Numerous studies from different investigators published in peer-reviewed journals support the use of NLO or ELC for 5 minutes to enhance intraocular absorption and discourage systemic absorption of topically applied glaucoma medications.1–9
Although many investigators conclude that these simple techniques are important, there are no clinical studies of the efficacy and toxicity of the currently used glaucoma medications in our literature using these techniques for 5 minutes. In fact, the FDA, NIH, and NEI discourage the inclusion of these techniques in studies of the efficacy and toxicity of topically applied glaucoma medications. Consequently, all glaucoma studies sponsored by the pharmaceutical industry and approved by the FDA lack the inclusion of ELC or NLO for 5 minutes following eye drop instillation.
Although the specific reason for this attitude and influence reflected by several government agencies is unclear, it most likely reflects either concern about harming eyes during punctal occlusion or concern over the proven clinical value of these techniques, or it assumes patients will not comply with these techniques. Many ophthalmologists discourage patients from touching their eyes and periocular area because they fear inducing allergic symptoms or introducing infective organisms. Therefore, a preference for ELC rather than NLO for 5 minutes is understandable. It is reassuring that either technique can be used with adequate results because there is evidence that these procedures can be used interchangeably with insignificant difference in clinical effect.3
Although additional clinical studies to further establish the clinical value of these simple techniques may be interesting, the data that exist today in the literature are sufficient to enthusiastically recommend the universal inclusion of ELC or NLO for 5 minutes in all future clinical studies of glaucoma medications and within the clinical practice of glaucoma treatment, as investigators have previously suggested.1–9
Therefore, the burden of additional proof concerning the question of whether or not these techniques should be instituted now in all clinical studies is on those who choose to ignore the published data and those who minimize the importance of the basic principles of pharmacokinetics. After all, if a new drug demonstrated 70% increased ocular penetration and 70% decreased systemic absorption, even the FDA would approve these advertisements. In fact, such advertisements can frequently be found in our peer-reviewed journals.19
However, the most likely reason the FDA and NEI discourage the pharmaceutical industry from including these techniques in clinical studies is because of bias related to poor patient compliance issues. The usual argument against including ELC and NLO for 5 minutes in clinical studies recognizes published evidence that it is well proven that patients are poorly compliant with their application of glaucoma eye drops.20,21
Therefore, requesting that 5 additional minutes be added to the usual treatment regimen is at best “wishful thinking” and at worst may further reduce compliance. In recognition of this proven poor compliance, it is only prudent to design clinical studies that simulate “actual practice.” After all, it is only prudent to err on the side of caution when approving efficacy and safety of glaucoma medications.
There are at least 3 reasons to believe that patient compliance today is actually better than the current peer-reviewed literature suggests. First, patients are more informed and sophisticated today compared to the 1980s. For example, cartoons appearing in our daily newspapers often reflect our patients’ interests and concerns about their medical care and frequently demonstrate an understanding of medicine and pharmacology not commonly present within the general population 30 years ago. Humorous comments and illustrations concerning vitamins in place of mints on pillows in hotels at bedtime, the use and misuse of placebos, and the influence of the pharmaceutical industry on the practice of medicine can be found in many current periodicals on a regular basis.22–24
These clever and insightful artistic efforts suggest that the patient population and their fund of knowledge that we are treating today is quite different from that which we treated during the 1980s. Second, there is reason to believe that the classic studies of compliance completed in 1986 and 1987, the studies most frequently referred to as proof of patient poor compliance, were inadvertently designed to encourage poor compliance.20,21
More specifically, within the study of pilocarpine compliance, “Patients were instructed to use the medication as usual,” and within the study of timolol compliance, “Patients were instructed not to alter their normal use of the drug.”20,21
Therefore, both studies ignore the proven benefits of patient education on compliance within the methods of their protocol designs.25–29
Proper patient education about diagnosis and treatment is now recognized as the most successful method used in improving compliance. Therefore, by failing to educate the subjects about the proper technique and importance of treatment, the investigators inadvertently encouraged poor patient compliance within both of these studies. Finally, and most impressive of all, there is direct evidence from a well-designed study utilizing an eye drop monitor in a large population that demonstrates an excellent 96% to 98% adherence to once-daily dosing, which was present even in 2-drug patients.30
This study protocol included reminding patients they were being monitored, which could have influenced the results. Furthermore, the once-daily dosing lends itself to better compliance compared to 4 times daily or twice-daily dosing in the classic studies of compliance. Simpler dosing schedules can improve compliance as demonstrated by simply changing from 4 times daily to 3 times daily dosing.31
However, it is also possible that the increased compliance reported in this study reflects the 3 decades of research, education, and clinical efforts on the part of physicians and patients, activity that was initially stimulated by the classic compliance studies of the 1980s.20,21
However, even if we choose to assume that compliance remains a problem, it is difficult to avoid the important question, Is today’s evidence for poor compliance so compelling that we should continue to ignore the importance of ELC and NLO for 5 minutes? This query begs the related questions, What is the clinical importance of ELC and NLO for 5 minutes for clinical studies of glaucoma medications and patients’ treatments? and What clinical impact might the application of these techniques have on patient care and the integrity of clinical studies? The inclusion of these simple procedures in all treatments of experimental subjects and patients is important because it will (1) improve informed consent, (2) benefit study protocol consistency, (3) increase the value and usefulness of each clinical study, and (4) improve the therapeutic index of each of the drugs in all 5 of the major glaucoma medication groups. In other words, these improvements are important not only for further understanding the science of glaucoma treatment, but also for the ethics of informed consent relating to both medical treatment and the experimental study of glaucoma medications.
During February 2008, The Wall Street Journal
included an article on the importance of intelligible consent forms for patients.32
The article’s author emphasized the importance of a carefully crafted description of risks and benefits in simple terms for all patients and subjects treated with medications or surgical procedures. This description must include alternative treatments and a full disclosure of related risks and benefits, including how they might be increased and decreased. Therefore, the article implies that withholding an explanation of the value of NLO or ELC for 5 minutes from subjects recruited for studies of glaucoma medications does not fulfill the basic requirements of informed consent. Subjects and patients must not only be informed of the relative risks associated with treatments and procedures, but each subject must be given the opportunity to choose a less risky treatment that is likely more effective over one that is not, if there is evidence that one exists. Although every investigator and clinician may have a personal opinion as to the clinical importance of NLO and ELC for 5 minutes, it is reasonable that all investigators are obligated to share with their experimental subjects and patients a brief summary of the data that exist in the literature suggesting these techniques are of potential value. This permits the patient or subject to participate in the decision about treatment, providing an opportunity for an active role in adherence and not simply a passive role in compliance during their treatment regimen.
An excellent editorial published during 200033
describes potential “pitfalls” in studies on the efficacy and safety of glaucoma medications, pitfalls that might undermine the practice of evidence-based medicine, with the goal of improving future studies and educating readers to be critical during their review of clinical studies of glaucoma medications. Variable compliance is one of the potential problems noted that might adversely influence results in studies of medical treatments. The omission of a careful description of the technique of ELC or NLO for 5 minutes and an explanation of its value and importance during the study of glaucoma medications and during the practice of medicine guarantees variable and poor compliance. The method of eye drop administration must be carefully described within each protocol to permit each subject or patient to comply with the same regimen as other subjects to ensure consistency within the study and between studies. It would be unreasonable to advocate a less than optimum regimen. Therefore, to omit this education and description is not only the antithesis of informed consent, but it minimizes consistency within and between clinical studies. This ultimately makes the application of the study results and comparisons within the same patient and between patients difficult.
The value of any clinical study, even a study performed with great rigor and ultimately resulting in a paragon of evidence-based medicine, is minimal if the results cannot be applied to patients within clinical practice. As investigators have emphasized, at the conclusion of a well-designed study one must always ask, “Does my patient and their treatment reflect this particular study population?” If patients’ characteristics or treatments differ significantly from the clinical study, the conclusions from this study must be applied with caution or perhaps not at all to these patients.34
Unfortunately, well-trained ophthalmologists who presently advocate NLO or ELC for 5 minutes following glaucoma medications within their practices will be unable to find studies within the current literature that simulate their practice. Clearly, this shortcoming limits the usefulness of all existing studies of glaucoma medications for determining the safety and efficacy of glaucoma medications as used in these practices.
Finally, improving the therapeutic index of any drug provides a more favorable balance of efficacy and safety. Therapeutic index is defined as the ratio of the toxic dose for 50% (TD 50) of a population to the effective dose for 50% (ED 50) of the population.35
It is a statement of how selective the drug is in producing its desired effects vs it adverse effects. Because NLO or ELC for 5 minutes improves intraocular penetration of the applied drug, favoring efficacy, and minimizes systemic absorption, discouraging systemic toxicity, the omission of these simple techniques from studies of efficacy and toxicity makes the determination of an accurate and consistent therapeutic index for the medication studied difficult. Furthermore, the omission of NLO or ELC from a study protocol has major implications for both the subjects recruited for the study and the study results. To ignore the pharmacokinetic advantages of NLO or ELC for 5 minutes in studies of efficacy and safety of topically applied glaucoma medications guarantees minimal and variable intraocular absorption and maximal and variable systemic absorption, making the drug potentially less effective and more toxic for the subject or patient. In addition, the study will report an inaccurate and variable therapeutic index for the drug. This is less than optimum treatment with undesirable and potentially dangerous results.
It is interesting to anticipate what the impact of NLO or ELC for 5 minutes may have on patient care and the results of clinical studies of glaucoma medications by reflecting on past clinical studies lacking these techniques. This consideration may reduce the cost of the medical therapy of glaucoma, may help provide us with more reproducible clinical studies, and may help to clarify appropriate dosing regimens for each group of glaucoma medications.
Encouraging consistent results during clinical studies and improving the therapeutic index of a drug from any of the 5 groups (parasympathomimetics, sympathomimetics, beta blockers, topical carbonic anhydrase inhibitors, prostaglandin analogs) of glaucoma medications is always desirable. It is of additional interest to identify studies relating to each of these groups of medications in an attempt to predict the potential impact of 5 minutes NLO or ELC on each of these experimental situations. For example, the usefulness of pilocarpine is limited by 3 or 4 times daily dosing. However, there is published evidence that pilocarpine gel can be used at each bedtime with good therapeutic effect in many patients, which permits a more convenient once-daily dosing.36
The inclusion of ELC or NLO for 5 minutes within this study would have improved the effects and increased the likelihood of more patients responding with a good effect. This suspicion is consistent with the demonstration that an ointment vehicle combined with ELC increased ocular contact time 350% in normal volunteers.5
In addition, ELC or NLO for 5 minutes would make twice-daily dosing with more viscous preparations of pilocarpine more likely to be effective in patients, as suggested by the 300% increased ocular contact times for methylcellulose vehicle systems when used without blinking reported in the literature.5
The indirect-acting parasympathomimetics, which can be used once or twice daily, are less popular today because their potential systemic toxicity is greater than that of many of the newer glaucoma medications. Obviously, NLO or ELC for 5 minutes after their instillation would make them safer to use. Presently, the parasympathomimetics are infrequently used.37
If the therapeutic index of these drugs were improved and their dosing regimen simplified by proper eye drop administration, the increased use of these agents would provide another useful group for the treatment of glaucoma with a savings in cost of therapy.
The sympathomimetics include epinephrine, its related prodrug dipivalyl epinephrine, and the relatively specific α2
agonists apraclonidine and brimonidine. The use of each of these agents has been associated with clinically significant systemic side effects.38–41
Five minutes NLO or ELC decreases systemic absorption of these drugs and makes systemic toxicity from their use less likely. Furthermore, the associated increased ocular penetration would make adequate therapeutic effects more likely with lower concentrations of epinephrine. The relatively specific α2
agonists apraclonidine and brimonidine are most effective given 3 times daily, but with twice-daily dosing, they achieve 80% of their maximal pressure-lowering effect.42
The increased ocular penetrance associated with NLO and ELC for 5 minutes would allow more patients to have an adequate therapeutic effect with only twice-daily dosing. In addition, the increased ocular absorption would make a missed dose within any of these sympathomimetic regimens less important for the patient.
Oral carbonic anhydrase inhibitors, which are sulfonamide derivatives, are the most toxic group of glaucoma medications commercially available.43
They are capable of inducing any of the sulfonamide-related systemic toxicities, which include life-threatening side effects. Therefore, topically applied carbonic anhydrase inhibitors, if systemically absorbed to an excessive extent, may be capable of demonstrating some these same toxicities. Obviously, NLO and ELC for 5 minutes would help avoid this increased absorption and the associated increased blood levels. Furthermore, the European Glaucoma Study showed that topically applied dorzolamide was no different from placebo in its ability to lower intraocular pressure.44
Although a thoughtful editorial suggests the results may relate to the lack of choosing a target pressure, a substantial regression to the mean, and/or to patient dropout, NLO or ELC for 5 minutes might have influenced the results of this study.45
Dorzolamide is not absorbed particularly well by the eye compared to many drugs, and it is likely that the additional intraocular absorption following ELC or NLO for 5 minutes would have influenced the study results.
Topically applied beta blockers can be associated with significant systemic toxicity.46
For many years, many investigators have suggested that the systemic blood levels of these drugs can be minimized with ELC and NLO for 5 minutes.2,5,8,46
However, these simple techniques are never used in clinical studies of efficacy and toxicity of these sympatholytic drugs. This not only exposes experimental subjects to unnecessary risks but also provides variable data, resulting in confusion over appropriate daily dosing. For example, new formulations of beta blockers are claiming effectiveness with once-daily dosing for the first time with this group of drugs.47
However, the literature has much evidence that once-daily dosing with the existing commercially available beta blockers is frequently sufficient for a therapeutic effect in many patients, even without the use of NLO and ELC for 5 minutes.48–53
Obviously, the use of these simple techniques would make once-daily dosing effective for more patients more often and help avoid excessive systemic toxicity. Furthermore, the use of the older beta blockers, once daily with ELC or NLO, in place of newer agents will be associated with decreased cost of therapy.
In recent years, many studies have been published attempting to prove that one prostaglandin analog among the several commercially available preparations has greater efficacy or less toxicity than another does. An editorial referred to these publications as the “prostaglandin wars,” marveled over the small differences of 1 to 2 mm Hg between studies, and admitted that some of the results appear to be conflicting without a clear explanation.54
It is possible that the inconsistent approach to eye drop application from one study to another or even within the same study and the unavoidable variability associated with this lack of consistency could explain some of these puzzling variations and inconsistencies. One study not mentioned within this editorial included NLO for 1 minute.17
Even these investigators wondered, within their article’s discussion, why their results differed from others in the literature, without considering that the other studies’ unspecified, and therefore inconsistent, techniques of eye drop instillation might possibly be responsible. Furthermore, it is possible that properly administered eye drops including 5 minutes NLO or ELC in all of the published studies of prostaglandin analogs would have made greater differences in intraocular pressure more apparent in these studies.
Recently, topically applied combination preparations have been reintroduced with the hopes of simplifying patients’ therapeutic regimens.55,56
These preparations each include 2 different drugs from 2 different classifications of glaucoma medications—more specifically, a beta blocker combined with either a topical carbonic anhydrase inhibitor or a relatively specific α2
blocker provided in each combination preparation to be given 1 drop twice daily.54,55
These combination preparations are puzzling from the viewpoint of pharmacokinetics. For example, brimonidine tartrate 0.2%, usually administered 3 times daily for optimum effect, is combined with timolol maleate 0.5%, which can be effective given once daily, and provided in a single drop to be administered twice daily, resulting in an effect on intraocular pressure less than the 2 drugs given separately.56
Five minutes NLO or ELC added to future clinical studies of combination preparations can only help clarify this confusing pharmacokinetic mismatch and the apparent effects on efficacy and safety reported within the results. In addition, proper eye drop instillation should help to ensure less toxicity and a greater clinical effect with these regimens, making the combination preparations safer to use for both patients and experimental subjects.
In view of the importance of ELC and NLO for 5 minutes and the potential impact of these techniques for clinical studies and for patients during their treatment of glaucoma, it seems clear that these simple additions should be routinely described and encouraged in all clinical studies of glaucoma medications and during the treatment of glaucoma patients. This includes all private and all academic medical practices. Furthermore, all clinical studies of the efficacy and toxicity of glaucoma medications, without regard to their source of funding, should include instruction about the techniques and their potential importance in achieving an optimum therapeutic index. The fundamental ethics of informed consent requires that all patients treated and all subjects included in clinical studies should be informed of the potential value of these simple techniques and that they should be encouraged to use them as part of the informed consent process. It seems apparent that patients are demanding to be fully informed about risks and benefits of all drugs administered to them.32
They should have the opportunity to choose less risky and more effective treatments if they are available.
In addition to these educational activities, appropriate additions to and changes in the existing therapeutic routines and experimental treatment descriptions should be adopted to help ensure that NLO or ELC for 5 minutes is used. These modifications of “usual” therapeutic routines are best guided by the experimental and clinical experience reflected within the existing literature. For example, investigators have suggested that written instructions be given to patients because this will enhance their compliance.57
These written instructions might be best be included within the prescription itself so these important instructions ultimately appear on the eye drop bottle that is dispensed by the pharmacist. For example, the resulting direction for treatment would read, “Instill one drop in each eye every morning followed by 5 minutes eyelid closure.”
Also, the instructions about ELC or NLO for 5 minutes should appear on the eye drop bottle dispensed to the patient as an obvious, additional, individual colored label to emphasize the importance of the added effort. No pharmacist would dispense an ophthalmic suspension within an eye drop container without a conspicuous “Shake well” label placed securely on the bottle. This important addition ensures that the proper amounts of drug are present in each eye drop dispensed from the bottle. Therefore, it is only reasonable that the same eye drop container should have a label reading “ELC or NLO for 5 minutes” to ensure that an optimum amount of drug enters the eye from the instilled eye drop and that the drug is not excessively absorbed systemically via the nasolacrimal outflow system.
Finally, the importance of the sociologic aspects of ophthalmology has been recognized for many decades.58
Throughout subsequent years, investigators mentioned the advantages of integrating daily treatment regimens into a patient’s daily routine.26
Some advocated linking the therapeutic activity with a specific daily event.27,28
With these suggestions in mind, it is useful to anticipate every patient’s reluctance to “wasting 5 minutes” once, twice, or even 3 times daily during eye drop instillation. After recognizing and sympathizing with how tedious this activity can be, physicians can underscore the importance of the technique for an optimum therapeutic effect and avoidance of excessive toxicity. Then proceed to identify specific daily activities the patient performs and emphasize how neatly the 5 minutes of ELC will fit within the given activity. For example, a busy mother can take 5 minutes just after a child is put down for a daily nap so she can preserve her good vision to enjoy her child for years to come. A couch potato, just prior to watching a video, can take 5 minutes for ELC to ensure a continued good visual acuity, permitting the enjoyment of seeing videos for years to come. For anyone who meditates or enjoys yoga, an additional 5 minutes before or after seems like a small additional sacrifice to maintain his or her sight. Everyone should exercise daily in some manner to maintain a healthy cardiovascular system. It is only a natural extension of preventative medicine to agree to an additional 5 minutes of ELC to help ensure healthy eyes. Finally, most patients watch some television, which provides a perfect setting to include 5 minutes of ELC at the end of one program and the beginning of the next. This time interval is approximately 5 minutes, resulting from the 2 successive commercial breaks. Using this interval for ELC will help the patient to enjoy seeing television for years to come. In summary, taking 5 minutes for ELC or NLO from, or adding to, any of these routine, daily tasks is usually less ominous for the patient. In addition, it will have the added advantage of more fully informing the clinician about the patient’s capabilities and interests, improving the physician-patient relationship. Appropriate charting of a few notes relating to these activities and suggestions will permit the particular activity to be discussed during subsequent appointments, serving to confirm that the patient is incorporating this technique into his or her daily life successfully. If a physician administers the patient’s diagnostic dilating drops, this instillation period provides the perfect time to review with the patient the appropriate techniques of ELC or NLO for 5 minutes and their importance and to confirm that the patient is adhering to the regimen.
A potential obstacle for introducing NLO or ELC for 5 minutes at this particular time reflects a significant financial bias. At present, many pharmaceutical companies have major, costly programs in progress to help remedy the perceived poor compliance. These programs usually include new ophthalmic formulations, such as combination preparations, and can be associated with innovative delivery devices. The addition of ELC for 5 minutes may be viewed as an obstacle to “improved compliance in glaucoma” and therefore potentially detrimental to the compliance programs. Therefore, efforts to encourage ELC or NLO for 5 minutes might be perceived as antagonistic to the commercial efforts and ultimate success. I hope that the laudable goal of “improved compliance” currently encouraged by the pharmaceutical industry can be viewed as synergistic with the universal introduction of NLO or ELC for 5 minutes. Ideally, the selling of “improved compliance” could be emphasized as part of pursuing a greater goal of “optimum compliance,” with an “optimum regimen,” for an “optimum therapeutic index,” with hopes of achieving the ultimate goal of an “optimum therapeutic effect.” Obviously, the industry’s “thought leaders” and their cooperation with this effort will be essential for the overall success of optimum patient treatment.
In summary, the ethical and clinical importance of encouraging ELC or NLO for 5 minutes during all glaucoma treatments and within all clinical studies of efficacy and toxicity is obvious. There may be those who continue to argue that subjects and patients are not compliant with their topical treatments, and these pessimists may insist that including NLO or ELC for 5 minutes will exacerbate this compliance problem. However, it is unfair and unethical to continue to penalize all of the compliant subjects and every compliant patient because of the potential of poor compliance by others. To continue to deprive patients and subjects from this basic informed consent will simply ensure that even the compliant individuals will continue to be denied the potential advantages of these simple techniques. In addition, investigators and clinicians will continue to suffer the confusing consequences of less than optimally designed clinical studies of glaucoma medications that are inadvertently designed to provide inconsistent and inaccurate conclusions about the therapeutic index for each of the glaucoma drugs studied. Finally, it is important that patients and physicians who adhere to the appropriate methods of using eye drops have access to studies that incorporate these techniques and provide results and conclusions that can be more reasonable extrapolated to themselves.