“Every nerve that can thrill with pleasure, can also agonize with pain.”
– Horace Mann

Neuropathic (Nerve) Pain

Assessment and Management

“Neuropathic” or nerve pain is:

“NP is usually chronic, defined as persistent or recurrent increased pain sensitivity or spontaneous pain stemming from a lesion, disease or dysfunction of the peripheral or central nervous system.”

 

The somatosensory system is the part of the sensory system concerned with the conscious perception of touch, pressure, pain, temperature, position, movement, and vibration, which arise from the muscles, joints, skin, and fascia.

 

 

It is recommended to first read the following sections to become familiarized with some of the terms and concepts related here:

 

see also:

 

Medications for Nerve Pain:

 

CAM Alternatives for Neuropathic Pain

 

For specific agents used in the treatment of neuropathic pain, see below.

 

 

Definitions and Terms Related to Pain

 

Key to Links:

  • Grey text – handout
  • Red text – another page on this website
  • Blue text – Journal publication

 

.

Prevalence of Neuropathic Pain (Nerve Pain)

According to an Institute of Medicine report released in 2011, one in three Americans experiences chronic pain—more than the total number aected by heart disease, cancer, and diabetes combined. In Europe, the prevalence of chronic pain is 20-30%. These statistics are not expected to improve. Around 15-25% of people with chronic pain are currently thought to have neuropathic pain. Studies have found that neuropathic pain is associated with a greater negative impact on quality of life than nociceptive pain.  

Understanding Neuropathic Pain

“Neuropathic” or nerve pain was recently redefined as “pain caused by a lesion or a disease of the somatosensory system.”

 

The somatosensory system is the part of the sensory system concerned with the conscious perception of touch, pressure, pain, temperature, position, movement, and vibration, which arise from the muscles, joints, skin, and fascia.

 

Nerve pain is usually experienced as burning, electric, shock-like, tingling or sharp and may start at one location and shoot, or “radiate” to another location (like sciatica). Neuropathic pain can be “peripheral,”  (outside the central nervous system),”  like carpal tunnel pain or “central,” originating in the spinal cord or brain.  Neuropathic pain is often a disease process, not simply the symptom of one.

 

Mechanism of Neuropathic Pain

Changes in Nerve Transmission

It is believed that neuropathic pain results from a multitude of mechanisms which contribute to the persistence of pain. When an injured nerve, such as might occur with a herniated disc injury to a nerve root causing “sciatica,” the persisting pain signals from pain receptors results in structural changes making the nerve hypersensitive, causing it to transmit pain signals excessively. The structural changes include changes in the calcium and/or sodium channels in nerves that allow for transmission of nerve signals. These channels are where medications such as gabapentin (Neurontin), pregabalin (Lyrica) and topiramate (Topamax) work to reduce nerve pain.

See: Gabapentin (Neurontin) & Pregabalin (Lyrica)

 

Changes in Nerve Receptors

After nerve injury, dorsal root ganglia exhibit decreased expression of μ opioid (mu-opioid) receptors and secondary spinal neurons become less responsive to opioids. (By contrast, inflammation may result in an increase in the number and affinity of opioid receptors, thereby enhancing the efficacy of opioids).  This may explain why patients with chronic neuropathic pain require higher doses of opioids than those with acute and chronic nociceptive pain.

 

Other changes related to nerve injury contributing to neuropathic pain include activation of nerve receptors, such as the NMDA receptors, which have been shown to increase nerve pain as well as opioid tolerance and hyperalgesia.  Blocking these NMDA receptors is another way in which nerve pain is treated.

 

For more information, please see Neurobiology of Opioids).

 

Neuro-Inflammation

In response to nerve damage, there is also a release of proinflammatory cytokines (proteins and other chemicals) in the area of nerve injury. Recent research suggests these inflammatory cytokines come from glial cells. Glia cells are specialized immune cells that make up the supportive network that surrounds nerve cells in both the peripheral and central nervous system, making up about 70% of the central nervous system.

 

Glial cells (including microglia and astrocytes) play an important role in the maintenance and repair of healthy nerves. Microglia are activated within 24 hours of nerve injury, and astrocytes follow shortly thereafter, with activation persisting for up to 12 weeks. Glial cells undergo structural and functional transformation after injury, with astrocytes releasing a host of different pronociceptive (pain-inducing) factors, such as prostaglandins, excitatory amino acids, and cytokines. This neuro-inflammatory process has been shown to be related to oxidative stress and inc
reased production of free radicals including superoxide. It has been suggested that reduction of this neuro-inflammation may be achieved by enhancing mitochondrial activity with use of NRF2 activators to stimulate sirtuins and facilitate production of natural antioxidants including superoxide dismutase.

  For more information, please see Mitochondrial Dysfunction, Antioxidants and NRF2 Activators).

 

This pro-inflammatory environment begins at the site of nerve injury but spreads to more distant sites, ultimately contributing to persisting pain states. Growing evidence also supports the role of glial cells in central sensitization as well as the development of neuropathic pain. That is, increased sensitivity of nerve cells of the dorsal horn at in the spinal cord causes lower pain thresholds and increased excitability within the ascending system of the pain pathway, resulting in stronger pain signals to the brain.

 

Because of this, research now focuses on glial cells as possible targets for controlling neuropathic pain and central sensitization. Preliminary studies suggest that medications that alter the activity of glial cells may reduce the nerve pain associated with peripheral neuropathy and the pain of fibromyalgia. Minocycline (200mg twice/day) is getting attention in this regard as well as palmitoylethanolamide (PEA).

For more information, please see “Neurobiology of Pain” and “Neurobiology of Opioids.“

 

Changes in Descending Pain Inhibition Pathways

Descending nerve pathways from the brain to the dorsal root in the spinal cord have an inhibitory effect on pain. In chronic pain states, these descending pathways become suppressed, leading to an increase in perception of pain. The inhibitory transmitters involved in these pathways include norepinephrine (noradrenaline), serotonin, dopamine, and endogenous opioids. These  neurotransmitters  play many roles that affect pain, mood, and sleep, which may partially explain the higer rates of depression, anxiety, and sleep disturbances in pain patients. These descending pathways and neurotransmitters are the site of activity of some of the medications used to treat neuropathic pain including the SNRI antidepressants duloxetine (Cymbalta) and milnaciprin (Savella) as well as some opioids including tramadol (Ultram), tapentadol (Nucynta), levorphanol and methadone).

For more information, please see “Neurobiology of Pain” and “Neurobiology of Opioids.“

 

Diagnoses Associated with Neuropathic Pain

Statistically, the most common neuropathic pain is diabetic peripheral neuropathy, a condition that commonly causes burning or tingling pain in the extremities and affects 30% or more patients with diabetes. The second most common cause is the shingles (post-herpetic neuralgia). Other common conditions include cancer-related pain, spinal cord injury, reflex sympathetic dystrophy, multiple sclerosis, HIV, trigeminal neuralgia, carpal tunnel syndrome, and post-stroke pain. Arthritis is also thought to have a component of neuropathic pain as well. Sciatica, a term often misused or poorly defined, is also a common neuropathic pain when a nerve root in the lumbar spine is damaged or compressed resulting in neuropathic pain radiating from the back down the leg. An analogous pain occurs in the neck resulting in neuropathic pain radiating from the neck to the shoulder or down the arm.

 

Symptoms of Neuropathic Pain

“Classic” neuropathic pain is described as burning or electric or hot, scalding or searing. However, it can also be experienced as sharp and stabbing or even less commonly sometimes as dull or throbbing although these descriptors more often reflect nociceptive pain. Neuropathic pain can also be perceived as tingling, crawling pain, “like ants walking on me.”

 

Peripheral and Central Sensitization of Pain

Central sensitization represents an enhancement in the function of neurons and pain pathways caused by increases in nerve excitability as well as reduced inhibition from higher levels in the brain. It is a manifestation of the remarkable plasticity (ability to change and adapt) of the nervous system in response to activity, inflammation, and nerve injury. The overall effect of central sensitization is t
o generate an increased or amplification of pain perception. Central sensitization is responsible for many of the changes in pain sensitivity in chronic pain. Because central sensitization results from changes in the properties of neurons in the central nervous system, the pain is no longer coupled to the presence, intensity, or duration of the original stimulus of pain. Instead, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations.

 

Over time, neuropathic pain is commonly manifest simply as described above, neuropathic pain also manifests as  hyperalgesia, allodynia (see above) and central sensitization. While some conditions such as fibromyalgia more commonly manifest these three aspects of neuropathic pain, it is believed that most chronic pain syndromes can ultimately lead to any or all of these three conditions.

See: YouTube explanation of  Peripheral and Central Sensitization

 

Treating Neuropathic Pain

Treating neuropathic pain is complex because simple, conventional approaches may not be very effective. Opioids, which are uniformly effective for nociceptive pain, are inconsistently effective for neuropathic pain. While it is often presented that opioids are not effective for neuropathic pain, this is not true. The management of neuropathic pain does generally requires higher opioid doses compared with nociceptive pain. Additionally, some opioids have been shown to be more effective than other opioids in reducing neuropathic pain.

 

Also, some types of neuropathic pain may be more effectively than other types. For example, it has been shown that cold allodynia, or the abnormally perceived pain associated with exposure to cold such as occurs with diabetic neuropathy, is more responsive to opioids than heat allodynia.

 

Optimal management of neuropathic pain often requires “adjuvant,”  or additional synergistic, forms of treatment beyond or in place of opioids. These adjuvants may be in the form of medications, nutritional or nutriceutical supplements or non-pharmacologic treatments including exercise, physical therapy, TENS  (electrical stimulation), acupuncture and mindful techniques including meditation, hypnosis and spiritual activities.

 

Interventional pain (IP) treatment options also offer potential benefit for patients with severe neuropathic pain, especially related to neck and back pain. IP modalities include epidural steroid injections, facet blocks, nerve ablations, sympathetic nerve blocks and spinal cord stimulators.

 

Medications for Nerve Pain

The incorrect belief that opioids are ineffective for neuropathic pain, as well as concerns over adverse effects and potential for abuse often discourages the use of opioids for neuropathic pain. Attention is then often focused on the use of  antidepressants or anticonvulsants, but even with the latest generations of these drugs, effective analgesia is achieved in fewer than half of this population. To achieve the best outcomes in managing neuropathic pain it is important to consider “rational polypharmacy,” in other words, combining different medications with different mechanisms of action.

 

Opioids for Neuropathic Pain (see also – Opioids)

Multiple systematic reviews (Eisenberg et al.; Kalso et al., 2004; Katz and Benoit, 2005) of randomized controlled trials (RCTs) have demonstrated the effectiveness of opioids in reducing spontaneous neuropathic pain. Additional research has also looked at evoked neuropathic pain, as compared to spontaneous pain. Evoked pain that results from light touch by garments (mechanical evoked pain), running water or even cold air (cold evoked pain) can be extremely bothersome for many patients with neuropathic pain. Studies have shown these types of evoked pain are also significantly reduced by opioids and there seems to be equal justification for the use of opioids for both spontaneous and mechanical evoked neuropathic pain regardless of whether the origin of pain is peripheral or central.

 

While some conventional opioids offer limited benefit for neuropathic pain, other opioids do provide better results. Insights into how or why these particular opioids can be more effective can be obtained by reading about the neurobiology of pain and reading about the specific medications linked below.

 

The best choices of opioids for neuropathic pain include:

1.tramadol (Ultram, Ultracet)

2.tapentadol (Nucynta)

3.fentanyl

4.methadone (Dolobid)

5.levorphanol

6.buprenorphine (Butrans, Belbuca, Suboxone, Zubsolv, Bunavail)

 

 

Anti-Epileptic Drugs (AEDs) for Neuropathic Pain

Some of the most effective medications for treating neuropathic pain belong to the class of medications referred to as “anti-epileptic drugs” (AEDs) because they were originally used to treat seizures due to their ability to reduce inappropriate nerve activity. The most common and most effective AEDs are:

 

1.gabapentin (Neurontin, Gralise, Horizant) – See: Gabapentin (Neurontin) & Pregabalin (Lyrica)

2.Lyrica (pregabalin) – See: Gabapentin (Neurontin) & Pregabalin (Lyrica)

3.Topamax (topiramate)

4. Lacosamide (Vimpat)

5.lamotrigine (Lamictal)

6.carbamazepine (Tegretol)

7.valproate (Depakene, Depakote)

 

The first three (gabapentin, Lyrica, and Topamax) are the most effective and have the best safety profile amongst the six. Lacosamide has been shown to be effective in diabetic peripheral neuropathy. Lamotrigine, carbamazepine and valproate are beneficial for some specific indications, such as carbamazepine for trigeminal neuralgia, but they come with the potential for more serious side effects and are not used as much in the management of chronic pain.

 

 

Antidepressants for Neuropathic Pain

The two classes of antidepressants most effective in treating neuropathic pain are the SNRIs (serotonin and norepinephrine uptake inhibitors) and the tricyclics. It is important to understand that while these “antidepressant” medications are labeled as such due to their effectiveness in treating depression, their benefit in treating pain is unrelated to depression. These “antidepressants” are very effective in reducing nerve pain regardless of whether a patient is also depressed or not. That being said, they do offer the benefit of treating comorbid (coexistant) depression or anxiety and might be considered as a preferred choice in the management of depression and/or anxiety in patients with neuropathic pain . These SNRIs are more effective than the SSRI (Selective Serotonin Reuptake Inhibitors) antidepressants for treating pain. The SSRIs include Paxil, Zoloft, Prozac, Celexa and others.

 

SNRI antidepressants:

1.Cymbalta (duloxetine)

2.Effexor (venlafaxine)

3.Savella (milnacaprine)

 

Tricyclic antidepressants:

1.amitriptyline (Elavil)

2.doxepin

3.imipramine

4.desipramine

5.nortriptyline

 

 

Topical Medications for Neuropathic Pain

1.Capsaicin

2.Ketamine

3.Lidocaine

4.Gabapentin

5.Clonidine

 

Alpha-2 Agonists [Clonidine (Catapres) and Tizanidine (Zanaflex)]

Clonidine and, perhaps to lesser extent tizanidine, have been found to offer potential significant benefit in treating neuropathic pain conditions including diabetic peripheral neuropathy and fibromyalgia.

 

It has also been found that opioids and α2-adrenoceptor agonists offer significant synergistic analgesic effects when co-administered. In spite of a large body of preclinical evidence describing their synergistic interaction, combination therapies of opioids and α2-adrenoceptor agonists remain underutilized clinically.

 

Skeletal Muscle Relaxants

There is some evidence that orphenadrine (Norflex) may have benefit for neuropathic pain. It has been shown to have NMDA antagonist activity as well as norepinephrine reuptake inhibitor activity that are thought to be the mechanisms, along with others, that contribute to analgesia. Baclofen is another muscle relaxant shown to offer neuropathic pain benefit in cancer pain.

 

 

Cannabis & Cannabinoids in the Management of Neuropathic Pain

As the popularity of the use of marijuana for medical benefits as grown, so has the research into the components found in marijuana that provide therapeutic benefits. Unfortunately, due to federal government limitations on marijuana research, the research is still limited, and our understanding of how the components found in marijuana work for pain and other conditions. The compounds that are believed, offer, therapeutic benefits, with cannabis include cannabinoids, terpines and flavonoids as reviewed below.

 

The Endocannabinoid System (ECS)

The anatomy and physiology of pain, particularly chronic pain, is known however, to have significant contribution from the endocannabinoid system (ECS) of the human body in a somewhat analogous way of the opioid systems of the human body. Just as the opioid system has opioid-specific cell receptors and endogenous opioids manufactured by the human body, called endorphins, there are also cannabinoid-specific receptors and endogenous cannabinoids manufactured by the human body. Cannabinoids are a family of compounds that are made by plants (phytocannabinoidss) including marijuana’s THC and CBD among others,  and those that are manufactured in the human body (endocannabionids).

The main components of endocannabinoid system (ECS)  are the cannabinoid receptors CB1 and CB2 , the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes involved in their metabolism, including fatty acid amino hydrolase (FAAH) and monoacylglycerol lipase (MAGL), that are responsible for breaking down AEA and 2-AG, respectively. The ECS is an on-demand system, meaning it largely produces its components when there is a need for the. and is present  throughout the peripheral and central nervous systems, including important regions of pain processing, such as the spinal cord (including the ascending and descending nerve pathways and the dorsal root ganglions (DRGs,) the thalamus, amygdala and periaquaqueductal gray matter (PAG).

The ECS also interfaces with the immune system, particularly cells involved with inflammation, particularly neuro-inflammation, that drive chronic pain. The immune cells that play significant roles in the production and maintenance of pain signalling are glial cells, including astrocytes and microglia, that are found adjacent to nerves in the peripheral nervous system, the spinal cord and the brain.  These cells have cannabinoid receptors on them, which makes them responsive to the presence of endocannabinoids (AEA & 2-AG), as well as phytocannabinoids (THC, CBD and BCP and others).

Finally, other important components associated with the ECS and its role in pain are nerve receptors of the transient receptor potential family (TRP). including TRPV1)and TRPM8, which are important n the transmission of pain signals.

The following is a brief overview of the components of the ECS where they may play a role in impacting pain, particularly neuropathic pain.

Nerve cells, astrocytes, and microglial cells have the ECS components, and communicate pain signals through CB1 and CB2 receptors that lead to different outcomes in each cell. Presynaptic neurons expresses CB1, TRPV1, TRPM8, and the endocannabinoid membrane transporter (EMT). These receptors are all targeted by endocannabinoids (AEA and 2-AG) that modify pain signaly by changing the neurotransmitter release flow. Postsynaptic neurons, besides having the same receptors, they also have the enzymes that synthesize the enzymes that manufacture and break down all the elements of the ECS, such as FAAH, MAGL, and other enzymes. Interactions with the ECS that can increase or decrease pain would include stimulation of these different receptors to enhance or decrease pain signaling or by influencing the enzymes that manufacture or degrade the cannabinoids.

Even though the most research has been done on the phytocannabinoids, THC and CBD, several other phytocannabinoids such as cannabidivarin (CBDV), 19 -tetrahydrocannabivarin (THCV) and their acidic forms also may offer therapeutic benefits.

 

Cannabinoids

THC  & THCV

THC acts as CB1 and CB2 agonists, it reduces neurotransmitters release by neurons, especially glutamate and it is also a TRPM8 antagonist and a TRPA1 agonist. Another proposed mechanism of action of THC is to inhibit COX-2, which leads to increased levels of AEA and decreased levels of prostaglandins, resulting in the reduction of pro-inflammatory signaling by glial and other immune cells.

THCV is a CB1 antagonist and TRPV1 agonist.

 

CBD & CBDV

CBD act as TRPV1 and TRPM8 antagonists. while both CBD and CBDV inhibit the cannabinoid degradation enzymes FAAH and MAGL. CBD also acts on the serotoninergic and glycinergic receptors present in other neurochemical  processing systems which are involved in pain processing. 

 

THC with CBD

It is also thought that the combination of CBD and THC synergizes their positive effects and reduces THC side effects.  Studies suggest the co- administration of CBD and THC decreases dysphoria, anxiety, panic attacks, and other psychoactive effects of THC.

 

CBN and CBC

Cannabinol (CBN) acts as a CB2R agonist while cannabichromene (CBC), acts as an inhibitor of cyclooxygenase (COX).

 

Terpenes & Flavonoids

Terpines and flavonoids are other compounds found in cannabis that offer therapeutic benefits. Terpines include many of the aromatic compounds found in cannabis that impart the particular aroma to marijuana flowers and vapors. Particularly important terpines found in cannabis and other plants are beta-caryophylline (BCP), myrcene, pinene and linalool. (See: BCP and Terpines).

Flavonoids, a group of chemical compounds present in many plants not just Cannabis, can reduce inflammation by decreasing the release of pro-inflammatory cytokines from astrocytes and microglia cells.

 

Newer Agents in the Management of Neuropathic Pain

Naloxone and Naltrexone for Neuropathic Pain

Recent research suggests that the opioid blockers, naltrexone and naloxone, may have clinical benefit for neuropathic pain and, especially, fibromyalgia. While not yet commonly used for treating most neuropathic pain, there is growing evidence suggesting the benefit of naltrexone in fibromyalgia and associated hyperalgesia and central sensitization. (See Fibromyalgia – CAM treatment).

 

Botox for Neuropathic Pain

New research suggests that Botulism Toxin (Botox) may have potential in the treatment of pain associated with a number of types of neuropathic pain including diabetic peripheral neuropathy, carpal tunnel syndrome, post-herpetic neuralgia, chronic regional pain syndrome, trigeminal neuroalgia, post-traumatic neuralgia and others. Botox treatment is well established as a useful option in preventing migraine headaches and is now covered by insurance in many cases.

 

Ketamine for Neuropathic Pain

 When used in chronic pain management, ketamine can be given via  intravenous, subcutaneous, intramuscular, epidural, intra-articular, oral, topical, intra-nasal and sublingual routes. However, oral use is associated with much fewer side effects and topical use with minimal if any side effects.

(See Ketamine)

 

Topical Ketamine

Depending on the source of pain, there may be an argument for the use of topical ketamine. Topical ketamine is not commercially available but can be a topical cream can be compounded at a cost of about $1/gm, representing a cost of use at about $3-4/day with use 3-4x/day. Topical ketamine is particularly effective in peripheral neuropathy, especially when associated with diabetes.

 

Oral Ketamine

Although the use of oral ketamine as an analgesic for neuropathic pain is now generally accepted, the amount of evidence remains weak. Little formal research has been performed on the effectiveness and safety of ketamine in chronic pain management, especially concerning long-term oral use. However, recent research shows that oral ketamine at low, slowly increasing doses may be effective in neuropathic pain. Ketamine is reported to reduce pain in patients with neuropathic pain of various origins, including postherpetic neuralgia, complex regional pain syndrome (CRPS), cancer pain, orofacial pain and phantom limb pain. Studies in fibromyalgia are lacking although it might be expected to be effective with fibromyalgia due to its mechanism of action blocking NMDA receptors.

For more information, See Ketamine

 

Dextromethorphan for Neuropathic Pain

Dextromethorphan has long been identified as a weak NMDA antagonist with the potential for improving neuropathic pain as well as reducing hyperalgesia and opioid tolerance. Clinical use of dextromethorphan has been limited by lack of research and the side effects associated with the higher doses often required for pain benefit. There is some recent research, however, that points to the potential for therapeutic usefulness with dextromethorphan.

For more information, See Dextromethorphan

 

Melatonin for Neuropathic Pain

Recent research indicates that melatonin plays a role in pain. Supplementing with melatonin may be an option for modulating neuropathic pain but current research is limited to pain benefits associated with fibromyalgia, headaches and endometriosis.

See: Melatonin

 

Nitrous Oxide (N20) for Neuropathic Pain

A recent study demonstrated that a single exposure to 50% N2O may represent a new and interesting therapeutic approach for providing persistent neuropathic pain relief, at least after spinal nerve injury. The mechanism behind this proposed benefit is not fully defined yet and its application to the management of chronic pain has not yet been explored fully. The use of nitrous oxide in the emergency management of acute pain in the pre-hospital and emergency room setting however has been getting significant attention as an effective analgesic. Please check back later.

 

Combining Medications with Other Medications:  Synergy for Neuropathic Pain

“Synergy” occurs when the combination of two or more medications results in a greater response than the simple additive response of the individual medications. These supra-additive interactions are potentially beneficial clinically; by increasing effectiveness and/or reducing the total drug required to produce sufficient pain relief, undesired side effects can be minimized.

 

Opioids and Clonidine

Clonidine (Catapres) is a medication commonly used in the treatment of high blood pressure and is classified as an α2-adrenoceptor agonist. Opioid and α2-adrenoceptor agonists are potent analgesic drugs and their analgesic effects can synergize when co-administered. In spite of a large body of preclinical evidence describing their synergistic interaction, combination therapies of opioids and α2-adrenoceptor agonists remain underutilized clinically. Clonidine has been found to offer potential significant benefit in treating certain chronic pain conditions including diabetic peripheral neuropathy, fibromyalgia and chronic headaches as well as being effective in the management of opioid withdrawal. A synergistic analges
ic benefit for neuropathic pain has also been proposed for clonidine with dextromethorphan.

 

Other Potential Synergistic Options

Numerous other synergistic benefits with opioids have been proposed, including morphine with gabapentin or ketamine, tapentadol with pregabalin and tramadol with venlafaxine or doxepin. Additional reported synergistic combinations for treating neuropathic pain is combining gabapentin with nortriptyline or amitriptyline.

 

 CAM Alternatives for Neuropathic Pain

1.Complementary and Alternative Medicine – Overview

2.Acetyl-L-Carnitine

3.Alpha-Lipoic Acid

4.Curcumin (Meriva)

5.Green Tea

6.NRF2 Activators

7.Palmitoylethanolamide (PEA)

8.PolyResveratrol

9.Quercetin

10.SynaptaGenX

 

Treating the Neuropathic Process

Due to the role of stress, anxiety and sleep deprivation in the evolution of hyperalgesia and central sensitivity, behavioral approaches are emphasized in the treatment of neuropathic pain. Foremost along these lines are mindful exercises including meditation, deep relaxation techniques, yoga, tai chi, music therapy and hypnosis. Cognitive Behavior Training (CBT) has also been shown to be effective. Amongst the mechanisms proposed to explain how these behavioral approaches impact CS include the enhancement of the descending inhibitory pathways from the brain to the spinal cord similar to the mechanisms of the SNRIs, levorphanol and buprenorphine. 

For more information, see: Cognitive Behavior Training (CBT)

 

 

References:

Neuropathic Pain – Overviews

  1. What is Neuropathic Pain? UW Health – 2010
  2. Pathophysiological Mechanisms of Neuropathic Pain – 2011, no highlights
  3. A Primer on Scientific Evidence and Treatment of Neurogenic Pain

Neuropathic Pain – Central and Peripheral Sensitization

  1. Peripheral and Central Mechanisms of Pain Generation_ 2006

 

Nociplastic Pain – Overviews

  1. Importance of nociplastic pain in patients with rheumatic diseases – 2023

 

Neuropathic Pain – Descending Pathways

  1. Descending Noradrenergic Inhibition – An Important Mechanism of Gabapentin Analgesia in Neuropathic Pain – 2018
  2. Strategies to Treat Chronic Pain and Strengthen Impaired Descending Noradrenergic Inhibitory System – 2019

 

Neuropathic Pain – Arthritis

  1. Prevalence and interference of neuropathic pain in the quality of life in patients with knee osteoarthritis – 2023

 

Neuropathic Pain – Diabetic Peripheral Neuropathy (DPN)

  1. diabetic-neuropathic-pain-physiopathology-and-treatment-2015
  2. pharmacological-treatment-of-diabetic-peripheral-neuropathy-2015
  3. metabolic-correction-in-the-management-of-diabetic-peripheral-neuropathy-improving-clinical-results-beyond-symptom-control-2011
  4. painful-diabetic-neuropathy-an-update-2011
  5. diabetic-neuropathy-mechanisms-to-management – 2008
  6. oxidative-stress-a-cause-a
    nd-therapeutic-target-of-diabetic-complications-2010
  7. Comparison of Amitriptyline, Duloxetine, and Pregabalin in DPN
  8. Vitamin D for the treatment of painful diabetic neuropathy – 2016
  9. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. – PubMed – NCBI
  10. effect-of-cosmos-caudatus-ulam-raja-supplementation-in-patients-with-type-2-diabetes-2016
  11. Biologic Basis of Nerve Decompression Surgery for Focal Entrapments in Diabetic Peripheral Neuropathy – 2014
  12. Reversal of the Symptoms of Diabetic Neuropathy through Correction of Vitamin D Deficiency in a Type 1 Diabetic Patient – 2012

 

 

Neuropathic Pain – Treatment Overviews

  1. Management of Neuropathic Pain
  2. Pharmacologic Treatments for Neuropathic Pain
  3. Pharmacological management of chronic neuropathic pain – Revised consensus statement from the Canadian Pain Society – 2014
  4. Clinical practice guidelines for the management of neuropathic pain – a systematic review -2016
  5. Pharmacological Treatment Of Diabetic Peripheral Neuropathy – 2015
  6. Neuropathic pain – mechanisms and their clinical implications – 2014
  7. Treatment_of_Neuropathic_Pain_The_Role_of_Unique_Opioid_Agents_-_2016
  8. Opioids and Neuropathic Pain – 2012
  9. A Comprehensive Algorithm for Management of Neuropathic Pain – 2019
  10. Pregabalin in the Management of Painful Diabetic Neuropathy – A Narrative Review – 2019
  11. An integrated review on new targets in the treatment of neuropathic pain – 2018
  12. Pharmacologic management of chronic neuropathic pain Review of the Canadian Pain Society consensus statement – 2017
  13. Combination Drug Therapy for the Management of Chronic Neuropathic Pain – 2023
  14. Pharmacotherapy for neuropathic pain in adults-a systematic review and meta-analysis
  15. Combination Therapy for Neuropathic Pain- A Review of Recent Evidence – 2021

 

Neuropathic Pain – Combination Therapy

  1. NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System – 2010
  2. Pharmacotherapy for neuropathic pain in adults-a systematic review and meta-analysis
  3. Combination Therapy for Neuropathic Pain- A Review of Recent Evidence – 2021
  4. Combination Drug Therapy for the Management of Chronic Neuropathic Pain – 2023

 

Neuropathic Pain – Cannabinoids

  1. Cannabinoid Therapeutics in Chronic Neuropathic Pain – From Animal Research to Human Treatment – 2021

 

Neuropathic Pain – Clonidine

  1. Analgesic synergy between opioid and α2-adrenoceptors – 2014
  2. Clonidine May Help in Chronic Fatigue Syndrome (CFS) and Fibromyalgia Because – 2013
  3. Idiopathic Peripheral Neuropathy Responsive to Sympathetic Nerve Blockade and Oral Clonidine – 2012
  4. Clonidine – clinical pharmacology and therapeutic use in pain management
  5. Clonidine for management of chronic pain – A brief review of the current evidences – 2014
  6. The Role of Topical Agents in Podiatric Medicine – 2013
  7. Topical clonidine for neuropathic pain – 2015
  8. Pharmacologic Treatments for Neuropathic Pain

Neuropathic Pain – Interventional Pain Treatment

  1.  Experiences With Spinal Cord Stimulator in Patients With Chronic Neuropathic Back Pain

 

Neuropathic Pain – Opioids

  1. Opioids and Chronic Neuropathic Pain – 2003
  2. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin – Sec 6 – 2005
  3. Efficacy of mu-opioid agonists in the treatment of evoke
    d neuropathic pain – Systematic review of randomized controlled trials 2006
  4. Opioids and Neuropathic Pain – 2012
  5. Tapentadol for neuropathic pain – a review of clinical studies – 2019

 

Neuropathic Pain – Tricyclic Antidepressants

  1. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. – PubMed – NCBI – 2009
  2. Nortriptyline for neuropathic pain in adults – 2015
  3. Nortriptyline safer than amitriptyline? – 2028
  4. Amitriptyline for neuropathic pain in adults (Review) – 2015
  5. Amitriptyline

 

Neuropathic Pain – Complementary and Alternative Medicine (CAM) Treatment Options

 

Neuropathic Pain – CAM Treatment Overview

  1. Food-Derived Natural Compounds for Pain Relief in Neuropathic Pain – 2016
  2. Nutritional Supplements for the Treatment of Neuropathic Pain – 2021
  3. A Nutritional Supplement as Adjuvant of Gabapentinoids for Adults with Neuropathic Pain following Spinal Cord Injury and Stroke- Preliminary Results – 2023

 

Neuropathic Pain – DPN – Alpa Lipoic Acid

  1. oxidative-stress-a-cause-and-therapeutic-target-of-diabetic-complications-2010
  2. A systematic review and meta-analysis of a-lipoic acid in the treatment of diabetic peripheral neuropathy
  3. switching-from-pathogenetic-treatment-with-alpha-lipoic-acid-to-gabapentin-and-other-analgesics-in-painful-diabetic-neuropathy-2009
  4. alpha-lipoic-acid-supplementation-and-diabetes
  5. critical-appraisal-of-the-use-of-alpha-lipoic-acid-thioctic-acid-in-the-treatment-of-symptomatic-diabetic-polyneuropathy-2011
  6. efficacy-and-safety-of-antioxidant-treatment-with-lipoic-acid-over-4-years-in-diabetic-polyneuropathy-the-nathan-1-trial
  7. alpha-lipoic-acid-may-improve-symptomatic-diabetic-polyneuropathy-pubmed-ncbi
  8. Oral Treatment With Alpha-Lipoic Acid Improves Symptomatic Diabetic Polyneuropathy
  9. Thioctic acid for patients with symptomatic… [Treat Endocrinol. 2004] – PubMed – NCBI
  10. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study) – 1995
  11. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid- a meta-analysis – 2004

Neuropathic Pain – Acetyl-L-Carnitine

  1. Carnitine (L-carnitine) | University of Maryland Medical Center
  2. Acetyl-L-Carnitine in the Treatment of Peripheral Neuropathic Pain – A Systematic Review and Meta-Analysis of Randomized Controlled Trials

  3. Role of acetyl-L-carnitine in the treatment… [Ann Pharmacother. 2008] – PubMed – NCBI

 

Neuropathic Pain – Botulism Toxin (Botox)

  1. Botulinum Toxin Type A for the Treatment of Neuropathic Pain in Neuro-Rehabilitation – 2015
  2. [Botulinum toxin and painful peripheral neuropathies: what should be expected?]. – PubMed – NCBI
  3. Botulinum Toxin Treatment of Neuropathic Pain – 2016
  4. Botulinum Toxin Type A—A Modulator of Spinal Neuron–Glia Interactions under Neuropathic Pain Conditions – 2018

 

Neuropathic Pain – Lipoic Acid

  1. Alpha-lipoic acid | University of Maryland Medical Center
  2. A systematic review and meta-analysis of a-lipoic acid in the treatment of diabetic peripheral neuropathy
  3. Oral Treatment With Alpha-Lipoic Acid Improves Symptomatic Diabetic Polyneuropathy

Neuropathic Pain – Ketamine

  1. Promising Data With Ketamine in Chronic and Phantom Limb Pain – 2016
  2. Sublingual Ketamine in chronic pain : Service evaluation by examining over 200 patient years of data | Jaitly | Journal of Observational Pain Medicine – 2013
  3. Ketamine for Treatment-Resistant Unipolar Depression – 2012
  4. Use of oral ketamine in chronic pain management – a review. – 2009
  5. Chronic postoperative pain: recent findings in understanding and management – 2017
  6. A Comprehensive Algorithm for Management of Neuropathic Pain – 2019
  7. Poorly controlled postoperative pain: prevalence, consequences, and prevention – 2017
  8. Preventing chronic postoperative pain – 2016
  9. Use of oral ketamine in chronic pain management – a review. – 2009
  10. Efficacy and safety of oral ketamine for the relief of intractable chronic pain: A retrospective 5-year study of 51 patients. – PubMed – NCBI – 2015
  11. Ketamine and Ketamine Metabolite Pharmacology – Insights into Therapeutic Mechanisms – 2018
  12. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain – 2018
  13. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management – 2018 Ketamine use in current clinical practice – 2016

 

Neuropathic Pain – Melatonin

  1. Melatonin in Antinociception – 2012
  2. Melatonin in Pain Modulation – Analgesic or Proalgesic? – 2014
  3. A COMBINED EFFECT OF DEXTROMETHORPHAN AND MELATONIN ON NEUROPATHIC PAIN BEHAVIOR IN RATS – 2009
  4. Melatonin prevents morphine-induced hyperalgesia and tolerance in rats -role of protein kinase C and N-methyl-D-aspartate receptors – 2015
  5. Comparative study between transdermal fentanyl and melatonin patches on postoperative pain relief after lumber laminectomy, a double-blind, placebo- controlled trial – 2015

 

Neuropathic Pain – Nitrous Oxide

  1. Nitrous oxide persistently alleviates pain hypersensitivity in neuropathic rats – A dose-dependent effect. – 2015

 

Neuropathic Pain – Naloxone and Naltrexone

  1. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone

Neuropathic Pain – Vitamin B-12

  1. low Vitamin B12 in Trigeminal Neuralgia

Emphasis on Education

 

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the speci
fics of choice of supplement, dosing and duration of treatment should be individualized thr
ough discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

 

For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.

 

Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.

 

For more information, please contact Accurate Clinic.

 

Supplements recommended by Dr. Ehlenberger may be purchased commercially online or at Accurate Clinic.

Please read about our statement regarding the sale of products recommended by Dr. Ehlenberger.

Accurate Supplement Prices

 

 

.