Efficacy and Safety of Intermittent Negative Pressure Treatment on Spasticity and Spasticity-Related Symptoms in Patients with Multiple Sclerosis: A Two-Arm Randomized Trial

Abstract

Introduction

To compare the efficacy of treatment with two different levels of intermittent negative pressure (INP), applied to the lower limb, on self-reported spasticity and pain in patients with multiple sclerosis (MS).

Methods

A randomized, two-arm multicenter trial enrolled patients with spasticity in the leg ≥ 4 on the numeric rating scale (NRS). Patients were randomized to treatment with −10 mmHg INP (low-dose group [LDG]) or −40 mmHg INP (high-dose group [HDG]) on the most affected leg, using the FlowOx 2.0 device (Otivio AS, Oslo, Norway). The device applies alternating cycles of 10 s of negative pressure and 7 s of ambient pressure via a sealed pressure chamber around the lower leg, for 1 h daily for 4 weeks.

Results

There was no difference in the change in NRS spasticity and pain score between the two groups after 4 weeks (estimated treatment effect 0.72; 95% CI [−0.17, 1.61]; p = 0.114, and 1.09; 95% CI [−0.35, 2.53]; p = 0.138, respectively). Both HDG and LDG experienced a statistically significant decrease in NRS spasticity compared with baseline (mean change −1.0; 95% CI [−1.6, −0.4]; p = 0.001, and mean change −1.6; 95% CI [−2.5, −0.6]; p = 0.002, respectively), and both groups had a significant decrease in NRS pain score compared with baseline (mean change −1.5; 95% CI [−2.6, −0.5]; p = 0.007, and mean change −3.0; 95% CI [−5.0, −1.0]; p = 0.006, respectively). No improvements in objective walking tests were observed. Treatment compliance was high, and device-related adverse events were mild to moderate.

Conclusion

There was no difference between treatment with a high and a low INP level in spasticity and pain. Both pressure levels led to significant improvements in spasticity and pain compared with baseline. INP treatment appears safe and may represent a useful non-pharmacological treatment option for spasticity in patients with MS.

Trial Registration

ClinicalTrials.gov identifier NCT05562453.

Key Summary Points

Why carry out this study?

Spasticity is one of the most prevalent and disabling symptoms in multiple sclerosis (MS), affecting 60–85% of patients. Current pharmacological treatments are associated with significant side effects, and effective non-pharmacological alternatives are lacking.

Preliminary evidence from a pilot study suggested that intermittent negative pressure (INP) applied to the lower leg may reduce spasticity and pain in patients with MS. This trial aimed to compare the efficacy and safety of treatment with two different levels of INP on self-reported spasticity and spasticity-related pain in patients with MS.

What was learned from the study?

Both −40 mmHg and −10 mmHg INP resulted in statistically significant and clinically meaningful within-group reductions in self-reported spasticity and pain after 4 weeks, with no significant between-group difference.

The absence of a placebo arm means that a contribution from placebo effects cannot be excluded; however, the findings suggest that INP may be a safe non-pharmacological treatment option for spasticity-related symptoms in MS.

Introduction

Multiple sclerosis (MS) is an inflammatory and degenerative disease affecting approximately 2.8 million people worldwide, resulting in a range of symptoms including visual impairment, gait difficulty, limb weakness, spasticity, pain, fatigue, disordered sleep, and autonomic dysfunction [1]. Onset of MS typically occurs in young adults and is clinically categorized into relapsing or progressive disease course [2]. Of people diagnosed with MS, relapsing–remitting MS (RRMS) accounts for approximately 90% of the patients, and primary progressive MS (PPMS) constitutes approximately 10%. Without sufficient treatment, a substantial proportion of RRMS patients will convert to a secondary progressive MS (SPMS) course with gradual, irreversible worsening [2, 3].

Spasticity occurs in different central nervous system diseases and is one of the most common symptoms in MS, affecting 60–85% of patients [4]. It is caused by an altered balance between the innervations of intra- and extrafusal fibers in muscles due to loss of inhibitory supraspinal control [5]. Spasticity is clinically observed as an increase in muscle tone, leading to restricted joint range of motion, loss of dexterity, abnormal limb postures, and pain. It may have a significant impact on activities of daily living, and increased severity of spasticity is correlated with a reduction in quality of life [6]. Antispastic drugs are the first-line treatment for spasticity in patients with MS [7]. Most of these drugs are associated with side effects such as fatigue, pronounced muscle weakness, dizziness, and deterioration of postural stability. For patients with severe or refractory spasticity, more intensive interventions may be employed: intrathecal baclofen (ITB) pump therapy delivers baclofen directly into the intrathecal space via an implanted pump and can effectively reduce generalized spasticity, but carries risks including infection, catheter malfunction, and abrupt drug withdrawal; focal botulinum toxin injections can reduce spasticity in specific muscle groups but require repeated administration and do not address generalized spasticity [8]. Physiotherapy interventions can be beneficial, but the effect on overall spasticity is uncertain [9]. Thus, currently, there is no non-pharmacological standard of care used to treat spasticity in patients with MS.

Intermittent negative pressure (INP) applied to the lower leg increases fluctuations in macro- and microcirculatory blood flow and is used to treat symptoms of peripheral artery disease [10]. Results from a recent Norwegian single-arm pilot study (n = 8) suggest that treatment with −40 mmHg INP could improve spasticity and pain in patients with MS [11, 12]. Our hypothesis was that INP of −40 mmHg applied to the lower limb activates sensory signals and, secondary to this, decreases spinal motor neuron activity by afferent neural modulation. Furthermore, we hypothesized that a smaller impact on blood flow induced by a lower level of −10 mmHg INP treatment would not trigger the same neural signals and thereby could act as comparator sham treatment. The aim of this study was to investigate the efficacy and safety of treatment with two different levels of INP, applied by FlowOx, on self-reported spasticity and spasticity-related pain in patients with MS.

Methods

Participants

This was a randomized, two-arm, multicenter trial, enrolling patients from neurological departments at six hospitals in Denmark, Sweden, and Norway (Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Motala Hospital, Motala, Sweden; Academic Specialist Center, Stockholm Health Care Services, Stockholm, Sweden; Uppsala University Hospital, Uppsala, Sweden; Linköping University Hospital, Linköping, Sweden; and Haukeland University Hospital, Bergen, Norway). The first patient was enrolled in October 2022, and data collection was completed in July 2023, giving a total trial duration of approximately 9 months. Following the 4-week randomized treatment period, an open-label extension phase (OEP) was offered to all participants wishing to continue, providing treatment with −40 mmHg INP for up to 6 months. Results from the OEP will be reported in a separate publication.

Patients diagnosed with MS according to the revised McDonald criteria [13], with self-reported spasticity of ≥ 4 rated according to a numeric rating scale (NRS) in the most affected leg and spasticity-related pain or discomfort, were assessed for eligibility. Eligible patients were in a stable disease state, with unchanged disease-modifying MS therapy for the last 6 months prior to inclusion. Patients were instructed to maintain all existing spasticity-related medications and physiotherapy regimens unchanged throughout the 4-week treatment period.

Intermittent Negative Pressure Treatment

Treatment with INP was applied in a pressure chamber sealed around one of the lower legs, coupled to a pump unit (FlowOx 2.0, Otivio AS, Oslo, Norway) that removed air from and vented the pressure chamber (Fig. 1). The pump unit was programmed to apply alternating 10 s of negative pressure and 7 s of ambient pressure. Patients received treatment with either −40 mmHg INP or −10 mmHg INP. The two different INP levels were chosen based on previous studies on blood flow parameters, demonstrating that −40 mmHg INP induced a significant increase in macro- and microcirculatory blood flow in the treated extremity, whereas −10 mmHg INP had only a minor effect on blood flow parameters [14]. Except for different INP levels, the two groups were treated with identical treatment devices. All patients were instructed to treat themselves at home for 1 h per day for 4 weeks and were trained in the use of the INP device before the start of treatment. Daily treatment time was automatically recorded by the device via a timer integrated into the FlowOx 2.0 control unit, which logged the cumulative duration of each treatment session; these data were downloaded by study staff at the end of the treatment period.

Fig. 1.

FlowOx 2.0. Intermittent negative pressure is applied in a pressure chamber sealed around the patient’s lower leg by a pump unit that removes air from and vents the pressure chamber

Randomization and Blinding

Patients were randomized (1:1) to treatment with either −40 mmHg INP (high-dose group) or −10 mmHg INP (low-dose group) using a computer-generated randomization list. Labeling of the treatment devices was carried out by the manufacturer (Otivio AS), by staff who were not involved in the recruitment or data collection. Patients and clinical staff, including the assessing neurologist, were blinded to the group allocation. The statistical analyses were performed blinded.

Data Collection and Variables

Clinical assessments of all eligible patients were performed by a clinical neurologist at the screening visits, including medical history, regular medications, physical examination, and assessment of the Expanded Disability Status Scale (EDSS) [15] and modified Ashworth Scale (MAS) [16]. Assessments were performed at baseline and after 4 weeks of treatment. Neither EDSS nor MAS was collected beyond the baseline visit.

The primary outcome was the change in self-reported spasticity between the groups after 4 weeks. Spasticity was scored using the NRS, a validated 11-point patient-reported outcome instrument with established reliability and construct validity in spasticity and pain research [17]. The NRS rated the average spasticity score over the last 24 h; it scores spasticity from 0 to 10, where 0 is no spasticity and 10 is the worst imaginable spasticity. Patients were instructed to perform the scoring at roughly the same time each day, and not during or immediately after the INP treatment. NRS values were recorded weekly during the 4-week treatment period.

Secondary endpoints included self-reported pain, sleep, and fatigue, which were also recorded weekly using the NRS. Quality of life was recorded at baseline and after 4 weeks of treatment using the Multiple Sclerosis Impact Scale (MSIS-29), a 29-item self-reporting measure, with 20 items belonging to the physical and 9 items to the psychological subscale dimensions, reflecting the impact of MS on day-to-day life in the past 2 weeks. Items are scored on a scale of 1 to 5 and converted to two 0–100 subscales, with higher numbers indicating more severe impact of the disease [18]. Walking ability was assessed with two different walk tests at baseline and after 4 weeks. In the timed 25-foot walk (T25-FW), patients were instructed to walk 25 feet as quickly as possible [19]. The average time of two walks was recorded. The 2-min walk test was performed in a hallway free of obstacles, and patients were instructed to cover as much ground as possible for 2 min. The distance covered was recorded [20].

Incidence of adverse events (AEs) was reported and documented continuously during the trial. All included patients were encouraged to report any AEs directly to the study staff at the study site. At all follow-up consultations, study staff asked whether patients had experienced any AEs since last contact. No follow-up data after treatment discontinuation were collected.

Statistics

Data are presented as mean ± standard deviation (SD) for continuous variables, and number (%) for categorical variables. Normality was assessed with histograms, Q–Q plots, and residual plots. The treatment groups were compared using a general linear model with mean values over 4 weeks as the response variable, and treatment and baseline values as explanatory variables. A set of predefined sensitivity analyses were performed to evaluate the assumption of a stable treatment effect. For changes in NRS pain score, only patients with a baseline pain level of NRS ≥ 4 were included in the analyses. Differences within the groups were analyzed with paired-samples t-tests. All analyses were performed according to the prespecified analysis plan. The last observation carried forward was used to manage missing data. A p-value ≤ 0.05 was considered statistically significant. Analyses were performed using Stata version 16 software (StataCorp LLC, College Station, TX, USA).

Based on a pilot study [11], the expected improvement after 4 weeks of treatment with INP was approximately 2 units in NRS spasticity. The standard deviation was estimated to be between 2.12 and 2.75. Assuming a treatment difference of 2 units between the groups and a standard deviation of 2.5 units, a sample size of 25 patients per group was suggested (alpha = 0.05, power = 0.80). A sample size of 60 patients in total was chosen to compensate for 20% dropout.

Ethical Approval

The study was approved by the Regional Committees for Medical and Health Research Ethics in Norway (reference no. 503097), Sweden (reference no. 2022-069904-02), and Denmark (reference no. 2208607), and registered on ClinicalTrials.gov (NCT05562453). Written informed consent was obtained from all patients before inclusion.

All procedures were performed in compliance with relevant laws and institutional guidelines and have been approved by the appropriate institutional committees. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. Approval of the investigation was given by the Independent Ethics Committee (IEC), and a favorable opinion was given by the Competent Authority (CA) in each participating country. Initial approval was obtained for clinical investigation plan number FO-NP-002, CIP version 5.1, 25-04-2023 (Sweden, Denmark), FO-NP-002, CIP version Norway 4.3, 31-05-2023 (Norway). The approvals were obtained as follows: Sweden – 27 June 2022 IEC, 15 June 2022 CA; Denmark – 13 July 2022 IEC, 8 August 2022 CA; Norway – 3 February 2023 IEC Conditional approval of main part only, 05 May 2023 IEC OEP part, 16 September 2022 CA.

Results

In total, 61 patients were screened for participation, and 58 patients were randomized (Fig. 2) (Copenhagen University Hospital, Rigshospitalet n = 14, Motala Hospital n = 4, Stockholm County Healthcare Services n = 15, Uppsala University Hospital n = 9, Linköping University Hospital n = 6, and Haukeland University Hospital n = 10). Two participants, one in each group, withdrew their participation consent before initiating treatment and were not included in any data analysis. Baseline characteristics are presented in Table 1.

Fig. 2.

Flow diagram showing inclusion, exclusion, treatment allocation, and outcomes after 4 weeks of treatment

Table 1.

Baseline characteristics according to group allocation

	−40 mmHg INP n = 29	−10 mmHg INP n = 27
Female sex	20 (69.0)	18 (66.7)
Male sex	9 (31.0)	9 (33.3)
Age, years	52.8 ± 11.5	54.5 ± 7.4
Ethnicity
White	28 (96.6)	27 (100)
Asian	1 (3.4)	0 (0)
MS subtype*
Primary progressive	3 (11.2)	1 (4)
Relapsing–remitting	12 (44.4)	11 (44)
Secondary progressive	12 (44.4)	13 (52)
EDSS	4.7 ± 1.4	5.3 ± 1.5
NRS spasticity	6.6 ± 1.4	6.1 ± 1.5
MAS, most affected leg, median (25th, 75th percentile)
Adductors	1.0 (0.0, 2.0)	0.0 (0.0, 2.0)
Knee extensors	2.0 (1.0, 3.0)	1.0 (1.0, 3.0)
Knee flexors	2.0 (1.0, 3.0)	1.0 (1.0, 3.0)
Plantar flexors	2.0 (1.0, 3.0)	2.0 (1.0, 3.0)

Data are presented as number (%) and mean ± SD unless otherwise stated

INP intermittent negative pressure, MS multiple sclerosis, EDSS Expanded Disability Status Scale, NRS numeric rating scale, MAS modified Ashworth scale

*MS subtype was missing for four patients

At baseline, mean ± SD NRS spasticity scores were 6.6 ± 1.4 in the high-dose group (−40 mmHg INP) and 6.1 ± 1.5 in the low-dose group (−10 mmHg INP). After 4 weeks of treatment, there was no statistically significant difference in the change in NRS spasticity score between the two groups (estimated treatment effect 0.72; 95% CI [−0.17, 1.61]; p = 0.114; Table 2). Patients in both the high-dose group and the low-dose group experienced a statistically significant decrease in NRS spasticity after 4 weeks compared with baseline (mean change −1.0; 95% CI [−1.6, −0.4]; p = 0.001, and mean change −1.6; 95% CI [−2.5, −0.6]; p = 0.002, respectively).

Table 2.

Changes between the groups after 4 weeks of treatment

	No. (available for analyses)	−10 mmHg INP		−40 mmHg INP		Estimated treatment effect [95% CI]	p-value
		Baseline*	4 weeks*	Baseline*	4 weeks*
NRS spasticity	56	6.1 ± 1.5	4.6 ± 2.0	6.6 ± 1.4	5.4 ± 1.4	0.72 [−0.17, 1.61]	0.114
NRS pain	31	6.8 ± 2.0	3.8 ± 2.1	6.3 ± 1.3	4.8 ± 1.9	1.09 [−0.35, 2.53]	0.138
NRS sleep	50	3.9 ±2.9	3.1 ± 2.6	4.8 ± 2.6	4.0 ± 2.8	0.16 [−1.26, 1.57]	0.826
NRS fatigue	50	4.0 ± 2.5	3.8 ± 3.0	4.5 ± 2.6	4.1 ± 2.4	−0.00 [−1.10, 1,09]	0.996
MSIS-29 physiological	54	50.4 ± 14.5	46.9 ± 16.5	54.1 ± 17.2	46.0 ± 16.9	−3.2 [−9.24, 2.85]	0.293
MSIS-29 psychological	54	32.3 ± 14.6	28.5 ± 17.1	40.0 ± 25.6	31.1 ± 20.2	−1.56 [−8.43, 5.30]	0.649
Timed 25-foot walk, (s)	56	12.3 ± 22.3	9.3 ± 8.5	11.8 ± 19.5	10.5 ± 14.3	1.47 [−0.84, 3.79]	0.208
Two-min walk test (m)	56	103.7 ± 40.6	107.3 ± 44.6	119.9 ± 47.2	124.0 ± 50.6	0.22 [-8.68, 9.12]	0.960

General linear model with baseline values as covariate

*Values are mean ± SD

General linear model, −10 mmHg INP vs. −40 mmHg INP

NRS numeric rating scale

MSIS-29 Multiple Sclerosis Impact Scale

Overall, 17 patients in the high-dose group and 14 patients in the low-dose group had a baseline NRS pain score ≥ 4. After 4 weeks of treatment, there was no difference in the change in NRS pain score between the two groups (estimated treatment effect 1.09; 95% CI [−0.35, 2.53]; p = 0.138; Table 2). Patients in both the high- and low-dose groups showed a statistically significant decrease in NRS pain score after 4 weeks of treatment compared with baseline (mean change −1.5; 95% CI [−2.6, −0.5]; p = 0.007, and mean change −3.0; 95% CI [−5.0, −1.0]; p = 0.006, respectively).

There were no statistically significant differences between or within groups regarding change in NRS fatigue and sleep scores after 4 weeks of treatment.

No significant changes were found between the groups in the MSIS-29 physical sub-score or MSIS-29 psychological sub-score after 4 weeks of treatment (Table 2). However, patients in the high-dose group showed statistically significant improvements in MSIS-29 physical and psychological sub-scores after 4 weeks compared with baseline (mean change −7.2; 95% CI [−11.4, −3.0]; p = 0.002, and mean change −7.1; 95% CI [−13.1, −1.1]; p = 0.022, respectively).

Mean daily treatment time was 52.2 ± 1.2 min in the high-dose group and 49.6 ± 13.8 in the low-dose group. There was no clear effect on NRS spasticity in relation to adherence to treatment.

There were no statistically significant differences in T25-FW and 2-min walk tests between the groups after 4 weeks (Table 2).

Overall, six patients in the high-dose group and four patients in the low-dose group reported adverse events possibly or probably related to the treatment device (Table 3). These adverse events included nausea, muscle weakness, muscle tightness, spasticity, limb discomfort/pain, and paresthesia. The intensity of all the device-related adverse events was rated as mild or moderate.

Table 3.

Registered device-related adverse events during the study period

	−40 mmHg INP n = 29	−10 mmHg INP n = 27
AE possibly related to investigational device	2 (7%)	4 (15%)
AE probably related to investigational device	4 (14%)	0 (0.0%)
AE with causal relationship to investigational device	0 (0.0%)	0 (0.0%)

Data are number (%)

INP intermittent negative pressure

AE adverse events

Discussion

In this 4-week randomized two-arm trial, there were no differences between treatment with a high and a low INP level on spasticity and spasticity-related symptoms in patients with MS. However, participants in both arms reported statistically significant improvement in self-reported spasticity and pain after 4 weeks compared with baseline. The primary basis for assessing treatment efficacy is the between-group comparison; the within-group pre/post changes should be considered as contextual information. The absence of a placebo arm limits the ability to draw definitive conclusions about true treatment effects.

There may be several reasons why there were no differences in outcomes between the two arms. The rationale for choosing −10 mmHg as the comparator device was that the effect on blood flow parameters was small [14], theorizing that the imposed effect on spasticity at this level would also be small. However, a potential effect of INP on spasticity and pain does not need to correlate with effects on blood flow parameters, as the INP stimuli could also affect other sensory and autonomic pathways. MS spasticity is not a blood flow-dependent phenomenon, and if one assumes that the treatment effect in the low-dose group was at least partly a true physiological effect, it seems that lower INP levels were sufficient to exert this effect.

The mechanism of action of INP on spasticity has not been established and was not the focus of this study. However, a recent study investigating the acute effects of treatment with INP in people with MS showed a statistically and clinically significant decrease in spinal excitability as measured by the soleus Hoffman reflex, suggesting a modulation of spinal reflex pathways [21]. The closest resemblance to this treatment method is found in other studies investigating pressure therapy to treat spasticity. In 2020, Bacca et al. treated stroke patients suffering from limb spasticity with circumferential pressure and found that this treatment reduced both the perceived spasticity and spasticity measured by MAS [22]. In addition, they reported a slowing of the H-wave, leading to increased release of GABA and slowing of the α-motor neuron. Another previous study treating spasticity with air pressure reported that circumferential pressure applied to the lower leg of patients with spinal cord injury led to decreased soleus muscle alpha motor neuron reflex excitability [23]. These results are in line with the clinical improvements observed in this study, and suggest that INP may activate afferent sensory neurons that modulate spinal reflexes and lead to a more general change in muscle tone and pain perception. However, further studies are needed to confirm this hypothesis.

It should be considered that the observed improvements in spasticity and pain could be due to a placebo effect, or conversely that the INP treatment had an actual physiological effect, or it could be a combination of both. The placebo effect in studies investigating self-reported spasticity and pain can potentially be quite substantial. It is known that treatment with a medical device is often a more powerful placebo inducer than a drug [24], and it was previously noted that studies examining treatment of pain and spasticity are challenging because the placebo effect often plays an important part [25–27]. In previous literature, a reduction of 29.5% in self-reported spasticity was considered to be clinically significant, and a reduction of 18% was considered a minimal clinically important difference [28]. The reduction in spasticity from baseline was comparable between the two groups in this trial. Patients in the low-dose group recorded a mean change of −21% in NRS spasticity (−1.6 NRS points), indicating that the observed change, whether due to placebo or not, constituted a clinically meaningful improvement.

We did not see any improvements in walking tests after 4 weeks of treatment. Hence, the reported improvement in spasticity did not seem to improve gait function. Spasticity is not the only symptom that can influence walking speed and walking distance, as balance also plays a part in this process. However, the observed improvement in MSIS-29 physiological and psychological scores may indicate that INP treatment could have a positive effect on a patient’s activities of daily living.

INP treatment is novel, and the literature on the effects of other non-pharmacological treatment options for spasticity is scarce. Transcutaneous electrical nerve stimulation (TENS) on stroke survivors is shown to be effective [29], but has not shown convincing results in MS [30]. Physiotherapy has been investigated in multiple studies regarding MS and spasticity. In one study, Ehling et al. [31] found a 38% self-reported reduction in perceived spasticity after treatment with an exercise program, yet no clear conclusion was reached about the effects.

In this study, both groups experienced a reduction in perceived pain compared with baseline. Generally, a reduction in self-reported pain of more than 2 points on the NRS, or a 30% change, is considered clinically significant, and a reduction of 18% constitutes a clinically important difference [32]. For patients with baseline NRS pain score ≥ 4, those in the higher-dose group reported a reduction of 2.5 NRS points (24%) and those in the lower-dose group reported a reduction of 3.0 NRS points (36%) in pain after 4 weeks. Hence, the observed improvements in pain from baseline seem to be clinically relevant in this trial.

Overall, the treatment compliance in this study was good, and comparable between the two groups. This indicates that true blinding was achieved and suggests that the handling and use of FlowOx worked well in this patient population.

In the current study, there were few device-related adverse events, the intensity of those that occurred was mild to moderate, and most resolved after the treatment was stopped. Hence, INP treatment seems to be safe for patients with MS.

Limitations

This study has several limitations. First and foremost, the absence of a true placebo or sham arm limits the ability to draw firm conclusions about true treatment efficacy, as placebo effects in self-reported pain and spasticity outcomes can be substantial. The treatment effect of −10 mmHg INP on spasticity and pain was larger than expected, limiting the possibility of recording a difference in outcomes between the two arms. Whether the observed effects in the low-dose group were purely due to a placebo response or a true neuromodulatory effect cannot be determined with certainty; MS spasticity is not blood flow-dependent, and −10 mmHg INP may have exerted genuine neurological effects. This also means that designing a valid placebo-controlled study for this treatment will be challenging due to the lack of a fully inert sham device. Second, no active comparator arm (e.g., an approved pharmacological treatment or physiotherapy intervention) was included, limiting the ability to contextualize the magnitude of effect relative to established treatments. Third, MAS was only assessed at baseline and not repeated at follow-up, meaning that objective assessment of spasticity severity is absent for the post-treatment time point. Fourth, the sample size calculation assumed a between-group difference of 2 NRS points, which may have been overly optimistic, and the study may therefore have been underpowered to detect smaller but clinically meaningful differences. Fifth, changes in NRS pain were analyzed only for patients with a baseline NRS pain score ≥4, so the effect on patients with lower pain scores is uncertain. Finally, while patients were recruited from six MS centers in Scandinavia, the specific inclusion and exclusion criteria limit generalizability to other patient populations or settings.

Conclusions

There were no differences in spasticity and spasticity-related symptoms between treatment with high and low INP levels. Treatment with both pressure levels resulted in improvements compared with baseline. The INP treatment was safe, with few side effects. The mode of action is unclear and requires further investigation; however, the findings suggest that INP may be a useful non-pharmacological treatment for spasticity and spasticity-related pain in patients with MS.

Author Contribution

Jesper Nørregaard: conceptualization, data collection, statistical analysis, drafting and critical revision. Henrik Hoel: conceptualization, study design, critical revision. Iacob Mathiesen: conceptualization, study design, critical revision. Sarah Haghighi: data collection, critical revision. Marie Kierkegaard: data collection, critical revision. Fredrik Piehl: data collection, critical revision. Morten Blinkenberg: data collection, critical revision. Kjell Morten Myhr: conceptualization, study design, data collection, critical revision.

Funding

This study was organized and funded by the sponsor, Otivio AS. The practical organization, monitoring and data handling were sub-contracted to an independent clinical research organization (SCRO, Uppsala, Sweden). A contract was established between the sponsor and each site. Each responsible investigator was obliged to comply with the commitments and obligations set out in the signed agreement. The hospital/clinic received a fee for each study participant who completed the study in accordance with the agreement. The study doctor and the study staff have no personal or financial ties to the sponsor, other than in connection with the sponsored study that they conducted, or services that they provided to the sponsor. The Rapid Service Fee for this publication is funded by Otivio AS.

Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Fredrik Piehl has received research grants from Janssen, Merck KGaA and UCB, and fees for serving on DMCs in clinical trials with Chugai, Lundbeck and Roche, and preparation of expert witness statement for Novartis. Marie Kierkegaard has received honoraria for lectures from Merck and Novartis. Kjell Morten Myhr has received speaker honoraria from Biogen, Sanofi and Novartis, and honoraria for participation in a scientific advisory board from Alexion, and has participated in clinical trials organized by Biogen, Merck, Novartis, Otivio, Sanofi and Roche. Jesper Nørregaard has received speaker honoraria from Merck, Sanofi and Novartis, and honoraria for participation in scientific advisory boards from Merck and Sanofi. Iacob Mathiesen and Henrik Hoel are shareholders and employees of Otivio AS. Iacob Mathiesen and Henrik Hoel have stock options and are inventors of multiple Otivio patents. Sarah Haghighi and Morten Blinkenberg have nothing to disclose.

Ethical Approval

The study was approved by the Regional Committees for Medical and Health Research Ethics in Norway (reference no. 503097), Sweden (reference no. 2022-069904-02) and Denmark (reference no. 2208607). Written informed consent was obtained from all patients before inclusion. All procedures were performed in compliance with relevant laws and institutional guidelines and have been approved by the appropriate institutional committees. The study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. Approval of the investigation was given by the Independent Ethics Committee (IEC), and a favorable opinion was given by the Competent Authority (CA) in each participating country. Initial approval was obtained for clinical investigation plan number FO-NP-002, CIP version 5.1, 25-04-2023 (Sweden, Denmark), FO-NP-002, CIP version Norway 4.3,31-05-2023 (Norway). The approvals were obtained as follows: Sweden – 27 June 2022 IEC, 15 June 2022 CA; Denmark – 13 July 2022 IEC, 8 August 2022 CA; Norway – 3 February 2023 IEC Conditional approval of main part only, 05 May 2023 IEC OEP part, 16 September 2022 CA.