Neuropathic Ocular Pain: An Important Yet Underevaluated Feature of Dry Eye

A Galor; RC Levitt; ER Felix; ER Martin; CD Sarantopoulos


Eye. 2015;29(3):301-312. 

In This Article

Neuropathic Ocular Pain and Implications for Dry Eye Treatment

Understanding the neuropathology of dry eye will be important in developing alternative approaches to treating the disorder. The above data suggest that patients with evidence of neuropathic pain and central sensitization may be the patients who continue to have dry eye symptoms while on current therapies. In these patients, a multimodal approach may be more beneficial including treating ongoing ocular surface damage with ocular surface protection and anti-inflammatory agents, and ocular sensory apparatus dysfunction with anti-neuropathic pain treatment. Other untested therapies for dry eye include glial inhibitors, anti-inflammatory cytokines, and/or NMDA receptor inhibitors, all of which have been shown to attenuate facial pain-mediated via central mechanisms potentially common to those of dry eye.[111–113] With many agents available to treat neuropathic pain, research is needed to understand the role, if any, of these agents in treating ocular sensory apparatus dysfunction associated with dry eye.

Systemically, there is still controversy on the best management algorithm for patients with neuropathic pain, and this may vary depending on pain severity, underlying pathophysiology (eg, postherpetic neuralgia (PHN), diabetic polyneuropathy), and systemic comorbidities. Our general algorithm for nonocular neuropathic pain includes the use of the novel alpha 2 delta ligand antiepileptics (eg, gabapentin; pregabalin) as first-line agents, serotonin–norepinephrine reuptake inhibitors (eg, duloxetine; venlafaxine) as second-line agents (or as first-line agents in certain patients, such as those with concomitant musculoskeletal pain or with concomitant depression), and tricyclic antidepressants (eg, nortriptyline, amitriptyline) as third-line agents because of their side effects. Combination therapies (antiepileptics and antidepressants) are also frequently used in cases where monotherapy provides only partial relief. In addition, depending on pain severity, opiods (eg, tramadol) can be used in selected patients, in conjunction with the therapies above. Topical agents (lidocaine and capsaicin) are also used even as first-line therapies or as parts of multimodal therapies or in specific conditions such as in the treatment of PHN. Short courses of corticosteroids or other anticonvulsants (topiramate, lamotrigine, carbamazepine, and so on) may be used in specific circumstances. More aggressive measures (eg, nerve blocks, spinal cord stimulation) are used in patients who have failed conservative therapy or if there are specific indications, such as for neuropathic pain localized in the area of innervation of a specific nerve and related to neuropathy of that nerve (eg, sympathetically maintained arm pain treated with stellate ganglion block). In addition, delivering all these therapies in a multidisciplinary approach is important. Therapies such as cognitive, behavioral, and physical therapy should be considered in most patients with chronic neuropathic pain.

Limited data are available to suggest whether a similar approach should be utilized in appropriately selected dry eye patients. One study that evaluated topical analgesics found that one drop of diclofenac decreased discomfort to high-intensity mechanical, chemical, and thermal stimuli (applied with the Belmonte aesthesiometer) in six healthy volunteers. Interestingly, in the same study, flurbiprofen was not found to have a similar effect.[114] This differential effect may be because of the fact that diclofenac, in addition to its antiprostaglandin effects, also acts as a neuronal potassium (including KATP) channel opener.[115,116] Activation of neuronal potassium currents suppresses primary afferent neuronal excitability and firing, and attenuates increased excitatory neurotransmitter release and synaptic transmission, thus resulting in an antiallodynic and antihyperalgesic effect.[115,117,118]

In a similar manner, gabapentin and pregabalin, modulators of both peripheral central neuronal activity, have been shown to decrease postoperative pain after photorefractive keratectomy in prospective, randomized, placebo-controlled studies.[119,120] Furthermore, some current dry eye treatments, such as omega 3 and doxycycline (an MMP inhibitor), likely have a direct effect on nerve function along with secondary effects by improving the ocular surface environment.[121–123] Further studies are needed to assess whether topical and/or centrally acting neuromodulators have a role in the treatment of dry eye patients with features of NOP.