Chronic Pain, Fibromyalgia, Orofacial Pain, Osteoporosis
Conditions
Keywords
medical cannabis, cannabidiol, tetrahydrocannabinol, bone turnover, CB1 receptor, CB2 receptor, TRPV1 receptor, Women, crossover trial, bone mineral density, chronic pain
Brief summary
Chronic pain disproportionately affects women and may coexist with impaired bone health, particularly during midlife and after menopause. The endocannabinoid system is involved in pain modulation and bone homeostasis; however, clinical studies that integrate pain outcomes, bone-related biomarkers, genetic variants, and salivary endocannabinoids remain limited.This randomized, triple-masked, placebo-controlled crossover trial will evaluate the effects of a full-spectrum medicinal cannabis extract with a cannabidiol to tetrahydrocannabinol ratio of 5:1 on chronic pain in women aged 45 to 80 years with chronic pain refractory to conventional treatment. Eighty participants will be randomly assigned to one of two treatment sequences: full-spectrum cannabis extract followed by matching placebo, or matching placebo followed by full-spectrum cannabis extract. The treatment periods, washout interval, and visit schedule will follow the final approved protocol.The primary outcome is change in chronic pain intensity measured using the Visual Analog Scale. Secondary outcomes include quality of life, sleep quality, functional impact, bone health biomarkers, bone mineral density measured by dualenergy X-ray absorptiometry, salivary endocannabinoids, the association of CB and TRPV genetic variants with treatment response, and adverse events. The study aims to generate evidence on the clinical effects and biological correlates of medicinal cannabis therapy in women with chronic pain.
Detailed description
This is a randomized, triple-masked, placebo-controlled crossover clinical trial conducted in women aged 45 to 80 years with moderate to severe chronic pain that has persisted for at least 3 months and has not responded adequately to conventional pharmacological or non-pharmacological treatments. Participants will be randomlyallocated in permuted blocks to one of two treatments sequences. Sequence A will receive a full-spectrum medicinal cannabis extract with a cannabidiol to tetrahydrocannabinol ratio of 5:1 during the first treatment period, followed by a protocol-defined washout interval and matching placebo during the second treatment period. Sequence B will receive matching placebo during the first treatment period, followed by the washout interval and the full-spectrum medicinal cannabis extract during the second treatment period. The study product will be administered orally as softgel capsules. The target daily dose is 25 milligrams of cannabidiol and 5 milligrams of tetrahydrocannabinol. Dose titration during the first 2 weeks of each active treatment period will follow the final approved protocol.Participants, care providers, investigators, and outcome assessors will remain masked to treatment assignment as operationally applicable. Randomization will use a computer-generated sequence with permuted blocks of 4 and allocation concealment through opaque, sealed envelopes. The product and matching placebo will be supplied in indistinguishable presentations.Clinical evaluations will include pain intensity, quality of life, functional impact, sleep quality, concomitant medications, adherence, and adverse events. Laboratory assessments will include safety tests, selected bone metabolism biomarkers, inflammatory markers, and oxidative stress biomarkers. Bone mineral density and body composition will be assessed using dualenergy X-ray absorptiometry at protocol-defined baseline and final visits. Genetic analysis will evaluate CB and TRPV variants. Salivary anandamide, 2-arachidonoylglycerol, palmitoylethanolamide, and oleoylethanolamide will be quantified using liquid chromatography coupled with tandem mass spectrometry according to the final sample collection schedule.The primary efficacy analysis will compare pain outcomes across cannabis and placebo treatment periods while accounting for the crossover design. Secondary analyses will evaluate changes in patient-reported outcomes and biomarkers, treatment safety, and associations between genetic variants or salivary endocannabinoid profiles and treatment response.
Interventions
DRUGFull-Spectrum Cannabis Extract 5:1 (CBD:THC)
Oral softgel capsule containing full-spectrum medicinal cannabis extract with a cannabidiol to tetrahydrocannabinol ratio of 5:1. The target daily dose is 25 milligrams of cannabidiol and 5 milligrams of tetrahydrocannabinol. Participants will receive the study product once daily in the evening, with gradual dose titration during the first 2 weeks of each active treatment period, according to the final approved protocol. The product will be administered for the duration of each protocol-defined active treatment period.
Sponsors
Associação Pan-Americana Multidisciplinar de Endocanabinologia
Mackenzie Presbiterian University, São Paulo, Brazil
Associação Brasileira de Cannabis Medicinal
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
The study uses triple masking. Participants, clinical care providers, and investigators involved in participant assessment and study conduct will remain unaware of treatment assignment. The statistician will analyze coded treatment groups until the prespecified unmasking procedure is completed. Study products and placebo will be matched in presentation and dispensing procedures.
Intervention model description
Participants will be randomly assigned in a 1:1 ratio to one of two crossover sequences. Sequence A will receive full-spectrum cannabis extract during Period 1 and matching placebo during Period 2. Sequence B will receive matching placebo during Period 1 and full-spectrum cannabis extract during Period 2. The treatment periods will be separatedby a protocol-defined washout interval. Randomization will use computer-generated permuted blocks of 4 with allocation concealment through opaque, sealed envelopes.
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Female sex, age 45 to 80 years * Moderate to severe chronic pain, defined as a pain score of at least 4 on a 0 to 10 Visual Analog Scale, persisting for more than 3 months * Documented inadequate response to at least 2 classes of analgesic treatments or non-pharmacological treatments * Willingness to abstain from smoked cannabis and non-study cannabinoid products during the study * Ability to understand the informed consent form and study questionnaires * Willingness and ability to attend scheduled visits and biological sample collections during the study follow-up period
Exclusion criteria
* Cognitive impairment that precludes understanding of the informed consent form or study questionnaires * Uncontrolled psychiatric condition, including uncontrolled psychotic disorder or bipolar disorder * Pregnancy, breastfeeding, or intention to become pregnant during the study * Current use of medicinal cannabis, smoked cannabis, or other cannabinoid products * Known hypersensitivity to cannabinoids or formulation excipients * Clinically significant hepatic impairment, defined as aspartate aminotransferase or alanine aminotransferase greater than 3 times the upper limit of normal, or severe heart failure classified as New York Heart Association class III or IV * History of substance use disorder that, in the investigator's judgment, may interfere with study participation * Use of medications that may interfere with bone metabolism, including bisphosphonates, systemic corticosteroids, or sex hormones, within 6 months before enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Period Baseline in Chronic Pain Intensity on the Visual Analog Scale | At the baseline and end of each treatment period, approximately 6 months per period. | Chronic pain intensity will be measured using a 0 to 10 Visual Analog Scale, where 0 indicates no pain and 10 indicates the worst imaginable pain. The baseline score will be the mean pain intensity reported over the preceding 7 days. A clinical response is defined as a reduction of at least 30 percent from the baseline score of the corresponding treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Period Baseline in Sleep Quality on the Pittsburgh Sleep Quality Index. | At baseline and at 3 and 6 Months each treatment period. | Sleep quality will be measured using the Pittsburgh Sleep Quality Index (PSQI), a self-reported instrument with a global score from 0 to 21. Higher scores indicate worse sleep quality. |
| Change From Period Baseline in Health-Related Quality of Life on the 36-Item Short Form Survey. | At baseline and at Months 3 and 6 of each treatment period. | Health-related quality of life will be assessed using the Medical Outcomes Study 36-Item Short Form Survey (SF-36). Scores are calculated for 8 domains from 0 to 100; higher scores indicate better health-related quality of life. |
| Change From Period Baseline in Pain-Related Quality of Life on the WHOQOL-Pain Instrument. | At baseline and at Months 3 and 6 of each treatment period. | Pain-related quality of life will be assessed using the Portuguese version of the WHOQOL-Pain instrument. Scoring and interpretation will follow the validated instrument manual. |
| Change From Period Baseline in Fibromyalgia Impact Questionnaire Score Among Participants With Fibromyalgia. | At baseline and at Months 3 and 6 of each treatment period. | Functional impact among participants with a clinical diagnosis of fibromyalgia will be assessed using the Fibromyalgia Impact Questionnaire (FIQ). The scale will be scored according to the validated Portuguese version; higher scores indicate greater disease impact. |
| Change From Baseline in Bone Mineral Density Measured by Dual-Energy X-Ray Absorptiometry. | At baseline and at the final study visit, approximately 12 months after enrollment. | Bone mineral density and body composition will be assessed using dual-energy X-ray absorptiometry (DXA). Bone mineral density will be reported in grams per square centimeter and interpreted using T-scores according to applicable clinical criteria. |
| Change From Period Baseline in Serum Bone Turnover Biomarkers. | At baseline and at protocol-defined follow-up visits through final study completion, approximately 12 months. | Serum bone health biomarkers will include the final protocol-specified panel of alkaline phosphatase, total and ionized calcium, 25-hydroxyvitamin D, and parathyroid hormone. If procollagen type 1 N-terminal propeptide and C-terminal telopeptide are retained in the final protocol, they should be listed here explicitly. |
| Association of CB2 and TRPV1 Genetic Variants With Pain Treatment Response. | Genotyping at baseline; association with pain response through the end of each treatment period, approximately 12 months. | Genotyping of cannabinoid receptor 2 (CB2/CNR2) and transient receptor potential vanilloid 1 (TRPV1) variants will be performed using real-time polymerase chain reaction. Associations between genotype or haplotype and the prespecified Visual Analog Scale pain response will be evaluated. |
| Change From Baseline in Salivary Endocannabinoid Concentrations. | Use the final collection schedule; do not submit this entry until the protocol is harmonized as baseline-only or serial sampling. | Salivary concentrations of anandamide, 2-arachidonoylglycerol, palmitoylethanolamide, and oleoylethanolamide will be quantified by liquid chromatography-tandem mass spectrometry and reported in nanograms per milliliter. |
| Change From Period Baseline in Hepatic and Renal Safety Laboratory Values. | At baseline and at protocol-defined follow-up visits through final study completion, approximately 12 months. | Safety laboratory assessments will include protocol-specified hepatic and renal tests, including aspartate aminotransferase, alanine aminotransferase, urea, and creatinine. Results will be reported in standard laboratory units. |
| Number of Participants With Treatment-Emergent Adverse Events. | From first study product administration through the end of each treatment period, approximately 6 months per period. | Adverse events will be collected through clinical visits and weekly remote pharmacotherapeutic monitoring. Events will be classified by severity, seriousness, relatedness to study treatment, and treatment period. |
Countries
Brazil
Contacts
CONTACTAlethéia B P Barbosa, PhD
CONTACTJosé Wilson N V Andrade, MD
PRINCIPAL_INVESTIGATORAlethéia B P Barbosa, PhD
Universidade Presbiteriana Mackenzie
Outcome results
None listed