Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size ⁴

Comments

McCormick, 2015

Type of study:

Cross-sectional matched cohort survey study.

Setting and country:

Urban academic rehabilitation outpatient clinics in the USA

Funding and conflicts of interest:

Authors had nothing to disclose. Funding information not reported.

Inclusion criteria:

³18 years treated with intrathecal or oral baclofen for at least 1 year before recruitment.

Exclusion criteria:

Individuals who were not able to understand the consent process because of cognitive impairment.

N total at baseline:

matched 1:1 for age, gender, and diagnosis.

Intervention: 31

Control: 31

Important prognostic factors:

age ± SD:

I: 45 y (±11)

C: 46 y (±12)

Sex:

I: 64 % M

C: 64 % M

Mean duration of

Treatment, ± SD:

I:  11 (±6) years

C: 12 (±10) years

Groups comparable at baseline? YES

Intrathecal administration of baclofen (with internal pump).

On date of survey, mean baclofen dose (SD) was 577(1429) µg/day

Oral administration of baclofen.

Mean baclofen dose on date of survey was 86 (50) mg/day. Dose differed per patient and depended on physician for real life management of spasticity, there was no dosing protocol.

N/A, cross-sectional

No information on missing outcome data is described.

Incomplete intervention data:

Baclofen dosage missing at date of survey:

I: 2/31 (6%)

C: 3/31 (10%)

Penn Spasm Frequency and Severity Scale (PSFS)

Mean Spasm Frequency Score, from 0-4 increasing frequency (SD):
I:  1.44 (0.92) | C: 2.37 (1.12) *

Mean Spasm Severity Score from 1-3 with increasing severity (SD):

I: 1.44 (0.92) | C: 2.16 (0.83) *

Brief Pain Inventory (BPI)

• Mean NRS pain score (SD)

I: 3.79 (2.72), C: 5.42 (2.81)

• Mean worst NRS pain score (24h)

I: 4.21 (2.99), C: 6.58 (3.31)

• Mean Least NRS pain score(24h)

I: 2.16 (2.43), C: 3.05 (2.39)

Mean pain severity score (SD)

I: 3.3 (2.54), C: 4.96 (2.65)

* = P<0.05)

Author’s conclusions:

“Long-term treatment with intrathecal compared with oral baclofen is associated with reduced spasm frequency and severity as well as greater dose stability.”

Strengths:

• Selection bias minimized by matching of participants.

Limitations:

• Cross-sectional design increases risk of selection bias
• Small sample size
• No dosing protocol for either intervention or control: “Study represents the real-life management of baclofen for patients with spasticity… and thus, these finding may be related to the particular cohort studied and the management style of their physicians.”
• Not powered for pain, quality of life or sleep

Creamer, 2018

(published in two separate journals, same study different reported outcomes)

Type of study:

phase 4, randomized, controlled, open-label, parallel-

group, multicentre study

Setting and country:

rehabilitation hospitals

at 11 centres across Europe (Austria, Belgium, Germany, Italy, the

Netherlands, Spain, United Kingdom, and Slovenia) and 7 centres

in the United States

Funding and conflicts of interest:

This study was supported by Medtronic International Trading Sàrl.

several authors report personal fees from Medtronic.

And one author also from, Allergan, Ipsen, Merz, and Sintetica. Two authors are employees of

Medtronic. The other author reports no conflicts

Inclusion criteria:

(1) Patients with generalised spasticity aged 18–75 years; (2) poststroke duration >6 months; (3) Therapy goal not reached with other treatment interventions; (4) spasticity in at least two extremities; (5) Ashworth Scale (AS) score ≥3 in a minimum of two muscle groups of the lower extremities (LE) on the affected body side

Exclusion criteria:

(1) known baclofen sensitivity; (2) uncontrolled refractory epilepsy; (3) active systemic infection; (4) presence of a cardiac pacemaker; (5) implantable cardioverter defibrillator, neurostimulator or drug delivery device; (6) use of oral vitamin K antagonists; (7) use of botulinum toxin within the 4 months prior to inclusion.

Chemodenervation (including botulinum toxin) and surgery affecting limb mobility were prohibited during the study.

N total at baseline:

Intervention: 31

Control:29

Important prognostic factors²:

For example

age ± SD:

I: 56.1 (11.1)

C: 55.7 (8.6)

Sex:

I: 77.4 % M

C: 62.1 % M

Ability to transfer:

(% high-level functional patient)

I: 71.0%

C:82.8%

Type of stroke:

% Cerebral ischaemic vs.  Cerebral haemorrhagic:

I: 58.1%

C: 41.4%

Groups comparable at baseline?

NO, comparable except for ability to transfer (high- vs. low-level functional patients) and type of stroke, but difference was not statistically tested.

Intrathecal baclofen (ITB) therapy

Lioresal Intrathecal (ITB arm patients underwent an ITB trial between days 1 and 10 during the run-in phase to evaluate drug response. Patients could continue their oral antispastic medications during this phase.

Patients fulfilling the test success criterion (1-point drop in the AS score in three muscle groups in the affected LE) were implanted between days 2 and 25 with the marketed SynchroMed II infusion system (Medtronic). After implant, patients underwent a 6-week titration period during which the ITB dose was increased until the desired clinical effect was achieved or reduced for side-effect management; oral antispastics were gradually reduced with complete discontinuation by week 6. Patients randomised to ITB who were not implanted remained on oral antispastic medications and physiotherapy until the study end.

oral medication (conventional

medical management (CMM))

CMM arm patients received a combination of oral antispastic medication (at least one of oral baclofen, tizanidine, diazepam (or other benzodiazepines), or dantrolene) and physiotherapy throughout the study. Oral antispastic medications were prescribed by the investigator at randomisation; medications (type and dose) were then reassessed at the end of the run-in phase at the second assessment visit (day 21±2) and could be adjusted as deemed necessary by the investigator at any time during the trial, in accordance with usual clinical practice and the needs of the individual patient.

Length of follow-up:

6 months

Only patients missing in both 3-month and 6-month follow-up were excluded from the analysis. If only 6-month follow up was missing, Last observation carried forward (LOCF) imputation was used.

Loss-to-follow-up:

Intervention:

7 (23%), of whom 6 (19%) before 3-month follow up

Reasons:

• 1 withdrew consent (before ITB test);
• 2 LTFU before implantation;
• 1 died after implantation;
• 1 LTFU after implantation;
• 1 withdrew consent after implantation;
• 1 discontinued after switching to CMM (major protocol deviation).

Control:

5 (17%), all before 3-month follow up

Reasons:

• 3 withdrew consent;
• 2 LTFU.

Incomplete outcome data:

Primary outcomes (ITT with LOCF for month 6):

Ashworth score in lower extremity & Ashworth score in higher extremity:

I = 6/31 (19%)

C = 4/29 (14%)

Reasons: loss-to-follow-up (see above) with LOCF from month 3 to month 6, further reasons unknown

Adverse events (modified. ITT with intervention = implanted ITB and control: control + non-implanted ITB):

I = 6/31

C: 35/29

Reasons: (not) implanted

First article (primary outcomes)

Spastic hypertonia and muscle tone

Ashworth score in the lower extremity

Mean change in AS score from baseline (SD)

I: -0.99 (0.75), C: - 0.43 (0.72) *

Ashworth score in the upper extremity

Mean change in AS score from baseline:

I: −0.66 (0.59), C:  -0.17(0.70) *

Functional Independence

FIM total score, mean change from baseline:

I: 2.68(10.31), C: -2.58(11.00)

Adverse events

(in modified ITT population, only described)

All AEs (%):

I: 24/25 (96.0%), C:22/35(62.9%);

Serious AEs

I: 13/25(/52%), C; 10/35(28.6%)

Second article

Pain

Mean change in NPRS (SD)

Actual pain:

I: -1.17(3.17), C: 0.00(3.29)*

Least pain

I: −1.61(2.29), C: +0.24 (3.07)*

Worst pain

I: −1.35 (2.42), C: −0.04 (3.69)

* = P<0.05)

Author’s conclusion:

“Our results suggest that intrathecal delivery of

baclofen provides an improved therapeutic effect versus conventional oral medications, with a reduction of the AS score in both upper and lower limbs when used in conjunction with physiotherapy.” and secondly “…results suggest that ITB delivery provides an improved therapeutic effect when compared with CMM using oral spastic medications and physiotherapy.”

Limitations:

• The small number of patients (lower than anticipated sample size owing to recruitment difficulties);
• 6-month follow-up period was relatively short;
• It was not powered to assess secondary outcomes;
• Assessment of pain was limited to the NPRS;
• assessment of patient-reported outcome measures was not blinded;
• Lack of data on caregiver burden.

Summaraiee, 2020

Type of study:

Prospective cohort

Setting and country:

Center for MS-related spasticity in London, UK

Funding and conflicts of interest:

The author(s) received no financial support for the research, authorship,

and/or publication of this article.

Authors have nothing to

disclose.

Only R. Farrell has received honoraria / consultant fees from GW Pharma, Biogen Idec, Merck, Allergan PLC

Inclusion criteria:

(1) Ambulatory subjects based on EDSS ≤ 7 (Some subjects with EDSS 7.5 who had recently stopped walking due to spasticity were included) (2) considered suitable for ITB.

Exclusion criteria:

None

N total at baseline:

Intervention (proceeded to pump): 20

Control (did not proceed to pump): 10 (of whom 1 non-responder)

Important prognostic factors²:

For example

Mean Age (range):

I:51.3(26-59)

C: 46.1 (39-64)

Sex:

I: 30% M

C: 50% M

Groups comparable at baseline?

No, significant difference in baseline mean MRC power grade in subjects who proceeded to pump (Grade 4) compared to those who did not (Grade 3; p=0.015), but no significant difference in any other baseline measures including spasticity or 10MTW.

Intrathecal baclofen

Subjects were admitted for a trial of intrathecal baclofen as a bolus dose via lumbar puncture.  Trial doses ranged from 12.5– 50 mcg…. Those who reported subjective benefit, achieved goals, and demonstrated an objective response, proceeded with pump implantation during the same admission or shortly thereafter. In those who failed to respond to initial trial, subsequent trials were performed at a higher dose up to a maximum of 75 mcg.’

Medtronic Synchromed II pumps with 20 or 40ml reservoirs were implanted.

Subjects had regular follow up to optimise ITB dose and other medications, refill the pump, review spasticity, and monitor for any complications.

Case as usual (antispasmodic agents)

After the initial trials failed, subjects were elected not to proceed due to concerns over lower limb weakness impairing ambulation and independent transfers.

Length of follow-up:

minimum 12 months of follow- up.

mean years of follow-up(range)

I: 3.75(1-9), C: 4.1(1-8)

Loss-to-follow-up:

Follow-up was different for each patient, barely reasons for loss-to-follow-up reported.

One subject died during follow up for reasons unrelated to the ITB pump at 8 years post-pump insertion.

Incomplete outcome data:

Not reported in methods/results, yet stated in discussion: “This was a retrospective study that relied on routinely collected clinical data that was at times incomplete.”

10mtw (both pre-and post-trial):

15/30 (50%)

Reasons:

Two subjects who were unable to complete a timed walk at baseline, completed it at peak dose, due to reduced spasms facilitating improved walking. Conversely three subjects who could complete a 10MTW pre-trial were unable to complete one post-trial due to reduced strength post-trial 10mtw. 9 of the 10 subjects that did not proceed to implant were unable to complete a 10MTW at peak dose, whereas only 3 out of the 20 that did proceed could not complete a 10MTW at peak dose.

Outcome measures and effect size (include 95%CI and p-value if available):

4-hours post trial-dose (not implanted, n = 30)

Mean Ashworth score (range)

Pre-dose 1.44 (0.75-2.25); post-dose 0.98 (0.08-1.5)

Mean penn spasm score (range)

Pre-dose 3.0 (1.5-4.0), post-dose: 1.0 (0.0-3.5)*

Mean time 10m timed walk mobility (range)

Pre-dose: 76sec (20-186), post-dose: 94sec (23-401)

After implant,

Number of subjects ambulatory (able to walk)

t = 1 year

I: 16 (80%), C: 4 (40%)*

t = 2 years

I: 14 (70%), C: 3 (30%)*

t = 3 years

I = 12 (60%), C: 30 (30%)*

Differences in the preservation of

ambulation in patients with or without ITB implant (Kaplan-Meier)

log rank test χ2(1) = 2.733, p =0.09.

* = P<0.05)

Study reference

Was the allocation sequence adequately generated?

Was the allocation adequately concealed?

Blinding: Was knowledge of the allocated interventions adequately prevented?

Was loss to follow-up (missing outcome data) infrequent?

Are reports of the study free of selective outcome reporting?

Was the study apparently free of other problems that could put it at a risk of bias?

Overall risk of bias

LOW

Some concerns

HIGH

Creamer, 2018

Definitely yes

Reason: Central randomization with computer generated random numbers

Definitely no,

Reason: Due to nature of the treatments (implant vs. oral) the study was not blinded to either subject or investigator

Probably no

Reason: Patients and health care providers were not blinded due to nature of the treatment.

To avoid AS score assessment bias and inter-rater variability, all AS scores (except for those during the ITB test) were performed by the same blinded assessor.

Assessment of patient-reported outcome measures could not be blinded

Probably no

Reason: LTFU was 23% in intervention group and 19% in control group.

One LTFU was a major protocol deviation: subject discontinued after switching from intervention to control group.

Last Observation Carried Forward was used as an imputation method for 6-month measurement (inadequate).

For each (secondary) outcome, data from some subjects is missing, which does not all seem to be related to LTFU

Definitely yes

Reason: All relevant outcomes were reported

Definitely no

Potential publication bias due to commercial sponsoring and conflicts of interest.

Some concerns

• Risk of allocation bias due to no allocation concealment, but lower for primary outcome due to blinded assessor.
• Risk of selection bias due to data potentially missing not at random (selective loss to follow up) and simple method to handle missing data (LOCF). Loss to follow up for secondary outcomes unclear.

Author, year

Selection of participants

Was selection of exposed and non-exposed cohorts drawn from the same population?

Exposure

Can we be confident in the assessment of exposure?

Outcome of interest

Can we be confident that the outcome of interest was not present at start of study?

Confounding-assessment

Can we be confident in the assessment of confounding factors?

Confounding-analysis

Did the study match exposed and unexposed for all variables that are associated with the outcome of interest or did the statistical analysis adjust for these confounding variables?

Assessment of outcome

Can we be confident in the assessment of outcome?

Follow up

Was the follow up of cohorts adequate? In particular, was outcome data complete or imputed?

Co-interventions

Were co-interventions similar between groups?

Overall Risk of bias

McCormick, 2015

Probably yes,

All participants recruited from single site practice during routine visits and matched by age (+-10 years), gender, and etiologic diagnosis of spasticity. Only MS patients included.

Definitely no,

Due to nature of exposure probably no classification bias (implant), But dose was dependent on management style of physician and differs per subject.

Definitely no,

cross-sectional study, all outcomes only measured once.

Probably yes,

Due to nature of confounding factors (age (+-10 years), gender, and etiologic diagnosis of spasticity).

Probably no,

Matched subjects, but not via propensity score (or at least not reported).

Also, it is a cross-sectional study, thus baseline differences in outcomes or other related confounding factors may exist.

Other measured patient characteristics don’t differ significantly between groups.

Probably yes,

Outcomes assessed via standardized questionnaires.

Definitely no,

No follow-up because of cross- sectional design.

No information on missing data provided.

Definitely yes

Reason: Additional used medication was balanced between groups (no statistically significant difference between groups).

High

• Cross-sectional study, thus Baseline differences in outcomes or other related confounding factors may exist.
• Matching based on age groups, gender and etiologic diagnosis decreases risk of selection bias, but risk still present.
• No information on missing data provided.

Summaraiee, 2020

Definitely yes,

Study includes all ambulatory subjects treated with ITB in a center for MS related spasticity

Definitely no,

Comparator selection based on exclusion of intervention because of bad response (outcome related selection)

Definitely no,

Difference in outcome (walking preservation) at baseline.

Definitely no,

Selection based on first outcome.

Also, statistically significant baseline differences between groups and no correction for confounding.

Definitely no,

Selection based on first outcome

Probably yes,

Outcomes assessed via standardized scales, but no information on how it was assessed and who did the assessment.

Definitely no,

Follow-up was different for each patient, barely reasons for loss-to-follow-up reported.

Study was based on routinely collected clinical data that was at times incomplete.

Probably no,

Additional use of medication was balanced between groups at baseline, but changed during follow-up, which was not considered for the analyses.

High

• High risk of selection bias, as allocation is dependent on outcome and outcome differs significantly between groups at baseline.
• No correction for confounding factors
• Potential selection bias due to varying follow-up times

Reference

Reason for exclusion

Marathe A, Allahabadi S, Abd-Elsayed A, Saulino M, Hagedorn JM, Orhurhu V, Karri J. Intrathecal Baclofen Monotherapy and Polyanalgesia for Treating Chronic Pain in Patients with Severe Spasticity. Curr Pain Headache Rep. 2021 Dec 11;25(12):79. doi: 10.1007/s11916-021-00994-9. Erratum in: Curr Pain Headache Rep. 2022 Mar;26(3):279. PMID: 34894303.

Systematic review of insufficient quality, including wrong publication types (non-comparative studies)

Jacobs NW, Maas EM, Brusse-Keizer M, Rietman HJS. Effectiveness and safety of cervical catheter tip placement in intrathecal baclofen treatment of spasticity: A systematic review. J Rehabil Med. 2021 Jul 9;53(7):jrm00215. doi: 10.2340/16501977-2857. PMID: 34160624; PMCID: PMC8638738.

Systematic review including wrong publication types (case series and case reports)

Lee HP, Win T, Balakrishnan S. The impact of intrathecal baclofen on the ability to walk: A systematic review. Clin Rehabil. 2023 Apr;37(4):462-477. doi: 10.1177/02692155221135827. Epub 2022 Nov 4. PMID: 36330654.

Systematic review of insufficient quality, including wrong publication types

Dietz N, Wagers S, Harkema SJ, D'Amico JM. 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. Arch Phys Med Rehabil. 2023 Jan;104(1):119-131. doi: 10.1016/j.apmr.2022.05.011. Epub 2022 Jun 22. PMID: 35750207.

Systematic review with wrong study comparators (placebo instead of usual care)