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Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2018 Ene-Feb;18(1):e7144 doi: 10.5867/medwave.2018.01.7144
Do cannabinoids play a role in the control of glaucoma?
Javier Peña, Camila Jiménez, Jimena Schmidt
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Abstract

INTRODUCTION
The use of cannabinoids in diverse clinical conditions is today a subject of debate. Its use has been proposed for the control of glaucoma. However, there is controversy about its real effectiveness and safety.

METHODS
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 extracted data from the systematic reviews, reanalyzed data of primary studies and generated a summary of findings table using the GRADE approach.

RESULTS AND CONCLUSIONS
We identified five systematic reviews including three studies overall, all of them randomized controlled trials. We concluded that although cannabinoids could decrease intraocular pressure, the effect would be transient and associated with frequent adverse effects.


 
Problem

Glaucoma is a multifactorial optic neuropathy, often related to an increase in intraocular pressure (IOP). The permanently elevated intraocular pressure produces a slow and progressive damage in the optic nerve, generating different sequelae in the visual field and eventually it can lead to irreversible blindness. Although the elevation of intraocular pressure is present in most patients, there is a group of patients who develop glaucoma with normal pressure.

Today there are different medical therapies for the treatment of glaucoma, such as topical betablockers and prostaglandin analogues. The use of cannabinoids has been proposed, since its administration is associated with a decrease in intraocular pressure, through an effect on the production and exit of aqueous humor mediated by the activation of CB1 receptors. Also, neuroprotective properties on the optic nerve have been proposed. However, its actual clinical role is still controversial.

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 denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) 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 when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making. 

Key messages

  • Although the use of cannabinoids for glaucoma could decrease intraocular pressure, it would be transient and associated with frequent adverse effects.
  • The benefit/risk balance is probably not favorable.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found five systematic reviews [1],[2],[3],[4],[5] including three primary studies overall [6],[7],[8], all of which correspond to randomized controlled trials.

What types of patients were included*

All trials included adult patients with glaucoma [6],[7],[8], with average age over 50 years. Only one trial specified the type of glaucoma (primary open-angle glaucoma) [8]. Two trials [7],[8], included patients with intraocular hypertension.

What types of interventions were included*

One trial [8] used sublingual cannabinoid spray (Sativex®) at doses of 5, 20 and 40 mg. Another trial [6] used smoked marijuana with 2% tetrahydrocannabinol (THC), while the last trial [7] used marijuana in 0.01%, 0.05%, and 0.1% eye drops.All trials compared against placebo or standard treatment.

What types of outcomes
were measured

The different systematic reviews identified [1],[2],[3],[4],[5] grouped the outcomes as follows:

  • Decrease in intraocular pressure, measured immediately after cannabinoid administration.
  • Adverse effects.

Two trials [7],[8] analyzed the duration of the intraocular pressure decrease, while in the other trial this variable was not reported [6].

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

Summary of Findings

The information on the effects of cannabinoids for glaucoma is based on three randomized trials [6],[7],[8], which include 32 patients in total. All of the trials [6],[7],[8], reported intraocular pressure and adverse effects, and two of them [7],[8] specified the duration of the decrease in intraocular pressure. None of the trials reported decreased visual acuity or visual field deterioration. The summary of findings is the following:

  • The use of cannabinoids for glaucoma could be associated with a transient decrease in intraocular pressure, but the certainty of the evidence is low.
  • The use of cannabinoids for glaucoma leads to frequent adverse effects. The certainty of the evidence is high.

Other considerations for decision-making

To whom this evidence does and does not apply

  • The evidence presented in this summary comes from patients with primary open-angle glaucoma and patients with intraocular hypertension. However, in the absence of direct evidence it is reasonable to extrapolate to other forms of glaucoma with elevated intraocular pressure.
  • It is not applicable to patients with normal tension glaucoma. On the other hand, it is questionable to apply it to patients with congenital glaucoma, since although the majority of patients present elevated intraocular pressure, the pathophysiology of the increase is different.
About the outcomes included in this summary
  • The outcomes selected for the summary of findings table are those considered critical for decision-making in this clinical situation, according to the opinion of the authors of this article. In general, they coincide with those presented in the systematic reviews identified.
  • It is important to emphasize that patient's preferences are more concerned about the visual implications of the disease and the prevention of blindness. However, there is evidence that the decrease in intraocular pressure maintained over time delays the progression of this disease, including the deterioration of the visual field [9].
  • On the other hand, the decrease in intraocular pressure is a relevant element in clinical practice for follow-up and thus determine the success of the treatment or the need of new interventions.
  • Although information on adverse effects is scarce in the evaluated trials, these are frequent in other conditions [4], so something similar should be expected in glaucoma.
Balance between benefits and risks, and certainty of the evidence
  • It is not possible to make an adequate balance between benefits and risks due to the existing uncertainty about the benefits. However, it is unlikely that the observed effect, being transient, will translate into a clinically relevant benefit. On the other hand, the intervention has frequent adverse effects, so the benefit/risk balance is probably not favorable.
Resource considerations
  • Commercial formulations of cannabinoids generally have a high cost. Since there is no certainty about a possible benefit, it is not possible to make an adequate cost/benefit balance.
What would patients and their doctors think about this intervention
  • Most patients and doctors should lean against the use of this intervention based on the evidence presented in this summary.
  • In addition, nowadays there are proven therapies for the control of glaucoma, with good results both in the short and long term.
  • Some patients who place a greater value on an uncertain benefit may decide to use it, especially considering the preconceived ideas they may have about it.

Differences between this summary and other sources

  • The key messages of this summary are concordant with the conclusions of the systematic reviews identified.
  • This summary also coincides with the statement of the Canadian Ophthalmological Society [10] and the American Ophthalmological Society [11], who do not recommend the use of cannabinoids for the treatment of glaucoma, since although it produces a decrease in intraocular pressure, it is transient and is associated with frequent adverse effects.
Could this evidence change in the future?
  • The likelihood that future evidence changes the conclusions of this summary with respect to the benefits of cannabinoids in glaucoma is high due to the existing uncertainty. It is unlikely that the conclusions about adverse effects change.
  • We did not identify any ongoing trial evaluating this question in the International Clinical Trials Registry Platform of the World Health Organization.
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 glaucoma

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 matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE 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).

Potential 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.

 

INTRODUCCIÓN
El uso de cannabinoides en diversas condiciones clínicas es hoy un tema de debate. Se ha planteado su uso para el control del glaucoma. Sin embargo, existe controversia sobre su real efectividad y seguridad.

MÉTODOS
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. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios y preparamos una tabla de resumen de los resultados utilizando el método GRADE.

RESULTADOS Y CONCLUSIONES
Identificamos cinco revisiones sistemáticas que en conjunto incluyen 3 estudios primarios, todos correspondientes a ensayos aleatorizados. Concluimos que, si bien los cannabinoides podrían disminuir la presión intraocular, lo hacen de forma transitoria y se asocian a efectos adversos frecuentes.

Authors: Javier Peña[1.2], Camila Jiménez[1,2], Jimena Schmidt[2,3]

Affiliation:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Departamento de Oftalmología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: jimeschmidt@gmail.com

Author address:
[1] Centro Evidencia UC
Pontificia Universidad Católica de Chile
Centro de Innovación UC Anacleto Angelini
Avda.Vicuña Mackenna 4860
Macul
Santiago
Chile

Citation: Peña J, Jiménez C, Schmidt J. Do cannabinoids play a role in the control of glaucoma?. Medwave 2018 Ene-Feb;18(1):e7144 doi: 10.5867/medwave.2018.01.7144

Submission date: 23/11/2017

Acceptance date: 29/12/2017

Publication date: 24/1/2018

Origin: This article is a product of the Evidence Synthesis Project of Epistemonikos Fundation, in collaboration with Medwave for its publication.

Type of review: Non-blinded peer review by members of the methodological team of Epistemonikos Evidence Synthesis Project.

PubMed record

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  1. Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol. 2006 Apr 21;105(1-2):1-25. Review. | PubMed |
  2. Hazekamp, A, Grotenhermen, F. Review on clinical studies with cannabis and cannabinoids 2005-2009. Cannabinoids. 2010;5(special issue):1-21.
  3. Whiting P, Wolff R, Westwood M, Duffy S, Misso K, Keurentjes C, Lang S, Harker J, Despande S, Ryder S, Di Nisio M, Hernández AV, Schmidlkofer S, Kleijnen J. Systematic review of cannabis for medical use. Kleijnen Systematic Reviews Ltd. 2014.
  4. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015 Jun 23-30;313(24):2456-73. Erratum in: JAMA. 2016 Apr 12;315(14):1522. JAMA. 2015 Dec 1;314(21):2308. JAMA. 2015 Aug 4;314(5):520. JAMA. 2015 Aug 25;314(8):837. | CrossRef | PubMed |
  5. Welte AK, Hahn U, Büssing A, Krummenauer F. [Systematic Review of the Application of Complementary and Alternative Medicine and their Potential Therapeutic Benefits in the Treatment of Ophthalmology Patients]. Klin Monbl Augenheilkd. 2017 May;234(5):686-696. | CrossRef | PubMed |
  6. Merritt JC, Crawford WJ, Alexander PC, Anduze AL, Gelbart SS. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology. 1980 Mar;87(3):222-8. | PubMed |
  7. Merritt JC, Olsen JL, Armstrong JR, McKinnon SM. Topical delta 9-tetrahydrocannabinol in hypertensive glaucomas. J Pharm Pharmacol. 1981 Jan;33(1):40-1. | PubMed |
  8. Tomida I, Azuara-Blanco A, House H, Flint M, Pertwee RG, Robson PJ. Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study. J Glaucoma. 2006 Oct;15(5):349-53. | PubMed |
  9. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M; Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002 Oct;120(10):1268-79. | PubMed |
  10. Buys YM, Rafuse PE. Canadian Ophthalmological Society policy statement on the medical use of marijuana for glaucoma. Can J Ophthalmol. 2010 Aug;45(4):324-6. | CrossRef | PubMed |
  11. Jampel H. American glaucoma society position statement: marijuana and the treatment of glaucoma. J Glaucoma. 2010 Feb;19(2):75-6. | CrossRef | PubMed |
Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol. 2006 Apr 21;105(1-2):1-25. Review. | PubMed |

Hazekamp, A, Grotenhermen, F. Review on clinical studies with cannabis and cannabinoids 2005-2009. Cannabinoids. 2010;5(special issue):1-21.

Whiting P, Wolff R, Westwood M, Duffy S, Misso K, Keurentjes C, Lang S, Harker J, Despande S, Ryder S, Di Nisio M, Hernández AV, Schmidlkofer S, Kleijnen J. Systematic review of cannabis for medical use. Kleijnen Systematic Reviews Ltd. 2014.

Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015 Jun 23-30;313(24):2456-73. Erratum in: JAMA. 2016 Apr 12;315(14):1522. JAMA. 2015 Dec 1;314(21):2308. JAMA. 2015 Aug 4;314(5):520. JAMA. 2015 Aug 25;314(8):837. | CrossRef | PubMed |

Welte AK, Hahn U, Büssing A, Krummenauer F. [Systematic Review of the Application of Complementary and Alternative Medicine and their Potential Therapeutic Benefits in the Treatment of Ophthalmology Patients]. Klin Monbl Augenheilkd. 2017 May;234(5):686-696. | CrossRef | PubMed |

Merritt JC, Crawford WJ, Alexander PC, Anduze AL, Gelbart SS. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology. 1980 Mar;87(3):222-8. | PubMed |

Merritt JC, Olsen JL, Armstrong JR, McKinnon SM. Topical delta 9-tetrahydrocannabinol in hypertensive glaucomas. J Pharm Pharmacol. 1981 Jan;33(1):40-1. | PubMed |

Tomida I, Azuara-Blanco A, House H, Flint M, Pertwee RG, Robson PJ. Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study. J Glaucoma. 2006 Oct;15(5):349-53. | PubMed |

Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M; Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002 Oct;120(10):1268-79. | PubMed |

Buys YM, Rafuse PE. Canadian Ophthalmological Society policy statement on the medical use of marijuana for glaucoma. Can J Ophthalmol. 2010 Aug;45(4):324-6. | CrossRef | PubMed |

Jampel H. American glaucoma society position statement: marijuana and the treatment of glaucoma. J Glaucoma. 2010 Feb;19(2):75-6. | CrossRef | PubMed |