Clinical case reviews in multiple sclerosis spasticity

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Spasticity is one of the main symptoms associated with multiple sclerosis (MS). ... KEYWORDS: clinical cases • management • multiple sclerosis • nabiximols ...
Symposium Paper

Clinical case reviews in multiple sclerosis spasticity: experiences from around Europe Expert Rev. Neurother. 13(12s), 61–66 (2013)

Ju¨rgen Koehler*1, Maria P Amato2, Celia Oreja-Guevara3 and Jan Lycke4 1 Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen, Berg, Germany 2 University of Florence, Florence, Italy 3 Multiple Sclerosis Unit, Department of Neurology, University Hospital San Carlos, Madrid, Spain 4 University of Go¨teborg, Go¨teborg, Sweden *Author for correspondence: Tel.: +49 815 126 1920 Fax: +49 815 126 1923 [email protected]

Spasticity is one of the main symptoms associated with multiple sclerosis (MS). Epidemiological studies indicate that approximately two-thirds of MS patients experience spasticity and, in a relevant proportion of this group, spasticity is moderate to severe. Yet, spasticity remains largely undertreated. The most commonly used oral antispasticity agents (e.g., baclofen, tizanidine, gabapentin) generally do not reduce spasticity adequately at dosages that are well tolerated by patients. This review of MS spasticity cases from around Europe presents current knowledge of considerations for administration of a new agent (tetrahydrocannabinol/ cannabidiol-based nabiximols [Sativex!] oromucosal spray) for management of MS spasticity, with the aim of ensuring appropriate and optimal use for best outcomes. Assessment of the European clinical experience is intended to provide a better understanding of the prescribing regulations for MS spasticity treatments, facilitate identification of suitable candidate patients for Sativex and increase awareness of alternative management approaches for MS-related spasticity. KEYWORDS: clinical cases • management • multiple sclerosis • nabiximols • Sativex • spasticity • symptomatic treatment

Clinical experience with use of Sativex in Germany

At the Marianne-Strauß-Klinik in Berg, Germany, Sativex! (nabiximols) was initiated in 166 patients with multiple sclerosis (MS)-related spasticity between September 2011 and January 2013 (~10 patients/month). This review summarizes key data collected from these patients with regard to the use of Sativex in the management of MS spasticity. Clinical characteristics of Sativex-treated patients are shown in TABLE 1. The majority of patients (80.1%) had secondary progressive MS (mean age 50 years; mean Expanded Disability Status Scale [EDSS] score 7.5 ± 1.0). Most patients had received one or two previous antispasticity medications. Over the 15-month study period, 46 patients (27.7%) withdrew from Sativex treatment (TABLE 2). The main reasons (>2% incidence) for discontinuing treatment were lack of efficacy (8.4%), requirement for intrathecal baclofen (5.4%) or tolerability www.expert-reviews.com

10.1586/14737175.2013.865881

issues such as dizziness (3.0%), fatigue (3.0%) or oral discomfort (2.4%). One patient withdrew due to treatment noncompliance. The mean 0–10 Numerical Rating Scale (NRS) score for MS spasticity in ‘on therapy’ patients (n = 120) decreased from 7 (range: 4–10) before use of Sativex to 3 (range: 0–6) after use of Sativex. Reductions in NRS scores were similar whether patients were receiving Sativex as add-on therapy (n = 95) or as monotherapy (n = 25) (TABLE 2). Sixty patients received Sativex for ‡60 days and were followed for a mean of 9 months (TABLE 3). The mean Sativex dosage was 4 (range: 1–11) sprays/day. Only 6 (10%) of the patients maintained on Sativex withdrew from treatment during follow-up. Conclusions

These data are based on a review of clinical practice experience with Sativex over a 15-month period at the Marianne-Strauß-Klinik in Berg, Germany. The majority of patients used Sativex in combination with

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Koehler, Amato, Oreja-Guevara & Lycke

Table 1. Clinical characteristics of patients with multiple sclerosis spasticity (n = 166) treated with Sativex between September 2011 and January 2013 at the Marianne-Strauß-Klinik in Berg, Germany. Relapsing–remitting

Secondary progressive

Primary progressive

Patients (n; M:F)

13 (8:5)

133 (78:55)

20 (11:9)

Age (years)

45

50

53

Mean EDSS (0–10) ± SD (range)

6.0 ± 1.7 (3.0–8.5)

7.5 ± 1.0 (3.0–9.5)

7.5 ± 1.0 (4.0–8.5)

Ashworth UE (0–4)

0.0

1.0

1.0

Ashworth LE (0–4)

2.0

3.0

3.0

Minimal muscle strength UE (0–5)

4.0

3.0

2.0

Minimal muscle strength LE (0–5)

2.5

0.0

0.5

Antispasticity medications (mean)

1.0

1.0

2.0

EDSS: Expanded Disability Status Scale; F: Female; LE: Lower extremities; M: Male; MS: Multiple sclerosis; SD: Standard deviation; UE: Upper extremities.

Table 2. Outcomes data for 166 patients treated with Sativex in Germany. Therapy

Patients (n)

Sativex dosage, sprays/day ± SD (range)

0–10 Numerical Rating Scale, mean (range) Before Sativex

On Sativex

On therapy

120

4.0 ± 2.6 (1–12)

7.0 (4–10)

3.0 (0–6)

Add-on

95

4.0 ± 2.6 (1–12)

7.0 (5–10)

3.0 (0–6)

Monotherapy

25

3.0 ± 2.6 (1–12)

7.0 (4–8)

3.0 (0–5)

Drop-outs

46 (27.7%)

4.0 ± 3.1 (1–12)

8.0 (6–10)

6.0 (2–9)

SD: Standard deviation.

Table 3. Longer term (‡60 days) follow-up data with Sativex: German experience. Therapy

Patients (n)

Mean follow-up duration, days ± SD (range)

Mean Sativex dosage, sprays/day ± SD (range)

On therapy

54

262 ± 98 (82–498)

4.0 ± 2.3 (1–11)

Add-on

45

264 ± 100 (82–498)

4.0 ± 2.3 (1–11)

Monotherapy

9

257 ± 87 (111–364)

4.0 ± 2.4 (1–8)

Drop-outs

6 (10%)

128 ± 139 (98–406)

6.0 ± 3.0 (1–9)

SD: Standard deviation.

baclofen. In contrast to pivotal clinical studies [1,2], patients receiving Sativex as add-on therapy in clinical practice required fewer dosages (4–5 vs 8 sprays/day) and a shorter period of dose titration (2 vs 4 weeks) to achieve reduction of MS spasticity. The responder rate (~72%) was higher than that reported in placebo-controlled clinical studies [1,2]. Tolerability was good overall. With regard to long-term use of Sativex, dosages tended to be stable and, in patients with moderate MS spasticity, the dosage tended to decrease over time. The efficacy of Sativex was sustained during mean 9 months’ follow-up in 60 patients and the ‘secondary’ drop-out rate was low (10%). Our experience indicated that, in some patients with MSinduced severe muscle weakness and spasticity, Sativex is advantageous compared with current oral antispasticity treatments. In 62

2012, Sativex received a positive evaluation by the German Federal Joint Committee. Clinical experience with use of Sativex in Italy

Baclofen is currently the first-line choice for treatment of MS spasticity in Italy based on best-available evidence. As baclofen is funded by the Italian health care system, it is also a practical option for practitioners. Baclofen should be titrated slowly to achieve the best-tolerated dosage. Tizanidine tends to be used in combination with baclofen when higher baclofen dosages are not possible due to poor tolerability. Use of benzodiazepines is limited by tolerability issues, and gabapentin is reserved mainly for painful spasms. Physiotherapy is recognized in Italy as a mainstay in the management of MS spasticity despite limited Expert Rev. Neurother. 13(12s), (2013)

Clinical case reviews in MS spasticity

Symposium Paper

Table 4. Clinical features and outcomes of three patients with resistant multiple sclerosis spasticity treated with Sativex. Parameter

Case 1

Case 2

Case 3

Gender

Male

Male

Female

Age (years)

56

72

57

MS type

RRMS

SPMS

RRMS

MS duration (years)

17.5

52

11

EDSS score

7.5

7.5

8

MS spasticity area

Generalized

Legs

Generalized

Main associated symptoms

Spasms Sleep disorders

Spasms (day/night) Pain

Painful night spasms

MS spasticity severity

3–4 (0–4 Ashworth)

4 (0–4 Ashworth)

2–4 (0–4 Ashworth)

Previous MS treatments

Baclofen + tizanidine + benzodiazepines + gabapentin

Baclofen + rehabilitation + botulinum toxin

Baclofen + tizanidine

Current treatment

Sativex 8 sprays/day + antispasticity drugs (reduced dose)

Sativex 2–4 sprays/day + baclofen (no dosage change)

Sativex 7 sprays/day

Current disease status

Consolidation of results obtained with previous antispasticity treatments; increased tolerability with a gradual dose increase every 5 days

Remission of pain in both legs; improved voluntary mobility in left leg; normalized sleep pattern; no muscular spasms; reduced Ashworth scale scores

Marked improvement of spasticity (reduced Ashworth scores); no nocturnal muscle spasms; benefit maintained after 5 months of treatment

EDSS: Expanded Disability Status Scale; MS: Multiple sclerosis; RRMS: Relapsing–remitting MS; SPMS: Secondary progressive MS.

clinical evidence in support of its use. For localized spasticity, botulinum toxin A is often used in combination with physiotherapy. Other techniques employed by Italian clinicians include hydrotherapy, stretching and strengthening. Patient access to these techniques can vary, however, depending on the region of Italy. Intrathecal baclofen is usually reserved for severe disability, long-term disease or in cases of resistance to first- and second-line treatments, but may also have utility in patients who are still ambulatory. When planning to use intrathecal baclofen, consideration must be given to appropriate patient selection, patient and caregiver education, dose adjustments and expertise of the MS center. Clearly defined objectives and goals should be set to ensure realistic expectations from treatment. Once administration of disease-modifying drugs has been completed, our experience suggests that patient visit frequency in daily practice is about every 12 months in two-thirds of patients and about every 6 months in the remaining one-third of patients (monitored by neurologists and rehabilitation physicians). As with other MS symptoms, spasticity can vary over time and requires regular follow-up to monitor treatment response, adverse effects and dose adjustments, as well as to evaluate/modify factors that can trigger or increase spasticity and its related complications (e.g., urinary tract infections, fecal impaction, skin ulcerations). As Sativex oromucosal spray has only recently become available in Italy, experience with its use www.expert-reviews.com

is limited. To gain a better understanding of suitable candidate patients for Sativex, three clinical cases were reviewed in which Sativex was used to manage patients with resistant MS spasticity (TABLE 4). Sativex provided relevant relief of spasticity in these patients despite their lengthy history of treatment failure. A multidisciplinary approach is important in the management of MS spasticity to achieve best patient outcomes. In conjunction with current management options, more widespread availability of Sativex in Italy in future should represent an important step forward in addressing the unmet needs of patients with resistant MS spasticity. Clinical experience with use of Sativex in Spain

From the Spanish perspective, three clinical cases of Sativex use were reviewed with a focus on symptoms associated with MS spasticity (TABLE 5). The first case featured a patient with spasticity-related painful clonus. After treatment with Sativex, symptomatic improvement was noted, particularly at night, which allowed the patient to have better night sleep, although the physician’s perception of symptom improvement was higher than that of the patient. The second case involved a patient with moderate spasticity and associated spasms, which were highly resistant to treatment with oral antispasticity agents. The combination of botulinum toxin and Sativex was beneficial as indicated by an almost complete disappearance of right big toe extensor spasms. During 63

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Table 5. Clinical features and outcomes of three patients with multiple sclerosis spasticity treated with Sativex, with a focus on spasticity-associated symptoms. Parameter

Case 1

Case 2

Case 3

Gender

Female

Female

Male

Age (years)

50

44

58

MS type

RRMS

PPMS

SPMS

MS duration (years)

14

10

17

EDSS score (0–10)

3

6

7.5

MS spasticity area

1 leg

Legs, particularly right leg

Legs and right arm

Main associated symptoms

Painful clonus

Spasms

Spasms and frequent urinary infections

MS spasticity severity

2 (0–4 Ashworth)

6 (spasticity 0–10 NRS)

2–4 (0–4 Ashworth); 7 (spasticity 0–10 NRS)

Previous MS treatments

Baclofen

Baclofen + tizanidine + botulinum toxin + physiotherapy

Tizanidine + botulinum toxin

Current treatment

Sativex 8 sprays/day

Sativex 12 sprays/day

Sativex 5 sprays/day

Current disease status

After 6 weeks: improved pain and spasticity, particularly at night; better night sleep After 3 months: improved pain and spasticity, particularly at night; better night sleep; modified Ashworth scale: 1; VAS scale: 5/10

Right big toe extensor spasms almost disappeared; voluntary flexion of the toe; global decrease of right leg extremity spasticity; spasticity NRS reduced to 4/10

Improvement of spasticity (modified Ashworth); easier catheterization; no urinary tract infections; spasticity NRS reduced to 4/10

EDSS: Expanded Disability Status Scale; MS: Multiple sclerosis; NRS: Numerical rating scale; PPMS: Primary progressive MS; RRMS: Relapsing–remitting MS; SPMS: Secondary progressive MS; VAS: Visual analog scale.

case discussions, clinicians agreed that earlier use of Sativex, in combination with botulinum toxin if necessary, might be advantageous in such patients. The third case featured a patient with MS spasticity and spasticity-aggravated urinary dysfunction. Sativex provided relief of spasticity, which translated into easier catheterization and elimination of urinary infections. There was collective agreement among the Spanish clinicians that pain is the most commonly reported symptom in patients with MS spasticity; other associated symptoms such as sleep disturbances, spasms and bladder dysfunction tend to be reported less frequently. Clinicians perceived that spasticity and other MS-related symptoms tend to be reported spontaneously by patients prior to becoming severe only if they are associated with pain/cramps or are affecting the patient’s quality of life. In order to address issues earlier and improve patient care, a useful approach clinically might be to ask patients specifically about their MS-related spasticity symptoms at each consultation. Clinical experience with use of Sativex: perspective of other European countries

From an ‘other European countries’ perspective (Scandinavia, France, Poland, and so on), three clinical cases of Sativex use were evaluated with a particular view to the impact of 64

treatment on patient disability and quality of life (QoL) (TABLE 6). The first case featured a patient with active MS and severe spasticity who had been treated with high-dose baclofen without improvement. Sativex provided marked relief from spasticity and associated symptoms, which improved walking ability and had a positive impact on the patient’s QoL. During case discussions there was agreement that, in cases of severe spasticity, intrathecal baclofen and Sativex are both options to consider with a view to improving mobility. Lowdose diazepam can be considered for management of night spasms. Glatiramer acetate was considered to be insufficient to treat highly active MS with severe relapses, and there was agreement that interferon-b is best avoided in this situation due to its potential to increase spasticity. The second case described a patient with slowly progressing MS and severe spasticity in whom treatment with baclofen was limited by tolerability issues. Impaired QoL and sleep disorders prompted a switch to add-on Sativex. There was a wide-ranging response to Sativex in terms of various MS spasticity symptoms, which improved the patient’s autonomy. An alternative treatment option in this case might have been intrathecal baclofen. The third case featured a patient with primary progressive MS and severe spasticity treated with baclofen and tizanidine. As cumulative side effects often limit the use of this combination, there was general agreement that dosages must be reduced if these drugs are Expert Rev. Neurother. 13(12s), (2013)

Clinical case reviews in MS spasticity

Symposium Paper

Table 6. Clinical features and outcomes of three patients with multiple sclerosis spasticity treated with Sativex, with a focus on the impact of treatment on patient disability and quality of life. Parameter

Case 1

Case 2

Case 3

Gender

Male

Female

Male

Age (years)

42

55

55

MS type

Active MS

PPMS

PPMS

MS duration (years)

4

15

9

EDSS score (0–10)

6

7.5

7

MS spasticity area

Legs (mainly right leg)

Right limbs and left leg

Legs

Main associated symptoms

Night spasms and fatigue

Painful spasms and sleep disturbance

Night spasms

MS spasticity severity

Severe

3 (0–4 Ashworth)

2–4 (0–4 Ashworth)

Previous MS treatments

Baclofen

Baclofen + botulinum toxin in both legs

Baclofen + tizanidine

Current treatment

Sativex 7 sprays/day

Sativex 8–10 sprays/day

Sativex 6 sprays/day (after 3 weeks), 8 sprays/day (1 month later), 4 sprays/day (2 months later)

Current disease status/evolution

EDSS score: 5.5; decreased fatigue; ability to walk ~100 m without stopping or using a crutch; stable with considerable improvement of mood and a very positive effect on QoL (after 4 months)

Improved use of right arm; independent for partial washing and dressing; improvement of urinary urgency; able to walk 200 m with supports; no vibratory sensitivity in right leg and reduced in left leg; improved cramps and spasms; improved spasticity (modified Ashworth scale score: 2); reduced neuropathic pain, improved sleep quality; rehabilitation and exercises without pain

After 3 weeks: decreased frequency of night spasms and feeling of rigidity; more restorative sleep; discontinuation of tizanidine • 1 month later: improvement in spasticity, worsened walking due to weakness; Sativex dose reduction • 2 months later: baclofen dose reduction to 45 mg/day

EDSS: Expanded Disability Status Scale; MS: Multiple sclerosis; NRS: Numerical rating scale; PPMS: Primary progressive MS; QoL: Quality of life.

used in combination. Baclofen has a short half-life so a useful approach to improve tolerability is to divide the dose throughout the day (4 times daily). In addition to improving spasticity severity, add-on Sativex at a dose of 6 sprays/day improved the patient’s ability to walk. In this case, alternative treatments could have included intrathecal baclofen or clonazepam/ baclofen plus fampridine (to improve walking ability but not spasticity). With regard to determining MS patient status beyond the EDSS score, it is acknowledged that QoL questionnaires and measures of patients’ spasticity/fatigue/mood/depression are useful instruments but are not widely used outside of specific MS registry studies and in rehabilitation centers. As observed elsewhere in Europe, oral baclofen is the firstline choice for MS spasticity despite frequent issues with efficacy and tolerability; tizanidine is used less frequently due to inconsistent efficacy. Second-line choices include Sativex as add-on therapy and botulinum toxin for focal or regional www.expert-reviews.com

spasticity, sometimes combined with oral therapy. The thirdline choice is intrathecal baclofen therapy for severe spasticity that does not respond to current oral therapies. Acknowledgements

J Koehler wrote the section ‘Clinical experience with use of Sativex in Germany’. MP Amato wrote the section ‘Clinical experience with use of Sativex in Italy’. C Oreja-Guevara wrote the section ‘Clinical experience with use of Sativex in Spain’. J Lycke wrote the section ‘Clinical experience with use of Sativex: perspective of other European countries’. The authors would like to thank the following investigators for providing patient cases for Table 4: L Landete Pascual, Hospital Universitario Doctor Peset, Valencia, Spain (Case 1); T Ayuso Blanco, Y Piso´n Cadarso, Complejo Hospitalario de Navarra, Pamplona, Spain (Case 2); MC Calles- Herna´ndez, Hospital Universitario Son Espases, Palma de Mallorca, Spain (Case 3). The authors would also like to thank the following investigators for providing the patient cases for Table 5: R Blasco-Quilez, Hospital Puerta de Hierro Majadahonda, Madrid, Spain (Case 1); V de las 65

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Heras-Revilla, Hospital Universitario Infanta Sofia, S Sebastia´n de los Reyes, Madrid, Spain (Case 2); A Miralles-Martinez, Hospital Universitario Infanta Sofia, S Sebastia´n de los Reyes, Madrid, Spain (Case 3). The authors would also like to thank the following investigators for providing the patient cases for Table 6: J Mallada Frechı´n, Hospital General Universitario Virgen de La Salud, Elda, Alicante, Spain (Case 1); V Meca Lallana, Hospital Universitario de la Princesa, Madrid, Spain (Case 2); FC Pe´rez Miralles, M Escutia Roig, B Casanova Estruch, Hospital Universitari i Polite`cnic La Fe, Valencia, Spain (Case 3). Financial & competing interests disclosure

J Koehler has received honoraria or consultation fees or support of scientific events from Almirall, Bayer, BiogenIdec, Merck Serono, Novartis Pharma,

spasticity due to multiple sclerosis. Neurol. Res. 32(5), 451–459 (2010).

References 1

66

Collin C, Ehler E, Waberzinek G et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of

Sanofi Aventis and TEVA. J Lycke has received grant research/support from Biogen Idec and Novartis, honoraria from Almirall S.A., Biogen Idec, Novartis, Sanofi-Aventis, Teva, and has taken part in speaker bureaus for Almirall S.A., Biogen Idec, Novartis, Sanofi-Aventis and Teva. J Koehler, MP Amato, C Oreja-Guevara and J Lycke received honoraria from Laboratorios Almirall, S.A. (Barcelona, Spain) for participating in the symposium and producing this supplement article. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was provided by Content Ed Net with funding from Laboratorios Almirall, S.A., Barcelona, Spain.

2

Novotna A, Mares J, Ratcliffe S et al. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols*

(Sativex!), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur. J. Neurol. 18(9), 1122–1131 (2011).

Expert Rev. Neurother. 13(12s), (2013)