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Efficacy and safety of cannabidiol followed by an open label add-on of tetrahydrocannabinol for the treatment of chronic pain in patients with rheumatoid arthritis or ankylosing spondylitis: protocol for a multicentre, randomised, placebo-controlled study

Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic, systemic, inflammatory diseases, primarily in the musculoskeletal system. Pain and fatigue are key symptoms of RA and AS. Treatment presents a clinical challenge for several reasons, including the progressive nature of the diseases and the involvement of multiple pain mechanisms. Moreover, side effects of pain treatment pose an implicit risk. Currently, no well-controlled studies have investigated how medical cannabis affects pain and cognitive functions in RA and AS. The present study aims to evaluate the efficacy and safety of medical cannabis in the treatment of persistent pain in patients with RA and AS with low disease activity.

Methods and analysis

A double-blinded, randomised, placebo-controlled study of cannabidiol (CBD), followed by an open label add-on of tetrahydrocannabinol (THC) with collection of clinical data and biological materials in RA and AS patients treated in routine care. The oral treatment with CBD in the experimental group is compared with placebo in a control group for 12 weeks, followed by an observational 12-week period with an open label add-on of THC in the primary CBD non-responders. Disease characteristics, psychological parameters, demographics, comorbidities, lifestyle factors, blood samples and serious adverse events are collected at baseline, after 12 and 24 weeks of treatment, and at a follow-up visit at 36 weeks. Data will be analysed in accordance with a predefined statistical analysis plan.

Ethics and dissemination

The Danish Ethics Committee (S-20170217), the Danish Medicines Agency (S-2018010018) and the Danish Data Protection Agency approved the protocol. The project is registered in the European Clinical Trials Database (EudraCT 2017-004226-15). All participants will give written informed consent to participate prior to any study-related procedures. The results will be presented at international conferences and published in peer-reviewed journals.

Strengths and limitations of this study

The randomised, double-blind and placebo-controlled design aims to determine outcome data (on the defined endpoints) and, thus, reduces the risk of bias, especially selection bias.

Recruitment in routine care is expected to appropriately reflect the patients and conditions in the two diagnostic groups.

The performance of a controlled study demands the use of medical cannabidiol, and tetrahydrocannabinol instead of plant extracts, that is, tea or herbal preparations.

There is no clinical evidence for the optimal dosage and application ranges. Thus, the treatment regimens for the drugs used are an extrapolation of expert knowledge.

Both primary and secondary endpoints are based on patient-reported outcome measurements and may be influenced by bias.

Introduction

The treatment of rheumatoid arthritis (RA) and ankylosing spondylitis (AS) has improved significantly over the last three decades. 1–3 Chronic pain and fatigue are symptoms typical of these major inflammatory rheumatic disorders. 4–6 Cognitive dysfunctions, such as concentration and memory problems, are also often reported in patients with chronic pain. These cognitive dysfunctions can be related to pain itself, sleep problems or reflect a side effect of the pharmacological treatment. 4 6 RA affects the small joints of the hands and feet, but can also involve the larger joints. 7 AS mainly affects the spinal and sacroiliac joints and is characterised by back pain and stiffness. 8 Pain may involve nociceptive and non-nociceptive components and is based on the interaction between peripheral inflammation and central sensitisation. 9 10 The immediate pain is triggered by the inflammation of the synovial tissue and/or consecutive oedema of the subchondral bone, and leads to a sensitisation of the peripheral nociceptors. 11

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Thus, chronic pain is likely to be due to peripheral joint and central neuropathic pain mechanisms at various stages. 11–16

Treatment of moderate to severe chronic pain is difficult to overcome, for several reasons: heterogeneity of the patients in a given diagnostic group, the progressive nature of the disease, involvement of multiple pain mechanisms and the presence of comorbidities, particularly in elderly patients. 17 The rheumatologist is likely to pay full attention to the anti-inflammatory treatment. This approach implies the fact that chronic pain associated with increased mortality can be overlooked. 18 19

There is a lack of knowledge about the effect of cannabinoids in rheumatic diseases. Based on a Cochrane meta-analysis, the authors concluded that the existing clinical studies of c annabidiol (CBD) applied in monotherapy are of such poor quality that there is insufficient data to draw any conclusions about the effectiveness and/or long-term security of the compound. 20

Currently, only very few studies have investigated how medical cannabis affects cognitive functions, such as concentration and attention. 21 A few studies have investigated the impact of illegally obtained cannabis in RA. 20 Furthermore, studies that have assessed medical cannabis did so mostly in the context of multiple sclerosis. 20 22 23 In contrast to studies of recreational cannabis, the studies in persons with multiple sclerosis indicate that medical cannabis does not negatively affect cognition and could improve sleep quality. Given the limited data and the lack of a proper control condition, no definite conclusions of the potential cognitive impact of medical cannabis could be drawn. 20 24

Hence, concerns about potential negative side effects of medical cannabis on cognition have led the Danish health authorities’ attention on a patient’s ability to drive safely. 20 23 Furthermore, in the treatment of rheumatic diseases, there is no established routine nor rheumatological competence to prescribe medical cannabis. Consequently, there is considerable uncertainty and caution towards the use of medical cannabis, even in the North American countries, where it is already legal to prescribe these compounds for rheumatological conditions. 23 24 This can lead to patients resorting to self-medication with cannabinoids. 20 24 25 Thus, there is a strong need for high-quality studies of the efficacy and side effects of cannabinoids.

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The overall aim of the study is to investigate the effect of medical cannabis on pain in patients with RA and AS, to elaborate on the potential dosage of CBD and tetrahydrocannabinol (THC) and to explore if and how the test compounds affect patients’ cognitive functions and sleep.

Materials and methods

Setting and study design

The study is an investigator-initiated, double-blinded, randomised, placebo-controlled intervention study of CBD, followed by an open label add-on of THC. It is designed to evaluate the efficacy and safety of medical cannabis, either as CBD or in the form of the combination treatment of CBD and THC as ‘add-on’ treatment for chronic pain in RA and AS. The patient-reported outcome measurement (PROM), 26 a pain visual analogue scale (VAS) score 27 at a value of at least 50 are the key inclusion criterion. The score range is from 0 to 100; a higher score indicates greater pain intensity. Thus, the null hypothesis, H 0 , is that receiving the active treatment with cannabis derivatives does not improve the pain situation in clinical assessment after 12, 24 and 36 weeks.

Clinical data and outcomes are registered in an electronic Case Report Form (eCRF), based on the Reuma-eCRF system available within the Danish nationwide registry DANBIO. 15 28 DANBIO contains actualised data on ongoing treatment regiments, which therefore easily can be monitored.

Biological samples are collected via the Danish Rheumatologic Biobank. 29 Patients are recruited from four Danish university hospital departments. Patient inclusion is planned to start in November 2018 and is expected to continue for 14 months.

Participants

The study population consists of the following:

Patients with seropositive RA 1 currently treated with either conventional disease modifying antirheumatic drugs (cDMARDs) or biological disease modifying antirheumatic drugs (bDMARDs), and without clinical signs of arthritis, as assessed by a 40-swollen joint count.

Patients with AS, according to the modified New York criteria, 2 currently receiving either non-steroidal anti-inflammatory drugs (NSAIDs) and/or bDMARD, who show an absence of clinical signs of axial and peripheral arthritis and enthesitis, and who have an Ankylosing Spondylitis Disease Activity Score (ASDAS) <2.1.

Inclusion criteria

Minimum pain VAS 50, both at screening and inclusion.

Disease duration ≥2 years.

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Ongoing treatment or earlier attempt to treat with paracetamol or NSAIDs without clinical signs of arthritis or spondyloarthritis.

Analgesic treatment unchanged at least 4 weeks before trial start.

Exclusion criteria

Pregnancy, pregnancy wish or ongoing breast feeding.

C-reactive protein (CRP) >10 mg/L.

Comorbidities, more specific competitive rheumatological disorders, such as systemic lupus erythematosus, scleroderma, polymyositis or chronic pain condition based on a further clinical detectable aetiology (eg, fibromyalgia).

Evidence of serious uncontrolled concomitant cardiovascular, pneumological, neurological, endocrinological, gastroenterological, urogenital, nephrological or hepatic impairment.

Major surgery performed <8 weeks before randomisation or planned major surgical interventions.

Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease, where flares are commonly treated with oral or parenteral corticosteroids.

Evidence of active malignant disease, malignancies diagnosed or treated within the previous 2 years, including haematological malignancies and solid tumours.

Actual or previous harmful use of alcohol or drug abuse, in accordance with the WHO definition, 30 within the previous 2 years.

Ongoing treatment with opioids and/or cannabis products and/or neuroleptics, or treatment terminated <4 weeks before inclusion.

Hypersensitivity to the study compounds.

Suspected for, or evidence of, active schizophrenia, other psychotic illness in the family history (first degree relatives), other significant psychiatric disorder or treated depression associated with underlying condition.

Epilepsy or recurrent seizures.

Use of strong cytochrome P450 3A4 inducers.

Experimental treatment

The treatment starts with oral CBD 10 mg or placebo before bedtime, and increases after 2 weeks to 10 mg two times per day. Finally, and in case of lack of effect (VAS-pain reduction <20) from the beginning of the fifth week, the treatment increases to 10 mg three times per day.

The clinical assessment after 12 weeks defines how to proceed during the following 12 weeks: in case of a sufficient response, that is, a VAS-pain reduction of ≥20, the established treatment continues randomised and without any further adjustment.

In case of insufficient response, that is, a VAS-pain reduction of <20, randomisation is terminated. Patients who received placebo are shifted to the active compound, that is, CBD treatment, and dose adjustment is performed, as mentioned above. In patients who received CBD treatment during the randomised period, the open label follow-up combines CBD with THC, that is, oral THC 2.5 mg daily is added to the ongoing CBD treatment.

The THC dose is increased after 2 weeks to 2.5 mg two times per day (in total, 5 mg THC/day), and in case of lack of effect (VAS-pain reduction <20, compared with VAS 20, as defined at clinical assessment after 12 weeks), after another 2 weeks to 2.5 mg three times per day (in total, 7.5 mg THC/day) from the beginning of the 17th week.

Figure 1 presents the consort flowchart and figure 2 the treatment flowchart.