Effects on Spasticity and Neuropathic Pain of an Oral Formulation of δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis

Guido van Amerongen, Kawita Kanhai, Anne Catrien Baakman, Jules Heuberger, Erica Klaassen, Tim L. Beumer, Rob L M Strijers, Joep Killestein, Joop van Gerven, Adam Cohen, Geert Jan Groeneveld

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Purpose: The aim of the present study was to evaluate the efficacy of an oral formulation of δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS). Methods: This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-controlled treatment phase. Twenty-four patients with progressive MS and moderate spasticity were enrolled. During the treatment phase, biomarkers for efficacy and secondary pharmacodynamic effects were measured at baseline and after 2 and 4 weeks of treatment. Serum samples were collected to determine pharmacokinetic properties and perform population modeling. Safety and tolerability profiles were assessed based on adverse events and safety measurements. Findings: Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo.Implications. This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.

Original languageEnglish
Pages (from-to)1467-1482
Number of pages16
JournalClinical Therapeutics
Volume40
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

Cite this

van Amerongen, G., Kanhai, K., Baakman, A. C., Heuberger, J., Klaassen, E., Beumer, T. L., ... Groeneveld, G. J. (2018). Effects on Spasticity and Neuropathic Pain of an Oral Formulation of δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis. Clinical Therapeutics, 40(9), 1467-1482. https://doi.org/10.1016/j.clinthera.2017.01.016
van Amerongen, Guido ; Kanhai, Kawita ; Baakman, Anne Catrien ; Heuberger, Jules ; Klaassen, Erica ; Beumer, Tim L. ; Strijers, Rob L M ; Killestein, Joep ; van Gerven, Joop ; Cohen, Adam ; Groeneveld, Geert Jan. / Effects on Spasticity and Neuropathic Pain of an Oral Formulation of δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis. In: Clinical Therapeutics. 2018 ; Vol. 40, No. 9. pp. 1467-1482.
@article{f04b7efc63bd4d3e95a6ab70f87668ff,
title = "Effects on Spasticity and Neuropathic Pain of an Oral Formulation of δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis",
abstract = "Purpose: The aim of the present study was to evaluate the efficacy of an oral formulation of δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS). Methods: This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-controlled treatment phase. Twenty-four patients with progressive MS and moderate spasticity were enrolled. During the treatment phase, biomarkers for efficacy and secondary pharmacodynamic effects were measured at baseline and after 2 and 4 weeks of treatment. Serum samples were collected to determine pharmacokinetic properties and perform population modeling. Safety and tolerability profiles were assessed based on adverse events and safety measurements. Findings: Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo.Implications. This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.",
keywords = "Cannabinoid, Multiple sclerosis, Pain, Spasticity, δ9-tetrahydrocannabinol",
author = "{van Amerongen}, Guido and Kawita Kanhai and Baakman, {Anne Catrien} and Jules Heuberger and Erica Klaassen and Beumer, {Tim L.} and Strijers, {Rob L M} and Joep Killestein and {van Gerven}, Joop and Adam Cohen and Groeneveld, {Geert Jan}",
year = "2018",
month = "9",
day = "1",
doi = "10.1016/j.clinthera.2017.01.016",
language = "English",
volume = "40",
pages = "1467--1482",
journal = "Clinical Therapeutics",
issn = "0149-2918",
publisher = "Excerpta Medica",
number = "9",

}

van Amerongen, G, Kanhai, K, Baakman, AC, Heuberger, J, Klaassen, E, Beumer, TL, Strijers, RLM, Killestein, J, van Gerven, J, Cohen, A & Groeneveld, GJ 2018, 'Effects on Spasticity and Neuropathic Pain of an Oral Formulation of δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis' Clinical Therapeutics, vol. 40, no. 9, pp. 1467-1482. https://doi.org/10.1016/j.clinthera.2017.01.016

Effects on Spasticity and Neuropathic Pain of an Oral Formulation of δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis. / van Amerongen, Guido; Kanhai, Kawita; Baakman, Anne Catrien; Heuberger, Jules; Klaassen, Erica; Beumer, Tim L.; Strijers, Rob L M; Killestein, Joep; van Gerven, Joop; Cohen, Adam; Groeneveld, Geert Jan.

In: Clinical Therapeutics, Vol. 40, No. 9, 01.09.2018, p. 1467-1482.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Effects on Spasticity and Neuropathic Pain of an Oral Formulation of δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis

AU - van Amerongen, Guido

AU - Kanhai, Kawita

AU - Baakman, Anne Catrien

AU - Heuberger, Jules

AU - Klaassen, Erica

AU - Beumer, Tim L.

AU - Strijers, Rob L M

AU - Killestein, Joep

AU - van Gerven, Joop

AU - Cohen, Adam

AU - Groeneveld, Geert Jan

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Purpose: The aim of the present study was to evaluate the efficacy of an oral formulation of δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS). Methods: This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-controlled treatment phase. Twenty-four patients with progressive MS and moderate spasticity were enrolled. During the treatment phase, biomarkers for efficacy and secondary pharmacodynamic effects were measured at baseline and after 2 and 4 weeks of treatment. Serum samples were collected to determine pharmacokinetic properties and perform population modeling. Safety and tolerability profiles were assessed based on adverse events and safety measurements. Findings: Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo.Implications. This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.

AB - Purpose: The aim of the present study was to evaluate the efficacy of an oral formulation of δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS). Methods: This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-controlled treatment phase. Twenty-four patients with progressive MS and moderate spasticity were enrolled. During the treatment phase, biomarkers for efficacy and secondary pharmacodynamic effects were measured at baseline and after 2 and 4 weeks of treatment. Serum samples were collected to determine pharmacokinetic properties and perform population modeling. Safety and tolerability profiles were assessed based on adverse events and safety measurements. Findings: Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo.Implications. This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.

KW - Cannabinoid

KW - Multiple sclerosis

KW - Pain

KW - Spasticity

KW - δ9-tetrahydrocannabinol

UR - http://www.scopus.com/inward/record.url?scp=85012875224&partnerID=8YFLogxK

U2 - 10.1016/j.clinthera.2017.01.016

DO - 10.1016/j.clinthera.2017.01.016

M3 - Article

VL - 40

SP - 1467

EP - 1482

JO - Clinical Therapeutics

JF - Clinical Therapeutics

SN - 0149-2918

IS - 9

ER -