Cannabis Use for Glaucoma and Associated Pain

Earn CME/CE in your profession:

Free Review Questions

Continuing Education Activity

Cannabis plants and their derivatives delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been evaluated for the treatment of many disorders, including lowering intraocular pressure (IOP). Control of IOP is the most significant modifiable risk factor for glaucoma, an optic neuropathy that causes irreversible blindness. This activity reviews cannabinoids’ mechanisms of action in lowering intraocular pressure, their potential neuroprotective properties, and local and systemic side effects.

Objectives:

  • Summarize the mechanisms by which cannabinoids decrease intraocular pressure.

  • Describe the proposed pathways through which cannabinoids may exert their neuroprotective effect.

  • Identify the most common systemic side effects associated with cannabis use.

  • Review the most common acute psychotropic side effects associated with cannabis use.

Introduction

Glaucoma is an optic neuropathy characterized by the loss of retinal ganglion cells and subsequent progressive degeneration of the optic nerve. It is the most common cause of irreversible blindness in the world. The most significant modifiable risk factor is the control of intraocular pressure (IOP).[1]

Cannabis plants have been used as a therapeutic agent for many centuries, as early as the fourth century AD.[2] More recently, cannabis’ primary psychoactive component delta(9)-tetrahydrocannabinol (THC) and its major non-psychoactive ingredient cannabidiol (CBD) have been used for the treatment of sleep disorders, pain, skin disorders, and lowering of intraocular pressure (IOP).[3][4][5][6][7][8][9] 

Cannabinoid (CB) receptors are G protein receptors with an affinity for the agonists THC and CBD. Two types of CB receptors are described: CB1 and CB2. CB1 receptors are mostly limited to the central nervous system, where they modulate neurotransmitters, while CB2 receptors are confined to the immune and peripheral nervous system and are involved in cytokine signaling.[10]

Function

Cannabinoid Receptors in the Eye

CB1 and CB2 receptors have been identified widely in the eye. CB1 receptors have been identified in corneal epithelium and endothelium, ciliary body, iris, Schlemm canal, trabecular meshwork, choroid, and many retinal layers: ganglion cell, inner and outer plexiform, inner nuclear, and outer segments of photoreceptors cells.[11] CB2 receptors have been found in the corneal epithelium and, like CB1 receptors, in many retinal layers: ganglion cell nuclear layer, inner nuclear, and inner segments of photoreceptors cells.[12][13]

Cannabinoids Effects on Intraocular Pressure

THC has been identified as the metabolite relevant to IOP-lowering, and this potential to treat glaucoma has been the subject of research over the past five decades.[8][9]

Reports about the use of THC to regulate IOP date back to 1971 when Helper and Frank published preliminary data about the effect of marijuana in lowering IOP, in which healthy patients demonstrated a 25% decrease in IOP after smoking THC.[14]. A subsequent study demonstrated a 30% decrease in IOP in glaucoma patients, although this effect lasted only 4 to 5 hours.[15] The first placebo-controlled study also demonstrated a significant but transient (four hours) decrease in IOP after inhalation of THC.[16]

Other delivery methods have been studied in human and animal models with variable results. Healthy human subjects received intravenous (IV) THC at different doses resulting in a moderate decrease in IOP (average 37% decrease) with a reported increase in heart rate and pulse.[17] Tiedeman et al. tested two oral derivatives of THC in a double-masked study in patients with ocular hypertension. Only one of the compounds effectively decreased IOP independently of blood pressure with mild subjective side effects.[18] In a cross-over study conducted by Tomida et al., sublingual THC administration at a low dose (5 mg) effectively decreased IOP after two hours, with IOP returning to baseline levels after four hours. In the same study, patients who received CBD did not show changes in IOP at any time, and patients who received a higher dose of THC (40 mg) had a transient increase in IOP.[19]

One of the challenges of topical administration of THC is its poor aqueous solubility. In a study conducted in rabbits, combining a TCH prodrug with surfactants and cyclodextrins helped improve aqueous solubility and corneal permeability compared to THC alone. Its IOP lowering capacity was comparable in duration and potency to timolol and pilocarpine.[20] In another human study, the use of a CB1 receptor agonist combined with cyclodextrin demonstrated a peak reduction of IOP after one hour of administration; this effect subsided within two hours.[21] Green et al. demonstrated that although topical administration of THC alone was not associated with any signs of ocular toxicity, it did not result in any significant decrease in IOP either.[22]

The exact mechanism by which cannabinoids decrease IOP has not been elucidated. It has been proposed that CB1 receptors in the trabecular meshwork, Schelmm canal, and ciliary body may modulate aqueous production and also improve trabecular outflow.[23][24] Also, the lowering IOP effect might be related to a decrease in systemic blood pressure with concurrently decreased pressure perfusing the ciliary body.[16] Cannabinoids’ vasodilatory effects may also play a role in promoting uveoscleral outflow with subsequent lowering of IOP.[24]

Cannabinoids: Neuroprotective Effects

It has been hypothesized that THC may play a role in neuroprotection. In one study, healthy human subjects were administered a low dose of dronabinol, a synthetic form of THC, and an improvement in optic nerve head blood flow at rest was noted. However, IOP, ocular perfusion pressure (OPP), and mean arterial pressure (MAP) did not show any changes. Also, low-dose oral administration did not induce any psychoactive side effects.[25]

In another study in healthy human subjects, oral administration of a slightly higher dose of dronabinol resulted in a significant decrease in IOP and improved retinal arteriovenous passage time, indicating an increase in retinal hemodynamics suggesting potential use in ocular disorders associated with inadequate blood perfusion. This study showed no adverse cardiovascular or respiratory side effects.[26]

Other animal studies have shown that systemic administration of cannabinoids may increase blood flow to the choroid, iris, and ciliary body and reduce retinal ganglion cell layer loss in animal models of ischemic/traumatic optic nerve injury.[27][28][29] In one animal model of ischemia-reperfusion, IOP was artificially elevated, and animal groups were treated with either CB1 receptor agonists alone or combined with CB1 antagonist at different concentrations, followed by quantification of any ischemic damage to retinal ganglion cells (RGC). RGC density was noticeably higher in the group treated with CB1 agonist alone. Co-treatment with antagonists almost completely abolished the neuroprotective effect.[30]

There are three proposed pathways through which cannabinoids exert their neuroprotective effect: inhibition of glutamate, nitric oxide, and endothelin-1. It is known that glutamate is toxic to RGC in glaucoma and has been implicated in progressive degeneration in chronic optic neuropathies.[31] Glutamate activates nitric oxide synthase with a subsequent increase in oxidative damage.[32] Activation of CB1 and CB2 receptors leads to inhibition of glutamate release, suggesting that activating these receptors could be a way to protect RGCs from glutamate-induced death.[33] At the same time, such activation in the retina and central nervous system inhibits nitric oxide production and inflammatory cytokines that contribute to oxidative stress and loss of RGCs.[34] 

Cannabinoids also have vasodilation properties; once CB1 and CB2 receptors are activated, there is an inhibition of endothelin-1 release. Inhibition of endothelin-1 vasoconstrictive effect results in increased blood supply to the optic nerve head, which can play a neuroprotective role in disease progression.[35]

Issues of Concern

Cannabinoids: Deleterious Effects in the Retina

Some published data suggest that cannabinoids may be deleterious to retinal and ganglion cells. Lucas et al. studied the relationship between cannabis use and retinal neural activity in a resting state in the absence of stimulation, a phenomenon known as background noise. Their findings suggest that THC use is associated with increased neuronal background noise in the retina and the brain. This may reflect the neurotoxicity of cannabis on retinal neuron dynamic, likely attributable to altered neurotransmitter release.[36] 

Schwitzer et al. have shown a delay in responses of ganglion and bipolar cells in regular cannabis users that translate into delay of visual information transmission from the retina to the brain. Utilizing multifocal electroretinogram, they demonstrated that this delay in transmission could translate into alterations in precise and color vision. This same author also published a report of transient dysfunction of retinal activity thirty minutes after cannabis use by smoking. There was a marked decrease in the amplitude of the a-wave in electroretinogram compared with the responses five hours after smoking.[37][38][39] These data have opened the field for further investigations about the impact of cannabis on retinal processing.

Cannabinoids: Systemic Side Effects 

Cannabis use is associated with behavioral and end-organ toxicity and is contraindicated in the context of significant hepatic, renal, cardiovascular, or psychiatric disease.[40][41][42] Its use produces impairment in social and cognitive functions and may be associated with the use of other illicit drugs.[43] Acute effects are euphoria, relaxation, time distortion, perceptual alteration, and intensification of normal sensory experiences. Acute cannabis intoxication can cause impairment of short-term memory, attention, reaction time, and motor skills. Some users can develop anxiety and panic reactions.[44] It can also cause tachycardia within minutes of use and hypotension. Other systemic effects associated with chronic use of cannabis are impaired cell-mediated and humoral immunity, chronic bronchitis, increased risk of lung cancer, and male and female infertility.[45][44]

Clinical Significance

Further studies may help elucidate any IOP-independent potential neuroprotective benefits. In a 2009 statement, the American Glaucoma Society recommended against marijuana use in any form for the treatment of glaucoma.[46]

Enhancing Healthcare Team Outcomes

Managing patients who may independently choose to use cannabinoids to treat glaucoma requires an interprofessional team of healthcare professionals that may include a nurse, pharmacist, and several physicians in different specialties to improve outcomes and reduce morbidity. A patient may report their use of cannabinoids to the ophthalmic nurse or technician, and the ophthalmologist must educate the patient about the lack of clear evidence demonstrating these agents' usefulness in the treatment of glaucoma as the importance to not stop using proven glaucoma therapies.[47] [Level 1]

The care of such a patient does not stop at this discussion. Because of cannabinoids' potentially addictive nature, secondary systemic and psychotropic side effects, very short duration of action, management of chronic cannabinoid use in a patient, especially in the presence of comorbidities or mobility impairments, will also require the collaboration of the patient's primary care doctor, behavior and mental health professionals, and home health aides.[40][41][40] [Level 5, 3]

Details

Author

Maria J. Lopez

Editor:

Nathaniel Nataneli

Updated:

6/12/2023 7:50:12 PM

Feedback:

Send Us Your Comments

References

[1]

Jonas JB, Aung T, Bourne RR, Bron AM, Ritch R, Panda-Jonas S. Glaucoma. Lancet (London, England). 2017 Nov 11:390(10108):2183-2193. doi: 10.1016/S0140-6736(17)31469-1. Epub 2017 May 31     [PubMed PMID: 28577860]

[2]

Zias J, Stark H, Sellgman J, Levy R, Werker E, Breuer A, Mechoulam R. Early medical use of cannabis. Nature. 1993 May 20:363(6426):215     [PubMed PMID: 8387642]

[3]

Murillo-Rodríguez E. The role of the CB1 receptor in the regulation of sleep. Progress in neuro-psychopharmacology & biological psychiatry. 2008 Aug 1:32(6):1420-7. doi: 10.1016/j.pnpbp.2008.04.008. Epub 2008 Apr 18     [PubMed PMID: 18514375]

[4]

Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. Journal of pain and symptom management. 2010 Feb:39(2):167-79. doi: 10.1016/j.jpainsymman.2009.06.008. Epub 2009 Nov 5     [PubMed PMID: 19896326]

Level 1 (high-level) evidence

[5]

Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clinical therapeutics. 2007 Sep:29(9):2068-79     [PubMed PMID: 18035205]

[6]

Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005 Sep 27:65(6):812-9     [PubMed PMID: 16186518]

Level 1 (high-level) evidence

[7]

Mounessa JS, Siegel JA, Dunnick CA, Dellavalle RP. The role of cannabinoids in dermatology. Journal of the American Academy of Dermatology. 2017 Jul:77(1):188-190. doi: 10.1016/j.jaad.2017.02.056. Epub 2017 Apr 14     [PubMed PMID: 28416341]

[8]

Miller S, Daily L, Leishman E, Bradshaw H, Straiker A. Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Regulate Intraocular Pressure. Investigative ophthalmology & visual science. 2018 Dec 3:59(15):5904-5911. doi: 10.1167/iovs.18-24838. Epub     [PubMed PMID: 30550613]

[9]

Merritt JC, Perry DD, Russell DN, Jones BF. Topical delta 9-tetrahydrocannabinol and aqueous dynamics in glaucoma. Journal of clinical pharmacology. 1981 Aug-Sep:21(S1):467S-471S     [PubMed PMID: 6271841]

[10]

Amin MR, Ali DW. Pharmacology of Medical Cannabis. Advances in experimental medicine and biology. 2019:1162():151-165. doi: 10.1007/978-3-030-21737-2_8. Epub     [PubMed PMID: 31332738]

Level 3 (low-level) evidence

[11]

Porcella A, Maxia C, Gessa GL, Pani L. The human eye expresses high levels of CB1 cannabinoid receptor mRNA and protein. The European journal of neuroscience. 2000 Mar:12(3):1123-7     [PubMed PMID: 10762343]

[12]

Murataeva N, Miller S, Dhopeshwarkar A, Leishman E, Daily L, Taylor X, Morton B, Lashmet M, Bradshaw H, Hillard CJ, Romero J, Straiker A. Cannabinoid CB2R receptors are upregulated with corneal injury and regulate the course of corneal wound healing. Experimental eye research. 2019 May:182():74-84. doi: 10.1016/j.exer.2019.03.011. Epub 2019 Mar 21     [PubMed PMID: 30905716]

[13]

Lu Q, Straiker A, Lu Q, Maguire G. Expression of CB2 cannabinoid receptor mRNA in adult rat retina. Visual neuroscience. 2000 Jan-Feb:17(1):91-5     [PubMed PMID: 10750830]

[14]

Hepler RS, Frank IR. Marihuana smoking and intraocular pressure. JAMA. 1971 Sep 6:217(10):1392     [PubMed PMID: 5109652]

[15]

Cohen S. The 94-day cannabis study. Annals of the New York Academy of Sciences. 1976:282():211-20     [PubMed PMID: 1071381]

[16]

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 PMID: 7053160]

[17]

Cooler P, Gregg JM. Effect of delta-9-tetrahydrocannabinol on intraocular pressure in humans. Southern medical journal. 1977 Aug:70(8):951-4     [PubMed PMID: 329423]

[18]

Tiedeman JS, Shields MB, Weber PA, Crow JW, Cocchetto DM, Harris WA, Howes JF. Effect of synthetic cannabinoids on elevated intraocular pressure. Ophthalmology. 1981 Mar:88(3):270-7     [PubMed PMID: 7015221]

[19]

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. Journal of glaucoma. 2006 Oct:15(5):349-53     [PubMed PMID: 16988594]

Level 3 (low-level) evidence

[20]

Adelli GR, Bhagav P, Taskar P, Hingorani T, Pettaway S, Gul W, ElSohly MA, Repka MA, Majumdar S. Development of a Δ9-Tetrahydrocannabinol Amino Acid-Dicarboxylate Prodrug With Improved Ocular Bioavailability. Investigative ophthalmology & visual science. 2017 Apr 1:58(4):2167-2179. doi: 10.1167/iovs.16-20757. Epub     [PubMed PMID: 28399267]

[21]

Porcella A, Maxia C, Gessa GL, Pani L. The synthetic cannabinoid WIN55212-2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies. The European journal of neuroscience. 2001 Jan:13(2):409-12     [PubMed PMID: 11168547]

[22]

Green K, Roth M. Ocular effects of topical administration of delta 9-tetrahydrocannabinol in man. Archives of ophthalmology (Chicago, Ill. : 1960). 1982 Feb:100(2):265-7     [PubMed PMID: 6279061]

[23]

Chien FY, Wang RF, Mittag TW, Podos SM. Effect of WIN 55212-2, a cannabinoid receptor agonist, on aqueous humor dynamics in monkeys. Archives of ophthalmology (Chicago, Ill. : 1960). 2003 Jan:121(1):87-90     [PubMed PMID: 12523891]

[24]

Porcella A, Casellas P, Gessa GL, Pani L. Cannabinoid receptor CB1 mRNA is highly expressed in the rat ciliary body: implications for the antiglaucoma properties of marihuana. Brain research. Molecular brain research. 1998 Jul 15:58(1-2):240-5     [PubMed PMID: 9685662]

Level 3 (low-level) evidence

[25]

Hommer N, Kallab M, Szegedi S, Puchner S, Stjepanek K, Bauer M, Werkmeister RM, Schmetterer L, Abensperg-Traun M, Garhöfer G, Schmidl D. The Effect of Orally Administered Dronabinol on Optic Nerve Head Blood Flow in Healthy Subjects-A Randomized Clinical Trial. Clinical pharmacology and therapeutics. 2020 Jul:108(1):155-161. doi: 10.1002/cpt.1797. Epub 2020 Feb 23     [PubMed PMID: 31977076]

Level 1 (high-level) evidence

[26]

Plange N, Arend KO, Kaup M, Doehmen B, Adams H, Hendricks S, Cordes A, Huth J, Sponsel WE, Remky A. Dronabinol and retinal hemodynamics in humans. American journal of ophthalmology. 2007 Jan:143(1):173-4     [PubMed PMID: 17188063]

[27]

Green K, Wynn H, Padgett D. Effects of delta9-tetrahydrocannabinol on ocular blood flow and aqueous humor formation. Experimental eye research. 1978 Jan:26(1):65-9     [PubMed PMID: 624325]

[28]

Crandall J, Matragoon S, Khalifa YM, Borlongan C, Tsai NT, Caldwell RB, Liou GI. Neuroprotective and intraocular pressure-lowering effects of (-)Delta9-tetrahydrocannabinol in a rat model of glaucoma. Ophthalmic research. 2007:39(2):69-75     [PubMed PMID: 17284931]

[29]

Nucci C, Gasperi V, Tartaglione R, Cerulli A, Terrinoni A, Bari M, De Simone C, Agrò AF, Morrone LA, Corasaniti MT, Bagetta G, Maccarrone M. Involvement of the endocannabinoid system in retinal damage after high intraocular pressure-induced ischemia in rats. Investigative ophthalmology & visual science. 2007 Jul:48(7):2997-3004     [PubMed PMID: 17591864]

[30]

Pinar-Sueiro S, Zorrilla Hurtado JÁ, Veiga-Crespo P, Sharma SC, Vecino E. Neuroprotective effects of topical CB1 agonist WIN 55212-2 on retinal ganglion cells after acute rise in intraocular pressure induced ischemia in rat. Experimental eye research. 2013 May:110():55-8. doi: 10.1016/j.exer.2013.02.009. Epub 2013 Feb 20     [PubMed PMID: 23454099]

[31]

Sucher NJ, Lipton SA, Dreyer EB. Molecular basis of glutamate toxicity in retinal ganglion cells. Vision research. 1997 Dec:37(24):3483-93     [PubMed PMID: 9425525]

[32]

Vorwerk CK, Lipton SA, Zurakowski D, Hyman BT, Sabel BA, Dreyer EB. Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine. Investigative ophthalmology & visual science. 1996 Jul:37(8):1618-24     [PubMed PMID: 8675405]

[33]

El-Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai NJ, Roon P, Caldwell RB, Caldwell RW, Green K, Liou GI. Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. The American journal of pathology. 2003 Nov:163(5):1997-2008     [PubMed PMID: 14578199]

[34]

Krishnan G, Chatterjee N. Endocannabinoids alleviate proinflammatory conditions by modulating innate immune response in muller glia during inflammation. Glia. 2012 Nov:60(11):1629-45. doi: 10.1002/glia.22380. Epub 2012 Jul 17     [PubMed PMID: 22807196]

[35]

Kim SH, Kim JY, Kim DM, Ko HS, Kim SY, Yoo T, Hwang SS, Park SS. Investigations on the association between normal tension glaucoma and single nucleotide polymorphisms of the endothelin-1 and endothelin receptor genes. Molecular vision. 2006 Aug 29:12():1016-21     [PubMed PMID: 16971893]

[36]

Lucas A, Thirion A, Schwan R, Krieg J, Angioi-Duprez K, Laprevote V, Schwitzer T. Association between increased retinal background noise and co-occurrent regular cannabis and alcohol use. Progress in neuro-psychopharmacology & biological psychiatry. 2019 Mar 8:89():335-340. doi: 10.1016/j.pnpbp.2018.10.002. Epub 2018 Oct 5     [PubMed PMID: 30292729]

[37]

Schwitzer T, Henrion ML, Sarre D, Albuisson E, Angioi-Duprez K, Giersch A, Lalanne L, Schwan R, Laprevote V. Spatial localization of retinal anomalies in regular cannabis users: The relevance of the multifocal electroretinogram. Schizophrenia research. 2020 May:219():56-61. doi: 10.1016/j.schres.2019.01.013. Epub 2019 Jan 26     [PubMed PMID: 30696610]

[38]

Schwitzer T, Schwan R, Albuisson E, Giersch A, Lalanne L, Angioi-Duprez K, Laprevote V. Association Between Regular Cannabis Use and Ganglion Cell Dysfunction. JAMA ophthalmology. 2017 Jan 1:135(1):54-60. doi: 10.1001/jamaophthalmol.2016.4761. Epub     [PubMed PMID: 27930757]

[39]

Schwitzer T, Robert MP, Giersch A, Angioi-Duprez K, Ingster-Moati I, Pon-Monnier A, Schwan R, Laprevote V. Transient Retinal Dysfunctions after Acute Cannabis Use. European addiction research. 2016:22(6):287-291     [PubMed PMID: 27376753]

[40]

Kazory A, Aiyer R. Synthetic marijuana and acute kidney injury: an unforeseen association. Clinical kidney journal. 2013 Jun:6(3):330-3. doi: 10.1093/ckj/sft047. Epub     [PubMed PMID: 26064495]

[41]

Zawatsky CN, Abdalla J, Cinar R. Synthetic cannabinoids induce acute lung inflammation via cannabinoid receptor 1 activation. ERJ open research. 2020 Jul:6(3):. pii: 00121-2020. doi: 10.1183/23120541.00121-2020. Epub 2020 Aug 17     [PubMed PMID: 32832534]

[42]

Lucas CJ, Galettis P, Schneider J. The pharmacokinetics and the pharmacodynamics of cannabinoids. British journal of clinical pharmacology. 2018 Nov:84(11):2477-2482. doi: 10.1111/bcp.13710. Epub 2018 Aug 7     [PubMed PMID: 30001569]

[43]

Fergusson DM, Horwood LJ. Early onset cannabis use and psychosocial adjustment in young adults. Addiction (Abingdon, England). 1997 Mar:92(3):279-96     [PubMed PMID: 9219390]

[44]

Kumar RN, Chambers WA, Pertwee RG. Pharmacological actions and therapeutic uses of cannabis and cannabinoids. Anaesthesia. 2001 Nov:56(11):1059-68     [PubMed PMID: 11703238]

[45]

Sridhar KS, Raub WA Jr, Weatherby NL, Metsch LR, Surratt HL, Inciardi JA, Duncan RC, Anwyl RS, McCoy CB. Possible role of marijuana smoking as a carcinogen in the development of lung cancer at a young age. Journal of psychoactive drugs. 1994 Jul-Sep:26(3):285-8     [PubMed PMID: 7844658]

[46]

Jampel H. American glaucoma society position statement: marijuana and the treatment of glaucoma. Journal of glaucoma. 2010 Feb:19(2):75-6. doi: 10.1097/IJG.0b013e3181d12e39. Epub     [PubMed PMID: 20160576]

[47]

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. Archives of ophthalmology (Chicago, Ill. : 1960). 2002 Oct:120(10):1268-79     [PubMed PMID: 12365904]