with the long-term use of intrathecal baclofen are relatively low although complications can occasionally be severe.

There is level 4 evidence (from one case series; Meythaler et al. 2003) that adding cyprohetptadine to baclofen and benzodiazepines may be useful for the treatment of intrathecal baclofen withdrawal.

Bolus or long-term intrathecal baclofen decreases spasticity and may improve functional outcomes with low complication rates and is a cost effective intervention.