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Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2016; 16(Suppl2):e6972 doi: 10.5867/medwave.2017.6972
Are cannabinoids an effective treatment for chronic non-cancer pain?
Rubén F Allende-Salazar, Gabriel Rada
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Abstract

The use of cannabinoids has been proposed as an analgesic for different painful conditions, especially for chronic pain refractory to usual treatment. However, its real efficacy and safety remains controversial. We sought to determine whether cannabinoids are an effective treatment for chronic non-cancer pain. To answer this question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified 37 systematic reviews including 41 studies overall, of which 32 were randomized trials relevant for the question of interest. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded it is not clear whether cannabinoids decrease pain in patients with chronic non-cancer pain because the certainty of available evidence is very low. On the other hand, they are associated with significant adverse effects.


 
Problem

Cannabis has been used for centuries for recreational and therapeutic purposes for various conditions, including pain. However, since the United Nations 1961 Single Convention on Narcotic Drugs, Cannabis has seen a worldwide ban and its use has been limited. Despite this, research on its therapeutic use led to the discovery of the endocannabinoid receptors CB1 and CB2, which through a mechanism associated with G protein would have an effect on pain reduction. Since many patients with different causes of chronic pain remain symptomatic despite standard therapy, it has been proposed that the use of Cannabis sativa plant extracts with its active ingredients delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), or its analogues, could be of use. Several studies have delved into this premise with different results and have revealed several associated adverse effects, ranging from gastrointestinal and neurological to psychiatric symptoms, with cannabinoids’ clinical utility still unproven. Given this scenario, we sought to determine whether cannabinoids constitute an effective treatment for chronic non-cancer pain.

Methods

To answer the question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making. 

Key messages

  • It is not clear whether cannabinoids decrease pain in patients with chronic non-cancer pain because the certainty of the available evidence is very low.
  • The use of cannabinoids is associated with a high rate of adverse events in patients with chronic non-cancer pain.
  • Multiple ongoing studies or high-quality systematic reviews reanalyzing existing data could provide more certainty about these findings.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found 37 systematic reviews reported  in 38 references [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],
[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],
[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38] which include 41 primary studies reported in 85 references
[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],
[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],
[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],
[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],
[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],
[99],[100],[101],[102],[103],[104],[105],[106],[107],[108],
[109],[110],[111],[112],[113],[114],[115],[116],[117],
[118],[119],[120],[121],[122],[123] of which 32 correspond to randomized controlled trials comparing cannabinoids against placebo, reported in 72 references [39],[40],[42],
[43],[44],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],
[56],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],
[69],[70],[72],[75],[76],[77],[78],[79],[80],[83],[84],[85],
[86],[87],[88],[90],[91],[92],[93],[94],[96],[97],[98],[99],
[100],[101],[102],[103],[104],[105],[106],[108],[109],
[110],[113],[114],[115],[116],[117],[118],[119],[120],
[121],[122],[123]. This table and the summary in general are based on the latter.

What types of patients were included*

Of the 32 trials comparing cannabinoids versus placebo, nine included patients with central neuropathic pain [43],[58],[76],[78],[79],[87],[108],[113],[115], nine included patients with multiple sclerosis [42],[54],[77],[93],[102],[104],[106],[119],[122], four included patients with diabetic neuropathy [61],[97],[103],[110], two included patients with HIV neuropathy [39],[56], two included patients with undifferentiated peripheral neuropathic pain [99],[114], one included patients with fibromyalgia [100], one included patients with musculoskeletal pain [90], one included patients with undifferentiated chronic non-cancer pain [85], one included patients with neurological pain of undifferentiated origin [86], one included patients with rheumatoid arthritis [46] and one included patients with pain associated with spasticity [117].

What types of interventions were included*

Cannabinoids extracted from Cannabis sativa (THC, CBD and combinations) and synthetic cannabinoids (nabilone and ajulemic acid) were used as interventions via different routes of administration. Twelve used nabiximol (Sativex®, THC and CBD) in oromucosal spray [42],[43],[46],[61],[77],[79],[86],[87],[93],[97],[99],[106], six used oral nabilone [58],[90],[100],[103],[104],[117], five used smoked THC [39],[54],[56],[113],[115], three used dronabinol (oral THC) [85],[102],[119], three used oral THC combined with CBD [108],[119],[122], two used oromucosal THC spray [43],[110], one used oral ajulemic acid [76], one used oral CBD [78] and one used vaporized THC [114].

What types of outcomes
were measured

The main outcome was significant pain reduction (≥ 30%) assessed on visual-analogue scale, 11 points numerical scale or neuropathic pain scale. Other outcomes evaluated were pain reduction ≥ 50%, quality of life and presence of gastrointestinal, central nervous system and psychiatric adverse effects, among others.

* The information about primary studies is extracted from the systematic reviews identified, unless otherwise specified.

Summary of findings

Information on the effects of cannabinoids for pain reduction ≥ 30% is based on 15 randomized trials involving 1,788 patients [39],[43],[56],[76],[77],[79],[86],[87],[93],[97],[99],[101],[113],[114],[115]. The other trials did not report any outcome of interest, or did not present the information in a way it could be incorporated in a meta-analysis. Information on adverse effects is based on a systematic review [37] assessing the adverse effects of cannabinoids in different populations, and includes 3,489 patients in 29 trials reporting this outcome. The summary of findings is as follows:

  • It is not clear whether cannabinoids decrease pain in patients with chronic non-cancer pain because the certainty of available evidence is very low.
  • The use of cannabinoids is associated with a high rate of adverse events. The certainty of the evidence is high.

Follow the link to access the interactive version of the Summary of Findings (iSoF) table

Other considerations for decision-making

To whom this evidence does and does not apply

  • This evidence applies to adults with chronic non-cancer pain.
About the outcomes included in this summary
  • Critical outcomes for decision-making in this clinical scenario were included, according to the opinion of the authors of this summary. These coincide with those presented in most of the identified reviews, and the main guidelines.
  • We did not include in the summary of findings table information regarding pain reduction ≥50% because the conclusions would not have changed (RR 1.69 [CI 0.97 to 2.94]) and the very low certainty of the evidence.
Balance between benefits and risks, and certainty of the evidence
  • It is not possible to make an adequate risk/benefit balance because the certainty of the evidence on the effects of cannabinoids for the treatment of chronic non-cancer pain is very low. Since adverse effects are frequent, the risk/benefit balance probably does not favor their use in these patients.
Resource considerations
  • Cannabinoids are generally expensive. In the case of synthetic cannabinoids, the cost is usually very high. In the case of Cannabis, there are high costs associated to production, regulation and distribution.
What would patients and their doctors think about this intervention
  • Existing evidence should lead most patients and physicians to exercise caution in using this intervention. However, given the connotation of natural medicines and Cannabis in particular, it is likely that some clinicians and patients might favor its use despite the information provided in this summary.

Differences between this summary and other sources

  • The conclusions of this summary agree with several systematic reviews included [4],[7],[9],[10],[13],[14],[15],[17],[34]. Others were more optimistic about cannabinoids’ analgesic effect [1],[5],[19],[22],[23],[24],[27],[30],
    [33],[36],[37], and three claim there is moderate quality evidence to support its use [24],[36],[37]. An old systematic review completely disregards the prescription of cannabinoids [35], while others discourage its use based on its adverse effects profile despite admitting its analgesic effect [2],[8],[25].
  • There are at least two clinical guidelines [124],[125] that are consistent with the results of this summary stating there is low certainty evidence to provide sound conclusions. On the other hand, there are neuropathic pain clinical guidelines that consider cannabinoids as second line analgesics [126], third line analgesics [127], after failure of other options [128], as adjuvant analgesics [129] or as an alternative to consider in patients with multiple sclerosis [132]. A chronic pain guideline considers cannabinoids as an analgesic after failure of other options [130], and a fibromyalgia guideline considers them as an option in patients with sleep problems [131].
Could this evidence change in the future?
  • The likelihood that the conclusions of this summary about the benefits of cannabinoids in patients with chronic non-cancer pain change with future evidence is high given the very low certainty of the evidence.
  • There are at least three primary studies [133],[134],[135] not included in any systematic review so far evaluating the analgesic effect of cannabinoids in patients with chronic non-cancer pain. We were also able to identify at least eight ongoing studies [136],[137],[138],[139],[140],[141],[142],[143] that could provide relevant clinical information.
  • Multiple ongoing primary studies and high quality systematic reviews reanalyzing existing data could provide more certainty to conclusions.
How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Cannabinoids for chronic non-cancer pain

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrices and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

El uso de cannabinoides se ha propuesto como analgésico para dolores de diversa índole, en especial para pacientes con dolor crónico refractario al tratamiento habitual. Sin embargo, su real eficacia y seguridad sigue siendo motivo de controversia, por lo que buscamos determinar sus efectos en pacientes con dolor crónico no asociado a cáncer. Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Identificamos 37 revisiones sistemáticas que en conjunto incluyen 41 estudios, de los que 32 son ensayos aleatorizados relevantes para nuestra pregunta. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metaanálisis y preparamos tablas de resumen de los resultados utilizando el método GRADE. Concluimos que no está claro si los cannabinoides disminuyen el dolor en pacientes con dolor crónico no asociado a cáncer porque la certeza de la evidencia disponible es muy baja. Por otra parte, se asocian a efectos adversos importantes.

Authors: Rubén F Allende-Salazar[1,2], Gabriel Rada[2,3,4,5,6]

Affiliation:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Departamento de Medicina Interna, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[4] Centro de Evidencia UC, Pontificia Universidad Católica de Chile, Santiago, Chile
[5] GRADE working group
[6] The Cochrane Collaboration

E-mail: radagabriel@epistemonikos.org

Author address:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Diagonal Paraguay 362
Santiago Centro
Chile.

Citation: Allende-Salazar RF, Rada G. Are cannabinoids an effective treatment for chronic non-cancer pain?. Medwave 2016; 16(Suppl2):e6972 doi: 10.5867/medwave.2017.6972

Submission date: 27/5/2017

Acceptance date: 6/6/2017

Publication date: 14/6/2017

PubMed record

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