Understand neuropathic pain treatments

ODs who treat dry eye or listen to patients complaining of eye pain are likely to encounter patients suffering from neuropathic pain. Neuropathic pain is a loss of homeostasis within the central nervous system. It was referred to in the Dry Eye Workshop (DEWS) II definition of dry eye1:

“Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.”

More from Dr. Swartz: How to handle dry eye follow-up visits

Other causes

ODs may also encounter patients suffering from neuropathic pain secondary to diabetes and herpes zoster infection, as these are the more common causes of the condition. While the prevalence of chronic neuropathic pain in the general population is approximately 6.9 to 10 percent, about 34 percent of patients with diabetes mellitus suffer from it.2

Nerve damage from diabetes or herpes infection has been shown to alter afferent neurons’ neurophysiological properties.3 When damaged axons degenerate and then regenerate, heightened sensitivity to afferent stimuli results. This manifests as spontaneous pain, including thermal hyperalgesia. This is perception of pain from stimuli normally perceived as “warm” or “cool.” This is important to note if you tell the patient to put their drops in the refrigerator. Increased and chronically elevated ectopic activity occurs via voltage-gated neuronal sodium channels and transient receptor potential channels. These channels are modulated using drugs such as carbamazepine, lidocaine, and capsaicin to reduce pain.4

Central sensitization

“Central sensitization” is a new term referring to neuronal hyperexcitability found mainly in the spinal cord. Clinically, this manifests as intensified spontaneous pain and hyperalgesia, mechanical allodynia, or pain due to a stimulus that does not normally provoke pain. For example, a patient may find using topical eye drops causes pain and refuse to use them. Drugs such as gabapentin (Neurontin), pregabalin (Lyrica), and opioids may modulate central sensitization.3 Inhibition of the reuptake of neurotransmitters from the synaptic cleft occurs using anti-depressant drugs.

Chronic pain treatments may include standard pain control agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotics. Increasing concerns over cardiovascular and renal risk from NSAIDs as well as their lack of efficacy in neuropathic pain and concerns with opioid addiction have resulted in increasing non-systemic topical alternatives.5 Topical agents block or inhibit the local or peripheral pain pathway with minimum systemic uptake. Topical analgesic agents avoiding systemic adverse effects and drug-drug interactions, a common challenge with systemic drug administration. Topical agents are preferred for elderly patients who often take multidrug therapies.6 In 2009, the American Geriatric Society recommended topical pain controls for safety.7 However, only 27 percent of physicians prescribe compounded topical medications for pain relief.5

The U.S. Food & Drug Administration (FDA) approved 8 percent capsaicin crème and 5 percent lidocaine patches to treat postherpetic neuralgia. Clinical studies were conducted to determine efficacy of topical ketamine, clonidine, gabapentin, baclofen and phenytoin, either alone or in combination.8 These can be compounded by a local pharmacy. If interested, ODs can contact their local compounding pharmacy to see what is available and discuss typical costs and reimbursement to better educate patients and community practitioners.

Systemic treatments include pregabalin, gabapentin, and anti-depressants.9,10 Pregabalin (Lyrica, Pfizer) and gabapentin (Neurontin, Pfizer, NY, NY) are common treatments for nerve pain. Side effects include severe allergic reactions, blurred vision, amblyopia, visual field constriction, diplopia, fatigue, headaches, xerostomia, vertigo, and twitching.11 The Drug Enforcement Administration (DEA) has classified both Neurontin and Lyrica as controlled substances.

Both gabapentin and pregabalin are similar to the amino acid leucine and undergo facilitated transport across cell membranes through L-amino acid transporters. Both are structurally similar to gamma-aminobutyric acid, an inhibitory neurotransmitter within the central nervous system. They may bind to voltage-gated calcium channels in the central nervous system (CNS), which may decrease neurotransmitter release throughout the CNS.12 Incomplete absorption of gabapentin is limited to the small intestine while pregabalin is absorbed completely by both small intestine and ascending colon. Gabapentin is more slowly absorbed while pregabalin is quickly absorbed, three times faster than gabapentin, reaching peak concentration 1 hour after ingestion. Gabapentin’s bioavailablity is more variable (20 to 30 percent) versus 10 to 15 percent with pregabalin. Drug elimination occurs via the kidney.

Antidepressants

Antidepressants are increasingly used for neuropathic pain. While it may be assumed that these patients are more likely to suffer from depression and often do, direct action upon pain has been demonstrated. Amitriptyline is a tricyclic antidepressant often used due to its effect on neurotransmitters and serotonin levels. While often referred to as its previous trade name of Elavil (Sandoz), it is available only generically. Side effects include headache, gastrointestinal (GI) upset, blurred vision, nausea, and sleepiness, so it is often taken at bedtime.

Other antidepressants have fewer side effects and can be taken in the morning. Serotonin-norepinephrine reuptake inhibitors (SNRI) are thought to be more effective for nerve pain than selective serotonin reuptake inhibitors (SSRI). Duloxetine (Cymbalta, Eli Lilly) is a SNRI approved for depression, anxiety, neuropathy, fibromyalgia, and chronic muscle/bone pain and is used off label for central sensitization. SSRIs (Prozac, Celexa, Luvox, Zoloft, Paxil) may have fewer side effects but may not be as effective. Mechanism of action of antidepressants is not fully understood but may increase neurotransmitters in the spinal cord to reduce the pain signals and central perception of pain.

All of the above oral medications listed may increase suicidal ideation and must be properly monitored for safety.

Dexmedetomidine

A new player to the game is dexmedetomidine, (Precedex, Pfizer) an α2 agonist. This highly selective activator targets the α2A receptor acting within the nucleus. It produces a sedative and hypnotic effect. Its action on the spinal cord can produces analgesia, while playing a role in inhibiting sympathetic excitation in both the peripheral and CNS.13 Dexmedetomidine could reduce the release of catecholamines in nerve endings by reducing the activity of the sympathetic nervous system, reducing neuronal damage.14

Nonpharmacological treatments are also being used to reduce pain in chronic pain patients. Alternative treatments which may be beneficial in more severe cases involving more than just the eye or face include acupuncture, transcutaneous electrical nerve stimulation (TENS), transcranial magnetic stimulation (TMS), andtranscranial direct current stimulation (tDCS). Acupuncture has been found to be more effective than sham treatments for diabetic neuropathy, bell’s palsy, and carpel tunnel, but less conclusive when the neuropathy was idiopathic.15 Meta-analysis suggests proof of effectiveness is inconclusive.16 This treatments may require frequent visits 2-3 times per week for 4 to 6 weeks, for acute pain.

TENS units typically use adhesive electrodes applied directly to the skin to deliver pulsed electrical stimulation.17 The electrical stimulation can be modified based upon frequency, intensity and duration, and may be combined with heat or cold to enhance the effect. While one study concluded the effects of TENS versus sham treatment may not be significantly different, the cost and risk of this treatment is low enough to warrant therapeutic trials in my opinion.17 Note that it should not be used in patients with a pacemaker, and adhesive pads should not be applied near or over eyes or mouth, front or side of neck, or on the head. This technology is FDA approved. While this may not be a great method to address ocular or facial pain, it may be an alternative for generalized chronic pain in your patients.

Transcranial magnetic stimulation (TMS) creates analgesia by stimulating the primary motor cortex.18 A strong but brief electrical current is passed through an insulated wire coil placed on the skull, generating a transient magnetic field. This creates a secondary current in the brain that is capable of depolarizing neurons when the coil is held over the subject’s head.19 The targeted pulsed magnetic field treatment analgesic effect may be due to increased neurotransmitters at the nerve junctions, excitation of horizontal fibers, modulation of deeper and remote brain structures, and the mediation of various neurotransmitters implicated in the pain pathway.20 In short, TMS is a neurostimulator. This treatment is FDA approved for major depression. Treatment visit schedules and exact dosing regimens vary.

The tDCS technique involves a portable, wearable brain stimulant that delivers a low electric current (1 to 2 mA). It changes neuronal firing and strengthens synaptic transmission between neurons by augmenting synaptic plasticity to retrain the nervous systems, but is currently not FDA approved.3 This can be performed near the supraorbital area. It is easy to combine with cognitive behavioral therapy and is a neuromodulator rather than a stimulator.21

Clinical testing

The assessment of ocular surface pain is typically by patient report, but a proparacaine challenge test and corneal esthesiometry may be used. Topical 0.5% proparacaine allows differentiation of central and peripheral sources of pain. Instilling 1 drop into each eye will resolve peripheral pain but has no effect on central sensitization.22 If the drop partially relieves the pain, the etiology would be considered mixed or combined. I often use this as a method to demonstrate to the patient why their pain persists despite improvement in clinical signs.

Mechanical nociceptor response can be assessed by direct somatosensory measurement using esthesiometry. The Cochet-Bonnet contact esthesiometer and the Belmonte noncontact esthesiometer are examples. Increased sensitivity as well as reduced sensitivity can direct treatment. Because I do not own either of these instruments, I use dental floss to touch the cornea and compare the responses between the two eyes.

Confocal microscopy can be used to assess corneal nerves, but this technology is not commonly found and may be unavailable. Laser scanning in-vivo confocal microscope (IVCM, Heidelberg Engineering) is a non-invasive, high-resolution device that is capable of visualization of corneal structures at the cellular level.

End goals

The main goal of neuropathic pain treatment is not resolution but rather improvement in quality of life. Realistic goals for the treatment of neuropathic pain include reduction of pain by more than 30 to 50 percent, improved sleep and quality of life, maintenance of social activities and relationships, and recovery and maintenance of the ability to work.2

Patients must be educated that the pain will not go away, and a team approach is required. If not discussed, patients may not return to your care out of frustration.

References

1. Craig JP, Nelson JD, Azar DT, Belmonte C, Bron AJ, Chauhan SK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017;15(3):276-283.

2. Binder A, Baron R. The Pharmacological Therapy of Chronic Neuropathic Pain. Dtsch Arztebl Int. 2016 Sep 16;113(37):616-625.

3. Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010;9(8):807-19.

4. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin R, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173.

5. Choi E, Nahm FS, Han WK, Lee PB, Jo J. Topical agents: a thoughtful choice for multimodal analgesia. Korean J Anesthesiol. 2020;73(5):384-393.

6. Pickering G, Lucchini C. Topical Treatment of Localized Neuropathic Pain in the Elderly. Drugs Aging. 2020;37(2):83-89.

7. American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc. 2009;57(8):1331-46.

8. Knezevic NN, Tverdohleb T, Nikibin F, Knezevic I, Candido KD. Management of chronic neuropathic pain with single and compounded topical analgesics. Pain Manag. 2017;7(6):537-558.

9. Gierthmühlen J, Baron R. Neuropathic Pain. Semin Neurol. 2016;36(5):462-468.

10. Zilliox LA. Neuropathic Pain. Continuum (Minneap Minn). 2017;23(2):512-532.

11. Bekkelund SI, Lilleng H, Tønseth S. Gabapentin may cause reversible visual field constriction. BMJ. 2006;332(7551):1193.

12. Fudin J. How Gabapentin Differs From Pregabalin. Pharm Times. Available at: https://www.pharmacytimes.com/contributor/jeffrey-fudin/2015/09/how-gabapentin-differs-from-pregabalin. Accessed 1/21/21.

13. Zhao Y, He J, Yu N, Jia C, Wang S. Mechanisms of Dexmedetomidine in Neuropathic Pain. Front Neurosci. 2020;14:330.

14. Wu W, Yu C, Chen J, Yang Q. Fluorometric detection of copper ions using click chemistry and the target-induced conjunction of split DNAzyme fragments. Int J Environl Analytical Chem. 2020. doi: 10.1080/03067319.2019.1636977.

15. Dimitrova A, Murchison C, Oken B. Acupuncture for the Treatment of Peripheral Neuropathy: A Systematic Review and Meta-Analysis. J Altern Complement Med. 2017;23(3):164-179.

16. Wang Y, Li W, Peng W, Zhou J, Liu Z. Acupuncture for postherpetic neuralgia: Systematic review and meta-analysis. Medicine. 2018 Aug;97(34):e11986.

17. Gibson W, Wand BM, O'Connell NE. Transcutaneous electrical nerve stimulation (TENS) for neuropathic pain in adults. Cochrane Database Syst Rev. 2017 Sep 14;9(9):CD011976.

18. Hamid P, Malik BH, Hussain ML. Noninvasive Transcranial Magnetic Stimulation (TMS) in Chronic Refractory Pain: A Systematic Review. Cureus. 2019 Oct 29;11(10):e6019.

19. Nicola Nardelli P, PhD. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS). AgliotiLab. Available at: https://agliotilab.org/facilities/transcranial-magnetic-stimulation-tms-and-transcranial-direct-current-stimulation-tdcs. Accessed 1/19/21.

20. Goudra B, Shah D, Balu G, Gouda G, Balu A, Borle A, Singh PM. Repetitive Transcranial Magnetic Stimulation in Chronic Pain: A Meta-analysis. Anesth Essays Res. 2017 Jul-Sep;11(3):751-757.

21. Pinto CB, Teixeira Costa B, Duarte D, Fregni F. Transcranial Direct Current Stimulation as a Therapeutic Tool for Chronic Pain. J ECT. 2018 Sep;34(3):e36-e50.

22. Dieckmann G, Goyal S, Hamrah P. Neuropathic Corneal Pain: Approaches for Management. Ophthalmology. 2017;124(11S):S34-S47.