Evidence for the therapeutic use of cannabidiol for pain caused by nail-patella syndrome in a real-world pilot study

Study design and ethics

This open-label, observational pilot study was conducted using real-world data collected during routine clinical practice in the Pain Management and Palliative Care Department of Necker-Enfants-malades Hospital (Assistance Publique–Hôpitaux de Paris (AP-HP)). Paris, France) between January 2, 2022 and July 1, 2023. The institutional review board of the Reference Center for Constitutional Bone Diseases, MOC-Necker Hospital (Paris, France) approved the study. In accordance with French legislation on studies carried out as part of routine clinical practice, the study protocol was registered by the AP-HP on May 16, 2022 under the reference MR004-2022-0516123418. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, the Good Clinical Practice Guidelines (CHMP/ICH/135/1995 and integrated addendum) and the General Data Protection Regulation (GDPR, Regulation (EU) No. 2016/). . 679 and local regulations). Written informed consent was obtained from the patients or their legal guardians in the case of children (<18 years) for the publication of their data included in this article.

Participant

Patients with NPS were referred to the pain unit if they had symptoms despite previous treatment with conventional analgesics (e.g. paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and serotonin and norepinephrine reuptake inhibitors (SNRIs)) or poor tolerance to these previous treatments. Data used in the current study were extracted from the medical records of patients referred to the department with a confirmed diagnosis of NPS due to an identified medical condition LMX1B Variant, without a history of liver or heart failure or use of cannabis or cannabidiol products, who were prescribed CBD in accordance with the department’s regular clinical practice.

Administration of CBD

The synthetic CBD prescribed to patients was Canapure^® PH), manufactured by Symrise (Holzminden, Germany) from the limonene of orange peels according to GMP guidelines. Canapure^® PH was purchased from the Belgian pharmaceutical distributor PharmaChemicals^®who reanalyzed the CanapurePH^® to confirm compliance with the monograph of the German Medicines Code (DAC). The substance is nature-identical to CBD and has no detectable traces of the psychoactive compound tetrahydrocannabinol (THC). Doses were prepared as needed and provided in the form of oral capsules.

Based on clinical experience in the department of pain management in patients with other genetic disorders (e.g. erythromelalgia, Hailey-Hailey disease, Olmsted syndrome, carriers of FOXP1 mutations and sickle cell anemia) and on the results of Rossignol et al. published study. ³⁴ For effective use of CBD in patients with mast cell disease, CBD (at M0) was started at a dosage of 50 mg three times daily (150 mg/day) and increased to 100 mg three times daily on day (D)7 and then increased by 100 mg 3- once a day every 7 days, depending on the intensity of the pain.

Patient follow-up care

Pain intensity, health-related quality of life, NPS-associated symptoms (gastrointestinal, attention and sleep disturbance symptoms) and occurrence of side effects were assessed by the physician during teleconsultations on day D7, D15, D21 and in-person consultations at M1, M2 and M3. These visits were part of the patients’ routine follow-up care. Patients were asked to document their pain and use of other analgesics in a diary, which was then evaluated at monthly visits. A blood sample was also collected at the monthly visits and used for routine liver enzyme testing and evaluation of other biological markers. The CBD dose was reduced if side effects occurred and increased if the pain score did not decrease by more than 20% compared to baseline.

Evaluation criteria

The primary evaluation criterion was the effectiveness of CBD for pain relief after three months of treatment. The secondary evaluation criteria were the safety of CBD therapy and its effectiveness in improving the quality of life related to physical and mental health and alleviating symptoms associated with NPS. Changes in biological parameters between baseline and M3 were also assessed, including changes in peripheral levels of neurotransmitters (serotonin (µmol/L), norepinephrine (nmol/L) and dopamine (nmol/L)) and tryptophan (µmol/L) . L) and factors involved in its metabolism (e.g. kynurenine (µmol/L), IDO1 (% activity) and tryptase (µg/L)).

Assessment methods

Pain intensity

Pain intensity was measured on a numerical rating scale (NRS) ranging from 0 (“no pain”) to 10 (“worst pain imaginable”).

Health-related quality of life

Physical and mental health were assessed using the RAND 36-Item Short Form (SF-36) Health Survey (version 1.0), previously developed as part of the Medical Outcomes Study⁵³. This survey is one of the most commonly used measures of health-related quality of life and has been applied to various populations. It consists of 36 items covering 8 domains of physical and mental health: physical functioning (PF), role limitations due to physical health problems (RF), physical pain (BP), perception of general health (GH), vitality (VT), social Functioning (SF), role limitations due to emotional problems (RE) and mental health (MH). The rating was based on a scale from 0 to 100, with higher values ​​indicating better physical performance and better psychological well-being. Patients were examined at baseline and M3.

NPS-associated symptoms

Gastrointestinal symptoms and attention and sleep disorders that have been reported to be associated with NPD⁵were assessed through open-ended questions to the patients.

Biological parameters

Serotonin concentrations in whole blood were measured using ultra-performance liquid chromatography (UPLC) with fluorometric detection. Plasma levels of epinephrine, norepinephrine, and dopamine were measured by UPLC using the ChromSystems kit for plasma catecholamines (ChromSystems Instruments & Chemicals GmbH, Munich, Germany). Plasma samples were collected after patients had rested undisturbed in a quiet environment for at least 5 minutes. Tryptophan and kynurenine were assayed by UPLC in conjunction with coulometric detection, and IDO1 activity was estimated by calculating the kynurenine/tryptophan ratio. Tryptase was quantified using the ImmunoCAP™ Tryptase kit and the Phadia™ 250 automated instrument (Thermo Fischer Scientific Inc., France).

The normal ranges for biological parameters were provided by the Laboratory of Biological Analysis (Laboratory of Biochemistry and Molecular Biology, Hôpital Lariboisière, AP-HP, Paris). The normal serotonin concentration in whole blood should be between 0.1 and 0.9 µmol/L in adults and between 0.09 and 0.75 µmol/L in people ≤ 18 years of age. The upper limit of plasma normal value (ULN) was 2.2 nmol/L for norepinephrine, 0.45 nmol/L for epinephrine, 0.56 nmol/L for dopamine, and 8.4 µg/L for tryptase. The normal plasma ranges for tryptophan and kynurenine were 35-90 µmol/L and 1.0-3.0 µmol/L, respectively, and the normal value for IDO activity was <5%.

Liver function tests, including alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), serum bilirubin, and total protein and albumin, were performed according to standard clinical protocols.

Adverse Events

Adverse reactions were recorded using the standard hospital system based on Medical Dictionary for Regulatory Activities (MedDRA) terminology and classified as severe (serious or life-threatening), moderate (not serious but requiring discontinuation of treatment), or mild (not serious). ) classified to allow treatment to continue).

Statistical analysis

Descriptive data are presented as mean ± standard deviation (SD) or standard error of the mean (SEM), median (range) or number (N), and percentage (%). Baseline and M3-NRS pain scores were compared using the paired two-tailed t test, and SF-36 scores were compared using the Wilcoxon test. Spearman correlation and simple linear regression were used for correlation analyses. The Spearman correlation coefficient was tested for significance against the null hypothesis using a two-tailed t test, and simple linear regression was tested using an F test. The threshold for statistical significance was set at P<0.05. All statistical analyzes were performed using Prism software (version 8.0, GraphPad Software, San Diego, CA).