Neuropathic Pain: How to Diagnose and How to Treat. A Primer For Eye Surgeons

Neuropathic pain results from damage to or dysfunction of peripheral nerves due to a variety of factors, such as the ones below.

Causes of Neuropathic Pain:
1. Idiopathic: meaning know knows why
2. Previous virus or bacterial infection
-Herpes Zoster: this is well known as Post Herpetic Neuralgia
3. Metabolic disorder
-Diabetes: this is well known as peripheral neuropathy
-Diet: some suspect Gluten is triggering nerve inflammation in some patients
4. Toxins
-Chemotherapy: well known to cause potential nerve damage
5. Severe ischemic injury:
-Post Stroke: patients can have pain after loss of oxygen to area and in particular the brain.
6. Disc Herniation:
-This is well known to cause chronic pain that can radiate down the leg, arm, back area, etc.
7. Post Dental Surgery or procedure or dental nerve root infection or inflammation
-patients can have a chronic orofacial pain syndrome
8. Trauma:
-Trauma to an area is well known to potentially cause a chronic pain syndrome. 
9. Inflammation
-Autoimmune disease: in some patients blood work will confirm this as the cause of chronic pain, but in other patients we are seeing NORMAL blood work but positive biopsies for Sjogren’s syndrome for instance.Likely there is sub-clinical inflammation that is causing a chronic pain syndrome in patients who are the spectrum of early autoimmune disease or an unidentified inflammatory condition. 
The frustrating issue is that despite over 50 years of research, there are not proven treatments to cure neuropathic pain which has been classified as a chronic and incurable disease (Ref 1).
For eye surgeons who are used to doing “just eye surgery,” the tsunami of chronic eye pain if shocking many of us who find we are unable to “just do a procedure” and get rid of the pain. Chronic pain is more complex and requires a team of doctors to remove the cause of the pain or control the pain in patients in whom we cannot find or cure the underlying reason. 
How do we determine if there is a chronic pain condition?
1.  Pharmacological tests conducted by a pain specialist can include the following:
A. A saline control lidoocaine
IV infusion to test for neuropathic pain
(local anesthetic sodium channel blockade)
and phentolamine infusion to test for
sympathetically maintained pain (sympathetic
blockade): but this has been called into question in Reference 2 below as not really helpful…
B. A trial of antidepressants
and/or anticonvulsants: 
C. Quantitative sensory testing provides
a standard set of validated neurosensory
measures to determine the presence of
D. Facial thermography: highly
selective in thermal accuracy (100%), with
results showing the affected (painful) side
of the face to be hotter than the nonpainful
side (range 0.4 to 3.1ºC, mean=1.1 ± 0.8).22

E. Magnetic
resonance spectroscopy has shown that
patients with trigeminal neuropathy have a
significant reduction in the N-acetylaspartate
to creatine ratio, a biochemical marker of
neural viability, in the region of the thalamus
that also displays grey matter volume loss: but this is still experimental

Treating or “Managing” Neuropathic Pain 

As with all disease process, most eye surgeons and doctors prefer or should prefer to try natural remedies first. 

Natural compounds have been used in mild neuropathic pain with varying results. 
Here are some options that have been used:

1. Topical capsaicin cream
(0.025% and 0.075% capsaicin concentration; 

TGA indicated for the treatment of postherpetic

The cream is applied for
five to 10 minutes twice daily for eight weeks
to the painful oral mucosa. The capsaicin
can cause an initial burning sensation in the
first few days; this can be reduced by pretreating
the mucosa with topical anaesthetic
mouthwash (lidocaine 1%).
There is some evidence for using 

ginger (containing gingerol) applied topically can work as antineuropathic.

3. Palmitoylethanolamide,
an active compound
from egg yolk and peanut oil, being effective
in the treatment of neuropathic pain.31

4. For nerve compression:
-acupuncture, massaging, physical therapy, electric heat massagers have been used to help. 

5. For Dry Eye Related Neuropathic pain:
-lid hygiene, warm compresses, non-preserved artificial tears, blinking exercises, lid massaging, high dose Omega 3, moisture chamber goggles, humidifier, anti-inflammatory diets, Lipiflow, Intense Pulse Light, Autologous Serum, Platelet Rich Plasma, –all try to noninvasively and naturally relieve pain. If these do not work or a patient does not mind using drugs, we try Xiidra, Restasis, Doxycycline pills, Punctal Plugs, Testosterone Cream, True Tear, Meibomian gland probing and expression, lid tarsorrhaphy if dryness is causing corneal abrasions or melts.

6. For chronic dental pain: a dental stent or mouth guard can be constructed by a dentist. 

Prescription Medicines for Neuropathic Pain:

1. First-line medicines:
1) Antidepressants: 
A. Tricyclic Antidepressants:
-can start with 25 mg for neuropathic pain: low doses ususally give less side effects, such as dry mouth, drowsiness, dry eye, weight gain.
If a patient is having terrible pain that he or she cannot sleep, we first get the pain under control before worrying about the worsening dry eye these medications can cause. It can be a Catch 22 with these medications but is important to find a non-narcotic to get rid of the pain to allow one to sleep. Lack of sleep or insomnia also worsens dry eye. 
a. Amitriptyline
b. Nortriptyline
c. Dothiepin

B. Selective serotonin and norepinephrine reuptake inhibitor (SNRI)
a. Duloxetine 
b. Venlafaxine

2) Anticonvulsants:
a. Gabapentin (aka GABA)
b. Pregabalin
c. Carbamazepine: this is used in  trigeminal neuralgia: another reported rare risk is below
d. Sodium valproate (aka oxcarbazepine: usually prescribed by neurologists): this is used off label for neuropathic pain

3) 5% lidocaine patches over pain area, such as in post herpetic neuralgia

2. Second-line medicines:
1) Opioids including tramadol and morphine: which we try to avoid at all costs as they are very addictive. 

3. Other: rarely used;
a. For eye pain:
Topical application of naltrexone hydrochloride (NTX), an opioid antagonist: has been used in Ref 3 below, but it is hard to get. 
Low Dose Naltrexone 1.5mg-4.5mg per day is sometimes used for Neuropathic Eye Pain, but side effects can limit effectiveness: side effects can include nightmares, insomnia, nausea. 

b. For other neuropathic pain: Mexiletine, a nonselective sodium channel blocker used for cardiac arrhythmias

b.  Stellate ganglion blocks with bupivacaine or guanethidine

For Severe Breakthrough Pain: Recommend hospitalization under the care of a pain clinic team for close supervision of use of IV opioids, antineuropathics and NMDA antagonists (ketamine).

Psychological and Behavioral
Management of Pain:

Psychological treatments are crucial for
many patients with chronic pain. Anxiety and depression is
common in patient struggling with chronic pain. Psychiatric diagnoses have been reported in
72% of patients with chronic pain conditions. The presence
of negative thoughts of anxiety, despair, depression increases pain intensity in patients
with acute postoperative pain.

Maintaining physical activity, social activities (especially with loved ones and friends), and even maintaining work schedules with its set order and plan of life likely helps prevent full focus on the chronic pain condition: though trying to limit electronic screen time or have more breaks is recommended.

Cognitive behavioral therapy can be helpful in pain rehabilitation.

Thus a recommended Overall Plan with treating chronic pain conditions could be:
1.  Explaining pain cause as best as possible
2. Try Natural treatments including prayer, meditation, relaxation, mindfulness
3. If natural options do not help, try Rx options under careful observation for side effects
4. Discuss and planned physical activity with pain specialist
5. Discuss psychological distress with PCP, MD, or pain specialist. 
6. Support restoration of social roles as best as can. 
7. Encourage active self-management
strategies to help wean
patients off medications over time.

1. A.B. O’Connor, R.H. Dworkin

Treatment of neuropathic pain: an overview of recent guidelines
Am J Med, 122 (2009), pp. S22-S32

2. Review Article  |   August 2009

Intravenous Infusion Tests Have Limited Utility for Selecting Long-term Drug Therapy in Patients with Chronic Pain: A Systematic Review
Steven P. Cohen, M.D.Shruti G. Kapoor, M.D., M.P.H.James P. Rathmell, M.D.
 Author Affiliations & Notes
Anesthesiology 8 2009, Vol.111, 416-431. doi:10.1097/ALN.0b013e3181ac1c47

INTRAVENOUS analgesic infusion tests have been used in a variety of contexts for almost 20 yr to facilitate the management of patients with chronic pain.1–4 Initially designed as diagnostic tools to help elucidate the cellular mechanisms of nociception,3,5 these brief and uncomplicated tests have experienced a recent resurgence as prognostic instruments used to predict analgesic response to specific classes of drugs. In the past two decades, intravenous formulations of phentolamine,6 lidocaine,7,8 several opioids,9–11 propofol,12 and ketamine,13 have been used in various contexts to attempt delineation of pain mechanisms and prediction of subsequent response to oral analogues. Analgesic infusion tests have also been used to predict response to surgical interventions, specifically motor cortex stimulation.14–16 

The rationale behind use of intravenous infusion tests is that they can quickly predict those patients who will respond to a subsequent course of oral medication, thereby eliminating the time and expense of a lengthy oral medication trial and reducing the risks of adverse effects associated with ineffective drug treatment. An infusion test can serve as a prognostic tool for a treatment associated with significant risk, such as implantable analgesic devices or oral opioid therapy.14,17 In these situations, a screening test with a high specificity and positive predictive value may prevent patients unlikely to respond to a high-risk therapy from receiving an unwarranted treatment. Intravenous infusion tests can also provide valuable information when the definitive treatment provides considerable relief to only a small subset of patients. An example is the use of an intravenous lidocaine infusion to predict response to mexiletine, a drug associated with few responders (a high number needed-to-treat) and significant side effects (a low number-needed-to-harm).18 In this circumstance, patients being considered for oral mexiletine might benefit from an intravenous screening test with a high sensitivity and negative predictive value, which would minimize the chances for a false-negative result, thereby identifying the patients most likely to respond to treatment with mexiletine. For an over-the-counter drug like dextromethorphan, which may offer significant benefit to a select group of patients but is not usually covered by third-party payers,19 a quick and simple screening test with a high observed agreement could help identify the patients most likely to respond to this therapy. Other potential advantages of intravenous infusion tests include elucidating pain mechanisms that may guide development of future treatments, establishing target doses for drugs with a wide therapeutic index, and predicting side effects in those patients inclined to experience them.

Despite the growing body of literature on intravenous infusion tests, there has been no previous attempt to systematically review the available evidence. The purpose of this article is to provide readers with an evidence-based framework outlining the rationale and existing literature on previously described intravenous infusion tests, along with informed conclusions regarding the validity and predictive value of these tests.

There are limited data available examining the use of intravenous analgesic testing. For all of these tests, there is simply not enough available evidence to make definitive conclusions regarding their predictive value. On the basis of the available evidence, this systematic review demonstrates that intravenous analgesic tests have limited overall clinical utility in selecting patients for long-term treatment with specific oral analgesic agents.

3.  2009 Nov;127(11):1468-73. doi: 10.1001/archophthalmol.2009.270.

Dry eye reversal and corneal sensation restoration with topical naltrexone in diabetes mellitus.



To determine if topical application of naltrexone hydrochloride (NTX), an opioid antagonist, restores tear production and corneal sensation in rats with diabetes mellitus.


Type 1 diabetes was induced with streptozotocin in rats. Tear production was measured by the Schirmer test, and corneal sensitivity, by an esthesiometer. Eye drops of 10(-5)M NTX or sterile vehicle were administered either once only or 4 times a day for 1 or 5 days; a single drop of insulin (1 U) was given once only.


Dry eye and corneal insensitivity were detected in the diabetic rats beginning 5 weeks after streptozotocin injection. One drop of NTX or 4 times a day for 1 or 5 days reestablished tear production and corneal sensitivity within 1 hour of administration. The reversal of dry eye lasted for up to 2 to 3 days depending on drug regimen, but restitution of corneal sensation lasted for 4 to 7 days. Topical application of 1 eye drop of insulin restored corneal sensitivity within 1 hour and lasted for at least 2 days. In contrast, 1 eye drop of insulin did not increase tear production at 1, 24, or 48 hours compared with diabetic animals receiving sterile vehicle.


Topical treatment with NTX normalizes tear production and corneal sensitivity in type 1 diabetic rats.


Topical application of NTX to the ocular surface may serve as an important strategy for treating dry eye and corneal anesthesia in diabetes. Its effect, if any, in other forms of decreased corneal sensitivity and/or dry eye should be investigated.

Rare risk with chronic carbamazepine

. 2016 Oct; 3: 31–33.
Published online 2016 May 28. doi:  10.1016/j.ajoc.2016.04.010
PMCID: PMC5757391
PMID: 29503903

Pediatric conjunctival lymphoma associated with oral carbamazepine use



To report a case of a pediatric patient diagnosed with conjunctival lymphoma associated with oral carbamazepine use.


An 11-year-old boy who presented with 5-month history of a small nasal conjunctival mass in the left eye that failed therapy with topical corticosteroids. Upon excision and molecular analysis, diagnosis of Follicular Lymphoma was favored. The patient was healthy and did not have any known risk factors except for a history of epilepsy treated with systemic carbamazepine.


We report a case of a rare childhood conjunctival lymphoma. Conjunctival lymphomas may masquerade as chronic conjunctivitis, or scleritis that fail therapy with topical corticosteroids. Furthermore, our patient did not have any known risk factors such as old age, systemic lymphoma or immunosuppression. The patient did have a history long-term use of systemic carbamazepine. This is to our knowledge the first case conjunctival lymphoma that may be associated to the use of carbamazepine.
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