March/April 2020

Fighting Neuropathic Pain — Stem Cell Research Points to New Treatments for a Debilitating Condition
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 13 No. 2 P. 14

Neuropathic pain (NP) is a common and difficult-to-treat symptom of nerve damage. Patients suffering from this chronic pain condition are at risk of incurring increased health care expenditures and experiencing significant reductions in quality of life. Patients with NP often report job loss or significant changes to their careers, limited social interactions, decreased quality time with family, and feelings of hopelessness and depression due to their disease.1 Furthermore, current treatment approaches for NP, which focus on symptom management, are frequently inadequate.

Advancements in stem cell research are promising and may lead to new treatment modalities for NP.

NP Symptoms
NP symptoms are frequently described as burning, electric, tingling, and shooting. Hallmarks of NP include allodynia (pain resulting from a stimulus that normally does not elicit a painful response) and hyperalgesia (greater pain than normally would be expected from a painful stimulus).

Symptoms of neuropathy range from mild to disabling and may include a loss of reflexes, problems feeling pain, changes in temperature, numbness and tingling, and pain that is often worse at night.2 Symptoms are often sudden and unpredictable and follow different patterns that vary over a period of days, weeks, or years.1,2

Causes/Types
Approximately 30% of cases of neuropathy are the result of diabetes, and about 60% to 70% of people with diabetes have mild to severe forms of damage to sensory, motor, and autonomic nerves that cause such symptoms as numb, tingling, or burning feet; one-sided bands of pain; and numbness and weakness on the trunk or pelvis.2

More than 100 types of neuropathy have been identified, each with its own characteristic set of symptoms and prognosis.2 Causes of NP include chronic medical conditions (eg, diabetes), physical injury (eg, fractures, spinal cord injury), alcoholism, amputation (resulting in phantom pain), use of some chemotherapeutic agents (eg, Cisplatin, Vincristine), radiation therapy, trigeminal neuralgia, infections (eg, shingles, HIV), central nervous system disorders (eg, Parkinson’s disease, multiple sclerosis), kidney and liver disorders, nutritional deficiencies and imbalances (eg, B12 deficiency, excess B6), autoimmune disorders (eg, Guillain-Barré syndrome, rheumatoid arthritis, lupus), and some cancers/tumors. In some cases, NP is idiopathic.1-3

Available Treatments
Existing treatments and approaches to NP focus on palliative management of symptoms. There are no drugs available that can restore nerve function. The management of NP is challenging, as this type of pain is frequently refractory to existing treatments.4 It’s been reported that in clinical trials, no more than one-half of patients with NP experience clinically meaningful pain relief.3 Similarly, several studies of individuals with NP living in the community have shown patients on average experience pain of moderate severity despite taking prescribed medications for their pain.4

Medications commonly used include analgesics such as opioids (eg morphine, methadone, tramadol) and over-the-counter pain medications (eg, NSAIDs), antidepressants (eg, amitriptyline, nortriptyline, venlafaxine, duloxetine), anticonvulsants (eg, gabapentin, pregabalin), muscle relaxers (eg, cyclobenzaprine), and topical agents such as lidocaine creams or patches. In addition to medications, nondrug therapies and lifestyle modifications such as exercise, physical therapy, acupuncture, and limiting physical activity may also be utilized to manage symptoms.

Stem Cells
Stem cell transplantation has the potential to repair, restore, replace, and regenerate cells, and may be able to treat a number of different medical conditions and diseases. Research increasingly is evaluating the use of stem cells for the treatment of NP. Unlike existing treatments that focus only on symptom management, stem cell transplantation may be able to replace damaged nerve cells, possibly offering a cure.

Stem cells, sometimes referred to as “master cells,” are the foundation for every organ and tissue in the human body. These include embryonic stem cells and tissue-specific adult stem cells. Due to the ethical issues associated with the use of embryonic stem cells, most of the research being done involves the use of adult stem cells. Regardless of the type used, stem cells have the unique ability to self-renew (make copies of themselves) and differentiate (develop into more specialized cells).

Stem cells can be transplanted in a number of different ways, including local delivery, intrathecal or intracerebroventricular administration, IV injection, intranasal delivery, and endogenous mobilization by drugs for chronic intractable pain treatment.

In early research, it had been thought that stem cells would need to be administered intrathecally to reduce pain as IV administration appeared to result in the stem cells becoming trapped in the lungs, preventing their migration to the site of injury. However, more recent evidence suggests this lung trapping effect may be transient.

Proposed Mechanisms
Animal studies have identified a number of mechanisms by which stem cells may help reverse neuropathy and NP. These include differentiation, immunomodulation, neutropic effects, angiogenesis, stem cells acting as a biologic minipump, possible stem cell effects on the endogenous opioid system, and improving glycemic control, which is implicated in diabetic neuropathy.4

Differentiation
It’s been demonstrated that under the right circumstances, transplanted stem cells can differentiate (into astrocytes, oligodendrocytes, neurons, and microglia) and migrate to areas of neuronal damage where they mediate functional recovery.4

Immunomodulation
With nerve injury, glial cell activation occurs as part of an immune system response, resulting in the release of proinflammatory cytokines and other substances that facilitate neuroinflammation and pain response.4,5 Stem cells have been shown to have immunomodulatory effects on glial cell activation, resulting in inhibition of the proinflammatory cytokines (eg, TNF-α, IL-1, and IL-6) and upregulation of anti-inflammatory cytokines (eg, IL-4, IL-10, and IL-13).4

Opioid System Effects
Efficacy data to support the use of opioids for the treatment of NP are mixed. NP frequently does not respond to morphine or other opioids, and although higher doses produce improved effects, they also increase the potential for opioid tolerance (OT) and opioid-induced hyperalgesia (OIH).

In addition to immune response activity, glia activation is believed to be associated with altered opioid system activity.5 In an animal model using rats, researchers from the Cleveland Clinic found that IV transplantation of bone marrow–derived stem cells significantly attenuated OT and OIH, whether the transplantation was performed seven days before or 14 days after the initiation of daily morphine injections. These data also suggest that stem cell transplantation not only prevents the development of OT and OIH but also can also reverse them.

In addition, the researchers reported that the stem cell transplantation resulted in immune modulatory and anti-inflammatory effects, produced sensory nerve repair, and demonstrated strong analgesic properties that could provide a safer and more effective alternative to current treatment modalities. The use of stem cell transplantation may also allow for the effective treatment of pain using lower doses of opioids.6

Neurotrophic Effects
Hyperglycemia—along with other contributing factors including inflammation, dyslipidemia, hypoxia, ischemia, impaired insulin signaling, metabolic syndrome, and vascular insufficiency—leads to nerve damage. As part of this process, peripheral blood vessels are destroyed, in particular the vasa nervorum. This destruction can cause microcirculation transformation and a reduction of neurotrophic factors in peripheral nerves.7 The resulting deficiency of neurotrophic factors results in distal axonal degeneration, axonal loss, demyelination, impaired nerve regeneration, and, ultimately, dysfunction of nerve fibers and NP.8

Stem cell transplantation has been shown to increase the release of neurotropic factors from both the transplanted stem cells and existing cell-stimulated resident cells. This subsequent increase in neurotrophic factors (eg, epidermal growth factor, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, neurotrophin-3, basic fibroblast growth factor, and vascular endothelial growth factor) helps to promote neuronal regeneration, regulate neuronal plasticity, repair damaged nerves, and maintain nerve function integrity, all of which help to address possible causes of NP.4

Angiogenic Effects
Studies have demonstrated that transplanted stem cells, in addition to their neurotrophic effects, can stimulate neovascularization and increase blood nerve flow as a result of their ability to produce multiple angiogenic factors (eg, vascular endothelial growth factor, insulinlike growth factor, fibroblast growth factor-2) and stimulate the release of angiogenic ligands.4

Combined Neurotrophic and Angiogenic Effects
In a study using high-fat feeding, diabetes was induced in rats that then had stem cells transplanted. Immunohistochemical analysis was used to compare the capillary-to-muscle fiber ratio and intraepidermal nerve fiber density (IENFD). Furthermore, the study quantified the expressions of angiogenesis-related and neurotrophic factors.

Stem cell transplantation relieved diabetic NP, enabled functional recovery of the peripheral nerves, and increased the capillary-to-muscle fiber ratio and IENFD. Both angiogenic and neurotrophic factors were found to be more prevalent in stem cell–treated rats. The authors concluded that stem cell transplantation ameliorated diabetic peripheral neuropathy in diabetic Goto-Kakizaki rats.9

In another recent study, Wang and associates examined whether mesenchymal stem cells (MSCs) or resveratrol (RSV) may improve diabetic hyperglycemia and diabetic neuropathy. RSV is a polyphenol compound with antioxidant properties.

The investigators examined the combined effect of MSCs and RSV on diabetic neuropathy. A total of 100 nonobese diabetic mice were divided into six groups: normal control, MSCs, RSV, MSCs + RSV, insulin, and diabetic control groups. Following homologous therapy, the authors wrote, the levels of blood glucose and C-peptide, islets, nuclear factor-κB, nerve growth factor and myelin basic protein, and the sciatic nerve structure in each group were examined and evaluated. Following the administration of therapy, the levels of blood glucose and C-peptide in mice in the MSCs + RSV group “were significantly improved compared with the other diabetic groups, and the dosage of insulin therapy required was the lowest among the six experimental groups (p < 0.05).” Furthermore, “the levels of nerve growth factor, myelin basic protein, and nuclear factor-κB in the MSCs + RSV group were significantly improved compared with those in the MSCs and RSV groups (p < 0.05).”

The authors went on to report that “the diameter of the axon, number of myelinated nerve fibers, and the depth of the myelin sheath in the MSCs + RSV group were greatest among the five examined groups (excluding the control). The combination of RSV and MSCs could relieve hyperglycemia and improve diabetic neuropathy.”

The authors concluded that the combination of RSV and MSCs may be a novel therapeutic method for the treatment of diabetic neuropathy.10

Biologic Minipumps
Pain is also known to be mediated by a number of different neurotransmitters and neurotrophins (eg, y-GABA, glycine, glial cell line-derived neurotrophic factor, and neurogenin-2). Genetically modified stem cells could be transplanted and allowed to migrate to areas of nerve damage, where they would act as biological minipumps, releasing neurotransmitters and neurotrophins, thereby mediating analgesic effects.4

The FDA Warns About Stem Cells
The FDA is concerned about stem cell clinics that may be offering some products that are both illegal and unproven.11

In the United States, doctors routinely use stems cells from bone marrow or blood in transplant procedures to treat patients with cancer and disorders of the blood and immune system. These are the only stem cell products that are FDA approved and identified on the FDA website.

The FDA advises patients who may be seeking stem cell treatments to do their part and make sure the stem cell treatments they’re considering are either FDA approved or being studied under an investigational new drug (IND) application, which is a clinical investigation plan submitted and allowed to proceed by the FDA. With limited exceptions, investigational products must also go through a thorough FDA review process as investigators prepare to determine the safety and effectiveness of products through well-controlled human studies (clinical trials).

As part of the FDA’s review, investigators must show how each product will be manufactured so the FDA can ensure appropriate steps are being taken to help assure the public of the product’s safety, purity, and strength (potency). The agency also requires sufficient data from animal studies to help evaluate any potential risks associated with product use. It also warns that some clinics are inappropriately advertising stem cell clinical trials without having submitted an IND application.

When clinical trials are not conducted under an IND, it means that the FDA has not reviewed the experimental therapy to help ensure it’s reasonably safe. Stem cell clinics also may falsely advertise that FDA review and approval of the stem cell therapy is unnecessary.

The FDA warns that unproven stem cell therapies can be particularly unsafe and has indicated that there have been reports of persons who became blind due to an injection of stem cells into the eye. One patient received a spinal cord injection that caused the growth of a spinal tumor. Additional potential safety concerns for unproven treatments include the following:

• administration site reactions;

• the ability of cells to move from placement sites and change into inappropriate cell types or multiply;

• failure of transplanted cells to work as expected; and

• the growth of tumors.

There are also concerns that even if a patient’s own stem cells are used during treatment, there are still safety risks such as those noted above, and if the stem cells are manipulated after removal, there’s a risk of contamination of the cells.

While stem cell research is promising, it’s important to remember that much of the evidence supporting the use of stem cells for NP is in early preclinical stages. Additional clinical studies in humans are needed to verify the safety of stem cell transportation and to prove its effectiveness.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. FDA, Patient-Focused Drug Development Initiative. Neuropathic pain associated with peripheral neuropathy. https://www.fda.gov/files/about%20fda/published/The-Voice-of-the-Patient--Neuropathic-Pain-Associated-with-Peripheral-Neuropathy.pdf. Published February 2017.

2. Peripheral neuropathy fact sheet. National Institute of Neurological Disorders and Stroke website. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet. Updated August 13, 2019.

3. Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010;85(3 Suppl):S3-S14.

4. Xie F, Yue Y, Guan Y, Wang Y. Stem cells for the treatment of neuropathic pain. J Anesth Perioper Med. 2017. doi: DOI:10.24015/JAPM.2017.0009.

5. Xiao L, Saiki C, Ide R. Stem cell therapy for central nerve system injuries: glial cells hold the key. Neural Regen Res. 2014;9(13):1253-1260.

6. Li F, Liu L, Cheng K, Chen Z, Cheng J. The use of stem cell therapy to reverse opioid tolerance. Clin Pharmacol Ther. 2018;103(6):971-974.

7. Ii M, Nishimura H, Kusano KF, et al. Neuronal nitric oxide synthase mediates statin-induced restoration of vasa nervorum and reversal of diabetic neuropathy. Circulation. 2005;112(1):93-102.

8. Obrosova IG. Diabetes and the peripheral nerve. Biochim Biophys Acta. 2009;1792(10):931-940.

9. Xie J, Rao N, Zhai Y, et al. Therapeutic effects of stem cells from human exfoliated deciduous teeth on diabetic peripheral neuropathy. Diabetol Metab Syndr. 2019;11:38.

10. Wang C, Chi J, Che K, et al. The combined effect of mesenchymal stem cells and resveratrol on type 1 diabetic neuropathy. Exp Ther Med. 2019;17(5):3555-3563.

11. FDA warns about stem cell therapies. FDA website. https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapies. Updated September 3, 2019.