Glaucoma is a progressive optic neuropathy and represents a leading cause of blindness worldwide.18
All forms of glaucoma therapy share the common target of lowering intraocular pressure to a level that minimizes or eliminates the risk of damage to the optic nerve. Reduction and control of increased intraocular pressure in most glaucomas is classically achieved by long-term topical therapy as first- line treatment.1
Pharmacological and histological studies support a direct role of ocular cannabinoid receptors in the intraocular pressure reduction induced by cannabinoids. Cannabinoid receptors have been found in the ocular tissues of the human eye, including the ciliary epithelium, the trabecular meshwork, Schlemm’s canal, ciliary muscle, ciliary body vessels, and retina.2
High levels of cannabinoid mRNA have also been demonstrated in the ciliary body.2
The anatomical distribution of these receptors suggests a possible influence of endogenous cannabinoids on trabecular and uveoscleral outflow as well as on production of aqueous humor. Tetrahydrocannabinol, the main psychoactive component of cannabis, decreases secretion of the ciliary processes and leads to dilatation of the ocular blood vessels, possibly via a beta-adrenergic action.2
In addition, cannabinoids may inhibit calcium influx through presynaptic channels and in this way reduce noradrenaline release in the ciliary body, leading to a decrease in production of aqueous humor.2
Furthermore, it has been proposed that cannabinoids may have a vasodilatory effect on the blood vessels of the anterior uvea, thus improving uveoscleral outflow.2
Some cannabinoids may also influence intraocular pressure via a prostaglandin-mediated mechanism.23
Recent studies have not only demonstrated the intraocular pressure-lowering capability of cannabinoids, but have also documented its neuroprotective properties, which are an additional advantage when treating patients with glaucoma.
In glaucoma, the final common pathway leading to visual loss is the selective death of retinal ganglion cells as a result of apoptosis. Apoptosis is initiated by axonal injury at the optic disc, either by ischemia and/or compression.2
In ischemia, glutamate is released and leads to activation of one of several pathways that eventually lead to apoptosis. There is evidence that tetrahydrocannabinol inhibits glutamic acid and thus prevents a cascade of events leading to apoptosis and death of retinal ganglion cells. The potential role of cannabinoids in improving ocular blood flow due to their innate vasorelaxant properties have also been postulated.2
The possible role of endothelin-1, a mediator involved in the regulation of local circulation by causing vasoconstriction, has been described previously in the pathogenesis of Raynaud’s phenomenon and ischemic heart disease.25
A possible link between primary open angle glaucoma and endothelin-1 is now postulated. It has been suggested that patients with this condition may have abnormally increased levels of endothelin-1 in response to vasospastic stimuli.2
It was also demonstrated that endogenous cannabinoids are able to inhibit vasoconstriction via reduction of endothelin-induced calcium mobilization.28
Thus, cannabinoids may have beneficial properties in arresting ischemia-induced optic nerve damage, which is an added benefit in the treatment of patients with open angle glaucoma. Clearly, there are several potential mechanisms of action in glaucoma if the cannabinoid receptor can be successfully stimulated.
The results of our pilot clinical study demonstrate that both topical levobunolol and oral paracetamol significantly reduced intraocular pressure from the untreated baseline at weeks 1 and 2 in patients with primary open angle and angle recession glaucoma. These patients were included in the study because both these glaucomas are “open angle” glaucomas, and presumably would respond similarly to treatment with either agent. In the levobunolol group, reduction in intraocular pressure increased from 25% (7.5 mmHg) at week 1% to 29% (9 mmHg) at week 2, while in the oral paracetamol subgroup, reduction in intraocular pressure decreased from 29% (8.8 mmHg) at week 1% to 21% (6.5 mmHg) at week 2 (). The change in intraocular pressure from week 1 to 2 in both subgroups was not clinically or statistically significant. The change in reduction of intraocular pressure in the paracetamol group may possibly be due to desensitization of cannabinoid receptors to the cannabinomimetic metabolic products of paracetamol. Equal lowering of intraocular pressure from baseline was obtained in the levobunol and paracetamol groups approximately 1.3 weeks following commencement of the study (). The intraocular pressure-lowering effect of paracetamol (21%) is consistent with previous reports of the ocular hypotensive efficacy of alpha-2 selective adrenergic agonists (20%–25%), topical carbonic anhydrase inhibitors (20%–25%), and pilocarpine (20%–25%).29
Intraocular pressure (IOP) (mmHg) versus time from baseline in the levobunolol and paracetamol groups.
Results of the Early Manifest Glaucoma Treatment Study suggest that each 1 mmHg of additional intraocular pressure-lowering reduces the risk of glaucomatous progression by approximately 10% in patients with early glaucoma.30
Often this may be achieved by adding an additional drug with a different mechanism of action to the treatment regimen. Paracetamol, as a prodrug for the active cannabinoid, AM404, which acts on the cannabinoid receptor, may add such value to the available treatment armementarium. Ocular administration of the metabolite, AM404, decreased intraocular pressure in rabbits, but provoked an initial ocular hypertension response in a study by Laine et al.31
Paracetamol is considered to be safe in oral doses of up to 4 g daily in adults.32
None of the patients in this study met the standard criteria for drug-induced hepatotoxicity as set out by the DILI Network criteria.11
However, a recent participant-blinded, diet-controlled study in selected healthy volunteers taking 4 g of paracetamol daily, either alone or in combination with selected opioids or placebo, was conducted.33
These researchers reported that 76% of subjects in the paracetamol group had concentrations of ALT above the upper limit of the reference range, and that 39% of these subjects had an elevation that was more than three times the upper limit of the reference range, and 25% had more than five times the upper limit of the reference range. None of those who had received placebo had an increase to these levels. On the other hand, other long-term studies with paracetamol have failed to detect evidence of liver injury.34
No statistically significant changes in liver function, systolic/diastolic blood pressure, or heart rate were observed over the 2-week period of the present study.
In a recent pilot study of sublingual delta-9-tetrahydro-cannabinol and cannabidiol, Tomida et al36
suggested that delta-9-tetrahydrocannabinol lowered intraocular pressure significantly in the short term, but that cannabidiol did not, thereby alluding to the need for further research on the clinical effect of systemically administered cannabinoid-like molecules in glaucoma. Using the same molecule (delta-9-tetrahydrocannabinol) in an experimental rat model, Crandall et al37
suggested that the molecule could have neuroprotective effects over and above its intraocular pressure-lowering potential. If cannabinoids and their precursors (like paracetamol) do have a neuroprotective effect on ganglion cells, especially if independent of intraocular pressure reduction, they could offer another treatment modality in patients with glaucoma.
Permeation of chemical substances through the human corneal tissue epithelium is dependent not only on the nature, conformation, lipid/water partition coefficient, and degree of ionization of the molecules involved, but also on their size.15
The molecular weight of paracetamol is 151.16 g/mol, so it is a relatively small molecule and our in vitro observations have demonstrated its ability to penetrate the human cornea rapidly and reach high steady-state levels within 4 hours.
One major limitation of this pilot study is the lack of a placebo-controlled arm. Because these were patients with known disease and needing therapy for their raised intraocular pressure, we were ethically bound to treat all of them. The short duration of the study and small sample size was chosen to satisfy patient safety concerns. This small sample size might thus be open to bias, but serves as a pilot study for ongoing clinical studies. The investigator was not masked to the medication, study eye, or when measuring the intraocular pressure, but because a single investigator performed all the measurements, we believe this limited any potential bias possible in our study design. Although diurnal variability of intraocular pressure was not taken into account, every attempt was made to measure the intraocular pressure at 9 am. The amount of intraocular pressure reduction achieved by levobunolol 0.5% was similar to that quoted by the European Glaucoma Society for β-blockers, whereas that achieved by paracetamol was similar to the degree of reduction achieved with topical application of cannabinoids or pilocarpine.29
Further, we relied on patient confirmation and not on serum paracetamol concentration levels to confirm compliance.