This was a retrospective study examining the analgesic efficacy of MC and AEs in adult Italian patients diagnosed with FMS who were deemed resistant to conventional drugs (e.g., tramadol, amitriptyline, duloxetine, and pregabalin).
Patients and eligibility
This study was carried out at the pain clinic of Nuovo Ospedale degli Infermi of Ponderano (Biella, Italy). Data from patient files were assessed between June 1, 2016, and October 31, 2018. During this period, 75 patients presented at the pain clinic with a previous FMS diagnosis. MC therapy was offered to patients who had previously used conventional FMS drugs. Patients who provided written informed consent to begin MC treatment were asked to follow the clinical practice schedule comprising repeated prescription of cannabis once per month. A health report was generated for each patient once per month and archived as MC was recently approved as a therapeutic option in Italy.
After the local ethics committee’s approval (CE 168/18) and patient’s informed consent, clinical information collected throughout the normal course of clinical care by the attending clinician (the referee for MC therapy of the hospital) at visits conducted after 1, 3, and 12 months of MC therapy, were stored using Microsoft Excel.
Eligible patients included those visiting the pain clinic and meeting the following inclusion criteria: written informed consent; age >18 years; diagnosis of FMS according to the ACR diagnostic criteria of 2010 and validated by a rheumatologist, including a WPI ≥ 7 (scale, 0–19) and an SyS ≥ 5 (scale 0–12) or a WPI of 3–6 with an SyS ≥ 9; symptoms present at a similar level for at least 3 months with no disorders to otherwise explain the pain; resistant or intolerant to the following conventional pharmacological treatments (Macfarlane et al. 2016):
Amitriptyline usually 25 mg/day (EULAR recommendation: weak for at low-dose, 100% agreement)
Duloxetine 60 mg/day (EULAR recommendation: weak for, 100% agreement)
Pregabalin at least 75 mg twice a day to 150 mg twice a day (EULAR recommendation: weak for, 94% agreement)
Gabapentin at least 300 mg thrice a day (EULAR recommendation: research only, 100% agreement)
Tramadol at least 100–150 mg/day (EULAR recommendation: weak for, 100% agreement)
Acetaminophen 1,000 mg thrice a day, used clinically even with little evidence of efficacy
Resistant or intolerant patients were those who developed AEs to conventional pharmacological drugs or continued to experience moderate-severe pain scores according to numerical rating scale (NRS ≥ 4) after at least 3 months of conventional pharmacological therapy.
The exclusion criteria were as follows: severe cardiopulmonary disease, severe liver disease or chronic hepatitis C, severe renal impairment, history of drug or alcohol addiction, psychiatric disorders or family history of schizophrenia, and women planning pregnancy or those who were pregnant or breast-feeding (no urine/blood pregnancy tests were performed before the initiation of MC treatment).
MC was administered as an adjunct therapy, and the baseline therapy was gradually decreased or interrupted as patients reported alleviation of their pain. The physician decided on the prescribed MC type and dose of herbal MC in milligrams. Accordingly, a one-month supply of MC was prepared by the chemist. The starting dose of the milled flowers in the sachet was 50 or 100 mg twice per day according to the patient’s sensitivity to drugs (patients who previously developed adverse side effects to drugs started at a dose of 50 mg). The dose could then be increased by the physician as needed to approximately 50–100 mg (100 or 200 mg/day). In the case of cannabis olive oil extract, patients were instructed to gradually increase their dosage at small intervals, i.e., a single oil drop every 3–4 days until the therapeutic effect was attained. To avoid AEs, patients were instructed to use the dosage that did not cause side effects. The titration period lasted from 1 to 3 months.
At the beginning of the study, the type of cannabis prescribed by the physician depended on the availability of the MC cultivar at the hospital pharmacy. When both types of cannabis, i.e., THC-dominant cultivar and hybrid MC cultivar (with a similar THC/CBD ratio), were available, the first choice was the hybrid MC cultivar to reduce the risk of side effects due to THC. The patients consumed only one cultivar at a time (during the 1-month period), however, could take both types of MC cultivars using different routes of administration over the course of the treatment.
Ethical considerations and source of cannabis
The study was approved by the local ethics committee of Eastern Piedmont (CE 168/18). All eligible patients provided informed consent after the study was explained by a physician. All eligible patients opted to participate in the study and signed a consent form. Patients were not compensated for participation in this study. The cannabis was provided by the hospital pharmacy at the institution where the study was conducted. Five varieties of MC were used in the study: FM1, FM2 (Military Chemical and Pharmaceutical Institution of Florence, Italy); Bediol, Bedrocan (Bedrocan International BV, Veendam, the Netherlands); and Pedanios (AURORA Cannabis Enterprises Inc., Canada; Table 1). MC was provided by the NHS, as prescribed by national and regional laws.
MC comprised dried, milled homogenized flowers or whole flowers of C. sativa. All plants were cultivated under standardized conditions according to the requirements of good manufacturing practices.
Preparation and administration of cannabis
FM2 and FM1 were delivered to the hospital pharmacy as minced flowers. Thereafter, the doses of cannabis prescribed by the physician were prepared as sachets by the chemists. Bedrocan, Bediol, and Pedanios were delivered as whole flowers and finely minced for decoction (administered orally) or roughly minced for vaporization by the chemist. Oil was purchased from an outside private pharmacy (Farmacia Ternelli, Reggio Emilia) where it was prepared by the Romano-Hazekamp technique using funds provided by the hospital. The oil extract was supplied to the patient by the hospital pharmacy and was paid for by NHS. All MC products were accompanied by an analysis form upon purchase.
All cannabinoids in the plant were primarily present in their acidic form. Application of heat was required for the decarboxylation of the cannabinoid acids into their active forms (THC acid into THC; CBD acid into CBD) (ElSohly and Gul 2014).
For administration, the decoction was administered orally after preparation by boiling the contents of a sachet containing minced MC in 200 mL water and 30 mL of milk for 15–20 min (Hazekamp et al. 2007). Alternatively, the cannabis was administered by vaporization using a cannabis vaporizer at a temperature of 210°C (Gieringer et al. 2008). Finally, sublingual administration was performed using olive oil extract prepared by the Romano-Hazekamp technique (Romano and Hazekamp 2013).
Data collection and endpoints
After obtaining consent, the demographic and clinical parameters of patients were extracted from medical reports and store using Microsoft Excel. Demographic data included gender, age, time from diagnosis of FMS and prescription of MC, body mass index (BMI), and comorbidities. The primary endpoint, pain relief, was evaluated with an NRS (a unidimensional measure of pain intensity). NRS is an 11-point scale used by patients to report pain and is designed for adults and children aged > 10 years old, with 0 indicating no pain and 10 indicating maximum pain, as follows: 0, no pain; 1–3, mild pain (nagging, annoying, interfering slightly with daily life activities); 4–6, moderate pain (significantly interfering with daily life activities); and 7–10, severe pain (disabling, unable to perform daily life activities) (Haefeli and Elfering 2006). The patients were asked to rate the average intensity of pain over the past week. Analgesic effects were considered when there was a reduction in pain intensity by at least 30%.
The secondary endpoint, AEs, was evaluated by the physician during monthly follow-up visits. The physician investigated whether the AEs reported by the patients were directly induced by MC or were already present. This assessment was used to determine whether treatment with MC should be continued.
Other secondary endpoints included disability, mood disorders, and severity of FMS. Disability was evaluated using a validated Italian version (Monticone et al. 2009) of the Oswestry Disability Index (ODI), a test evaluating disability in patients according to intensity of pain and its impact on daily activities (personal care, weight-lifting, walking, sitting, standing, sleeping, sexual activities, socialization, and traveling). Scores for disability were as follows: minimal disability, 0–20%; moderate disability, 21–40%; severe disability, 41–60%; crippling disability, 61–80% (pain impinges on all aspects of life); and complete disability, 81–100% (patients are either bed-bound or exaggerating their symptoms). Furthermore, ODI was applied in place of the Fibromyalgia Index Questionnaire as most patients visiting the pain clinic had lower back pain. ODI has not been previously used in patients with FMS, except for a recent study evaluating the prevalence of the FMS phenotype in patients with spinal pain (Brummett et al. 2013). Mood disorders were evaluated with the Hospital Anxiety and Depression Scale (HADS), a 14-item measure designed to assess anxiety and depression symptoms. The test identifies patients with anxiety and depression and stratifies them into four categories: 0–7, normal; 8–10, mild; 11–14, moderate; and 15–21, severe; the version used in this study had been previously validated in Italian patients (Costantini et al. 1999), as well as for hospitalized patients and mood disorders in outpatients (Habib and Avisar 2018). The severity of FMS was evaluated using the WPI, which assesses pain regions with a score between 0 and 19, and the SyS score, which assesses fatigue, waking unrefreshed, cognitive symptoms, and other somatic symptoms (scored between 0 and 12) (Wolfe et al. 2016; Wolfe et al. 2013; Wolfe et al. 2015; Yaseen et al. 2017; Wolfe et al. 2018).
Other clinical data collected included the dosage of cannabis reducing pain by at least 30%, route of administration, and development of tolerance (the need to increase dose after reaching analgesic dosage). Interruption of conventional FMS drugs during MC treatment was also evaluated. Complete drug interruption was considered significant. The use of the drug as everyday therapy was considered drug use, whereas rescue therapy was defined as occasional use of the drug. Evaluation of signs of withdrawal (Habib and Avisar 2018), such as loss of appetite, irritability, insomnia, or anxiety, was also performed to determine the possibility of addiction in patients who continued MC for at least one month and stopped treatment for any reason.
The validated Italian versions of ODI and HADS questionnaires were self-administered by the patient before medical examinations. The WPI or SyS was self-administered by the patient. NRS, side effects, other analgesic drug use, and signs of withdrawal were examined by the physician at each monthly follow-up.
Descriptive statistics of the clinical parameters were assessed before and during MC treatment. Additionally, the dosages of milled MC, THC, and THC + CBD in the sachets and oil drops were measured. All demographic data were reported as median and interquartile range (IQR) and mean and standard deviation (SD).
For statistical analysis, Wilcoxon signed-rank tests for paired data were used to compare the parameters (NRS, ODI, HADS, WPI, and SyS) before cannabis therapy and after 1, 3, and 12 months of MC therapy. The data are from per protocol analyses. Results with P values < 0.01 were considered significant. No calculation of required sample size was done because it was a post hoc study. IBM SPSS software, version 25.0, was used for the statistical analysis.