Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis)

Abstract

Background

In the absence of an ideal treatment for chronic pain associated with rheumatic diseases, there is interest in the potential effects of cannabinoid molecules, particularly in the context of global interest in the legalization of herbal cannabis for medicinal use.

Methods

A systematic search until April 2015 was conducted in Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, www.cannabis-med.org and clinicaltrials.gov for randomized controlled trials with a study duration of at least 2 weeks and at least ten patients per treatment arm with herbal cannabis or pharmaceutical cannabinoid products in fibromyalgia syndrome (FMS), osteoarthritis (OA), chronic spinal pain, and rheumatoid arthritis (RA) pain. Outcomes were reduction of pain, sleep problems, fatigue and limitations of quality of life for efficacy, dropout rates due to adverse events for tolerability, and serious adverse events for safety. The methodology quality of the randomized controlled trials (RCTs) was evaluated by the Cochrane Risk of Bias Tool.

Results

Two RCTs of 2 and 4 weeks duration respectively with nabilone, including 71 FMS patients, one 4-week trial with nabilone, including 30 spinal pain patients, and one 5-week study with tetrahydrocannbinol/cannabidiol, including 58 RA patients were included. One inclusion criterion was pain refractory to conventional treatment in three studies. No RCT with OA patients was found. The risk of bias was high for three studies. The findings of a superiority of cannabinoids over controls (placebo, amitriptyline) were not consistent. Cannabinoids were generally well tolerated despite some troublesome side effects and safe during the study duration.

Conclusions

Currently, there is insufficient evidence for recommendation for any cannabinoid preparations for symptom management in patients with chronic pain associated with rheumatic diseases.

Zusammenfassung

Hintergrund

Bei Fehlen einer optimalen Behandlung von chronischen Schmerzen bei rheumatischen Erkrankungen besteht ein Interesse in dem Potential von Cannabinoiden, insbesondere auf dem Hintergrund eines weltweiten Interesses der Legalisierung von Cannabis für medizinische Zwecke.

Methoden

Systematische Literatursuche bis April 2015 in CENTRAL, Pubmed, www.cannabis-med.org und clinicaltrials.gov nach randomisierten kontrollierten Studien (RCT) mit einer Studiendauer von mindestens zwei Wochen und mindestens 10 Patienten pro Behandlungsarm mit pflanzlichem Cannabis oder pharmazeutisch hergestellten Cannabisprodukten beim Fibromyalgiasyndrom (FMS), bei Arthrose (OA), beim Rückenschmerz und bei rheumatoider Arthritis (RA). Zielvariablen waren Reduktion von Schmerz, Müdigkeit, Schlafstörungen und Einschränkungen der Lebensqualität als Indikatoren der Wirksamkeit, Abbruchraten wegen Nebenwirkungen für Verträglichkeit und schwerwiegende Nebenwirkungen für Sicherheit. Die methodische Qualität der RCTs wurde mit dem Cochrane Risk of Bias Tool bewertet.

Ergebnisse

Zwei RCTs mit Nabilon und einer Dauer von 2 bzw. 6 Wochen mit 71 FMS –Patienten, eine 4-wöchige Studie mit Nabilon und 30 Rückenschmerzpatienten und eine 5-wöchige mit Tetrahydrocannbinol/Cannabidiol mit 58 RA-Patienten wurden eingeschlossen. Ein Einschlusskriterium in drei Studien waren Schmerzen, die auf eine konventionelle Therapie nicht ansprachen. Keine RCT mit OA-Patienten wurde gefunden. Das Verzerrungsrisiko war hoch in drei Studien. Die Ergebnisse einer Überlegenheit von Cannabinoiden gegenüber Kontrollsubstanzen (Placebo, Amitriptylin) waren nicht konsistent. Cannabinoide wurden trotz einiger unangenehmer Nebenwirkungen gut toleriert und waren sicher während der Studiendauer.

Schlussfolgerungen

Aktuell besteht keine ausreichende Evidenz, eine symptomatische Behandlung von Patienten mit chronischen Schmerzen bei rheumatischen Erkrankungen mit Cannabispräparaten zu empfehlen.

Appendices

Appendix 1

Risk of bias assessment (Cochrane Collaboration, Häuser 2015)

1. Randomization (systematic selection bias): There is a low risk of selection bias if the investigators describe the method of random allocation of patients in the therapy and control groups by the one of the following methods: referral to a random number table, use of computer-generated random numbers, coin tossing, shuffling cards or envelopes, dice throwing, or drawing lots. There is a high risk of selection bias if the allocation is generated in terms of odd or even numbers in the date of birth, date of hospital admission, or hospital record number, as well as in the case of allocation by judgment of the physician, the patient’s wishes, results of a laboratory test, or availability of the intervention.

2. Allocation concealment (selection bias): There is a low risk of systematic selection bias if the participants and investigators could not foresee allocations because one of the following methods, or an equivalent method, was used to conceal the allocation: central allocation (e.g., telephone, Internet, or pharmacy-controlled random allocation; sequentially numbered drug containers of identical appearance or sequentially numbered sealed opaque envelopes).There is a high risk of systematic selection bias if participants and investigators could possibly foresee allocations, for example due to the use of an openly available treatment plan (e.g., a list with randomly generated numbers); assignment envelopes were used without appropriate safeguards (e.g., if envelopes were unsealed, nonopaque, or not sequentially numbered); alternating or rotating treatment group allocation; date of birth; case record number; or other explicitly unconcealed allocation procedures.

3. Blinding of participants and personnel/treatment providers (systematic performance bias): There is a low risk of performance bias if blinding of participants was ensured, and it was unlikely that the blinding could have been lacking or incomplete; or if blinding was lacking or incomplete, the review authors judge that the outcome was not influenced by the lack of blinding. There is a high risk of performance bias if blinding of participants was not ensured.

4. Blinding of outcome assessor (systematic detection bias): There is low risk of systematic detection bias if the outcome assessor assessing patient-reported outcomes is not the clinical investigator but rather a statistician not involved in the treatment of the patient. There is an unclear risk of systematic detection bias if no details on the identity of the outcome assessor are reported. There is a high risk of systematic detection bias if the outcome assessor was involved in treatment of the patients.

5. Incomplete outcome data (systematic attrition bias due to loss of participants): There is low risk of systematic bias if all randomized patients were reported or analyzed in the group to which they were allocated by randomization, and dropouts were analyzed by the baseline observation carried forward (BOCF) method (baseline measurements used for data analysis). There is an unclear risk of systematic bias if all randomized patients were reported or analyzed in the group to which they were allocated by randomization, and dropouts were analyzed by the LOCF method (last measurements used for data analysis). There is a high risk of systematic bias if no intention-to-treat (ITT) analysis was carried out (analysis technique in which patients are analyzed according to their original group assignment, regardless of whether they received the intended therapy completely, in part, or not at all) or only study completers were evaluated.

6. Selective reporting (systematic reporting bias): There is low risk of reporting bias if the study protocol is available and all of the study’s prespecified primary and secondary endpoints that are of interest to the review have been reported in the prespecified way; or if the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were prespecified (a convincing text of this nature is probably uncommon). There is a high risk of systematic reporting bias if not all of the study’s prespecified primary outcomes have been reported; one or more primary outcomes are reported using measurements or analysis methods that were not prespecified; one or more of the reported primary outcomes were not prespecified (independently of whether justification for use of an unexpected result is provided); one or more outcomes that are of interest to the review are reported incompletely, such that they cannot be entered into meta-analysis; the study report fails to include results for a key outcome, which would be expected in a study of this nature.

7. Group similarity at baseline (systematic selection bias): There is low risk of bias if groups are similar at baseline for demographic factors, values of main outcome measures, and important prognostic factors. There is high risk of bias if groups are not similar at baseline for demographic factors, values of main outcome measures, and important prognostic factors.

Appendix 2

Characteristics of included studies (Blake 2006)

Methods

Study setting: Multi center study, no further details provided, UK

Study design: Parallel

Duration therapy: 5 weeks

Follow-up: 7–10 days

Participants: 58 (79 % women, race not reported, mean age 49 years)

Inclusion criteria

• Diagnosis of RA meeting ACR criteria

• Active arthritis not adequately controlled by standard medication

• NSAID and prednisolone regimes had to have been stabilized for 1 month and DMARDs for 3 months prior to enrolment

Exclusion criteria

• A history of psychiatric disorders or substance misuse

• Severe cardiovascular, renal, or hepatic disorder

• A history of epilepsy

Interventions

Active drug: Oromucosal spray, each activation delivering 2.7 mg THC and 2.5 mg CBD; starting dose was one actuation within 0.5 h of retiring, and this was increased by one actuation every 2 days to a maximum of six actuations according to individual response. Stable dosing was then maintained for a further 3 weeks; 31 participants

Placebo: 31 participants

Rescue or allowed medication: No details reported. NSAID, prednisolone, and DMARDs regimen maintained during the study

Outcomes

Pain: Daily morning pain intensity at rest and on movement (NRS 0–10); Short Form McGill Questionnaire total pain intensity

Fatigue: not assessed

Sleep: not assessed

Depression: not assessed

Anxiety: not assessed

Disability: not assessed

Health-related quality of life: not assessed

Patient-perceived improvement: not assessed

Activity scores: DAS 28

AEs: No details reported

Notes

Safety: Three serious adverse events occurred during the study in the placebo group.

Funding sources and any declaration of interest of primary investigators: supported by GW Pharmaceuticals.

Pinsger 2006

Methods

Study setting: single-center study, private clinic, Austria

Study design: crossover

Duration therapy: 4 weeks for each period, washout period 5 weeks

Follow-up: 16 weeks with free choice of study drugs

Participants: 30 (71 % women, race not reported, mean age 55 years)

Inclusion criteria

• Chronic therapy-resistant pain in causal relationship with a pathological status of the skeletal and locomotor system

• Pain intensity VAS > 5 despite conventional treatment with NSAIDs and/or opioids

Exclusion criteria

• Cancer

• Change of analgesic medication in the past 4 weeks

Interventions

Active drug: nabilone oral flexible between 0.25 and 1 mg/d, 30 participants

Placebo: 30 participants

Rescue or allowed medication: no details on rescue medication reported. NSAID and opioid regimen maintained during the study

Outcomes

Pain: change of current spine pain intensity and spine pain intensity during the past 4 weeks (Visual Analogue Scale 0–10)

Fatigue: not assessed

Sleep: not assessed

Depression: not assessed

Anxiety: not assessed

Disability: not assessed

Health-related quality of life: score of Mezzich and Cohen

Patient-perceived improvement: not assessed

AEs: no details reported

Notes

Safety: One serious adverse event occured during the study in the nabilone group.

Funding sources and any declaration of interest of primary investigators: No details reported

Skrabek 2008

Methods

Study setting: single-center study, Outpatient Musculoskeletal Rehabilitation Clinic, Canada

Study design: parallel

Duration of therapy: 4 weeks

Follow-up: 4 weeks

Participants: 40 (93 % women, race not reported, mean age 49 years)

Inclusion criteria

• The patient meets The American College of Rheumatology (1990) criteria for the classification of fibromyalgia. [5]

• 18–70 years old.

• Any gender.

• The patient has not received benefit from a tricyclic antidepressant (TCA), muscle relaxant, acetaminophen, or nonsteroidal anti-inflammatories for management of their pain.

• No previous use of oral cannabinoids for pain management.

Exclusion criteria

• The patient’s pain is better explained by a diagnosis other than fibromyalgia.

• Abnormalities on routine baseline blood work, including electrolytes, urea and creatinine, a complete blood count, and liver function tests (AST ALT GGT, Alk Phos, and LDH). Normal tests taken 3 months prior to the study will be accepted if there is no history of acute illness since the time the blood was drawn.

• Heart disease (cannabinoids can reduce heart rate and blood pressure). Patients with heart disease will be excluded based on a history of angina, MI, or CHF as well as a clinical exam.

• Schizophrenia or other psychotic disorder.

• Severe liver dysfunction (patients will be excluded if there is an elevation of any of the baseline liver enzymes).

• History of untreated nonpsychotic emotional disorders.

• Cognitive impairment.

• Major illness in another body area.

• Pregnancy.

• Nursing mothers.

• Patients less than 18 years old.

• History of drug dependency.

• A known sensitivity to marijuana or other cannabinoid agents.

Interventions

Active drug: nabilone 0.5 mg to 1 mg/twice a day: 20 participants

Placebo: 20 participants

Rescue or allowed medication: No details reported. Subjects were asked to continue any current medication including breakthrough medications but not to begin any new therapy

Outcomes

Pain: daily diary mean pain (VAS 0–10)

Fatigue: FIQ subscale VAS 0–100

Sleep: not assessed

Depression: FIQ subscale VAS 0–100

Anxiety: FIQ subscale VAS 0–100

Disability: FIQ subscale VAS 0–100

Health-related quality of life: FIQ total score (0–100)

Patient-perceived improvement: not assessed

AEs: AEs were recorded at each visit. No details reported

Notes

Safety: no serious adverse events occurred during the study

Funding sources and any declaration of interest of primary investigators: supported by Valeant Canada and an HSC Medical Stuff Council Fellowship Fund

No declaration of interest of primary investigators included

Ware 2010

Methods

Study setting: single-center study, pain clinic, Canada

Study design: crossover

Duration therapy: 2 weeks each with 2-week washout between the two periods

Follow-up: none

Participants: 32 (81 % women, race not reported, mean age 50 years)

Inclusion criteria

Patients aged ≥ 18 years

• A diagnosis of fibromyalgia according to the American College of Rheumatology classification criteria [51]

• Suffering from self-reported disturbed sleep

• Negative urine screen for cannabinoids

• Women of childbearing potential must agree to use adequate contraception during study and for 3 months after study

• Ability to attend research center every second week for approximately 7–9 weeks and be able to be contacted by telephone during the study period

• Stable drug regimen for 1 month prior to randomization

• Normal liver (AST < 3x normal) and renal function (serum creatinine < 133 µmol/L)

• Hematocrit > 38 %

• Negative serum bHCG

• Proficient in English or French

• Willing and able to give written informed consent

• Ability to follow study protocol (cognitive and situational)

Exclusion criteria:

• Patients currently using cannabis or cannabinoid or TCA and who are unable to undergo a 2-week washout period before entering the study

• Pain due to cancer

• Unstable cardiac disease such as cardiac arrhythmias, cardiac failure, ischemic heart disease, and/or hypertension on clinical history and examination

• History of psychotic disorder or schizophrenia

• Known hypersensitivity to cannabinoids, amitriptyline, or related TCAs

• Currently taking or unable to stop taking monoamine oxidase inhibitors (a two-week washout period is necessary for subjects taking MAOIs)

• History of seizures/epilepsy

• Diagnosis of glaucoma

• Urinary retention

• Pregnancy and/or breast-feeding

• Participation in other clinical trial in the 30 days prior to randomization

• A recent manic episode (within the past year)

• Current suicidal ideation or history of suicide attempts

Interventions

Active drug: nabilone 0.5 or 1 mg/d orally, flexible: 29 participants

Active comparator: amitriptyline oral, flexible, 10 or 20 mg/d: 29 participants

Rescue or allowed medication: no details reported

Outcomes

Pain: Mc Gill Pain Questionnaire total score

Fatigue: FIQ subscale VAS 0–100 (no details reported)

Sleep: Insomnia Severity Index (0–25) and Leeds Sleep Evaluation Questionnaire

Depression: FIQ subscale VAS 0–100

Anxiety: FIQ subscale VAS 0–100

Disability: FIQ subscale VAS 0–100

Health-related quality of life: FIQ total score (0–100)

Patient-perceived improvement: not assessed

AEs: AE were recorded at each visit by open questions to the patient (personal communication)

Notes

Safety: No serious adverse events occured during the study.

Funding sources and any declaration of interest of primary investigators: McGill Supported by the a grant of Valeant (Canada) and MC Gill University Health Center. Declaration of interest of primary investigators included