Chemotherapy Induced Peripheral Neuropathy(CIPN)

CIPN occurs in 30-60% of patients receiving neurotoxic chemotherapy drugs.

It is a constellation of symptoms mainly affecting the feeling or sensory portion of the nerves, but can involve the motor or muscular function. Commonly it occurs during chemotherapy treatment, but can develop after its conclusion. Regardless, it often is disruptive, potentially disabling, and sometimes persistent.

Western care assesses treatments, based on the standard using randomized blinded controlled clinical studies where some patients receive treatment and others act as controls with no treatment. For CIPN, there is actually only one drug that the American Society of Clinical Oncologists support for use.

Therapy using integrative supportive care also bases its treatments of CIPN on studies in which patients are treated, and the percentage that shows improvement determines the results.

And while the results are often less robust to support their use, clinical experience has shown them to potentially be beneficial in CIPN. Integrative treatments offer multiple options, patient selection is individualized, and one therapy is necessarily successful for everyone.

The topics discussed, CIPN, in this article are specific supplements, and/or acupuncture, and Chinese herbal formulas, as well as lifestyle options.

Introduction

Peripheral neuropathy (PN) is a common side effect that can be seen in the setting of chemotherapy, often when the following drugs are utilized.

Commonly

Cisplatin and Oxaliplatin which causes CIPN in up to 70% of patients develop)
Taxane family– Docetaxel and Paclitaxel

With paclitaxel approximately one-third of cancer survivors have persistent symptoms

Vinca Alkaloids
Bortezomib
Thalidomide
Ixabepilone

It has also been seen with:

Gemcitabine
5 FU
Etoposide

Treatment of breast and colon cancer are the most common cancers with the highest percentage of people who develop peripheral neuropathy and a large percentage of these women receive platinum and /or taxanes as primary chemotherapies.

While CIPN often occurs during chemotherapy, in one study of 4000 patients, it occurred in two-thirds of patients when measured one month after chemo, 60% after three months, and one-third after six months.

Knowledge as to causation from chemotherapy is limited and is initially believed to be multifactorial due to the chemotherapy.

These can include:

Inflammation from proinflammatory cytokines
Oxidative stress impairing mitochondrial energy production in the nerves.
Effects on the dorsal root ganglions, cells that transmit sensory information
Damaging effects to the “wire” or axon along which electrical transmissions are carried.
Impaired ion exchange affecting generation of electrical impulses
There is also conjecture that chemotherapy causes premature senescence or aging of the nerve.

The commonly used drugs involved in CIPN,in cancer treatment, are the platinum drugs, the taxanes, and the vinca alkaloids, and there are also risk factors associated with a greater risk. Identifiable risk factors include:

Specific drug types, their duration and dosage, as the drug effects are cumulative.
Excess BSA, body surface area or the bodies surface based on height and weight, similar to BMI
Low calcium levels in the blood
Pre-existing risks, especially diabetes which long term is known to cause neuropathy.
Specific B vitamin deficiencies
Alcohol and tobacco abuse
Aging

Correction of these modifiable risks, moderation in lifestyle, correcting deficiencies, primarily with diet if possible and controlling weight can lower the probability of CIPN, but the degree is unknown.

The impact on a person’s life has both direct and indirect effects.

Symptoms present in a distribution that is called a stocking/ glove, bilaterally,with symptoms moving from the tips of both hands and/or both feet. If damage is significant it can involve larger areas.

Sensory changes include:

Pain, at varying levels of intensity and disability
Burning
Numbness
A sensation of swelling but without a visible appearance

These symptoms are often exacerbated by use of the hands or feet and can interfere with walking and/or dexterity and use of the fingers and hands.

Motor symptoms include:

Muscle weakness
Impaired balance

When receiving these drugs, the development of symptoms is both dose-dependent and cumulative in effect. Sometimes, symptom development can become severe enough to require a reduction of drug dosage or even its cessation, obviously reducing its effectiveness to achieving long-term survivorship.

While CIPN Is commonly encountered during chemotherapy, its effects can sometimes not occur until after chemotherapy is concluded.

Regardless, with the impacts of a cancer diagnosis and the necessary therapies, CIPN adds significant effects on one’s quality of life, producing intrusive pain, often with use, limiting the use of fingers to perform daily needed activities, pain with walking and movement, affecting sleep and influencing overall recovery.

These concerns and symptoms encourage practitioners to seek out safe integrative recommendations in an attempt to limit the extent, duration and severity of these symptoms. Treatment with many supplements and Chinese herbal formulas is not introduced until after the conclusion of treatment. However, in Chinese medicine, acupuncture can be effectively used during chemotherapy.

Treatments: Western, Naturopathic/Functional and Chinese Medicine Treatments for CIPN

The following information will discuss the various treatments that are available for chemotherapy-induced peripheral neuropathy. Under consideration will be current therapies from Western medicine, nutritional supplementation, and Chinese medicine, including acupuncture and herbal formulas. Looking at the available studies, there are a number of different treatments, all of which appear to have some level of benefit but also are not uniformly helpful for all people. The outcomes suggest that there are no guarantees that any will necessarily be useful, but the significance of the disabilities associated with CIPN tends to make patients look for solutions.

Also, reviewing each treatment doesn't offer any guidelines as to what to begin, when to begin, how long it should be used to expect results, and when to consider a different therapy choice. Part of the decision is the training of the practitioner as well as their clinical experience.

It is worth noting that specific treatments help some people, but there are few randomized clinical studies that can provide consistent information on the percentage of people each therapy helps and that they will be effective and useful. So please recognize that there is no way to make a supported scientific recommendation, and because side effects are possible with any treatment, a discussion with your prescriber is needed to make your decision.

Exercise For Prevention and Treatment of CIPN

When looking at studies assessing the effect of exercise on CIPN, the goal is to evaluate its impact on reducing the severity of symptoms and how much and what type is beneficial. There are multiple studies that show there is a small improvement in these parameters but no study can say absolutely it should be incorporated into a person’s lifestyle. As a result, If CIPN is a major problem, the commendation would be to seek approval to do exercise from your oncologist and to see a physical therapist to develop a plan for you. Don’t forget balance and feeling may be diminished in the legs, posing a risk of even walking. Perhaps pool work might be considered.

In real-world situations, people with CIPN are suffering. Knowing that planned exercise programs for cancer are shown to impact cancer progression and survival for several cancers, consideration for adding it to lifestyle changes makes sense. It is nontoxic, improves mood and often sleep, helps control weight, and offers a proactive approach that makes it seem worthwhile to try to see if it affects CIPN.

Chinese Medicine for Peripheral Neuropathy

The concepts of treating peripheral neuropathy in Chinese medicine differ from the approach in the Western model, requiring an individual assessment of each person’s unique pattern of imbalance. As a result, while western medicine would label CIPN as a uniform problem, Chinese medicine would describe it based on numerous possible system imbalances creating the problem.

For a complete explanation of these aspects of Chinese medicine, please view this article in the treatment section of the website.

In Chinese medicine, the organ systems, while having similar names to Western medicine and having many equivalent functions, do vary in their presentation of disease with unique symptomatology and findings on examination.

Each organ is related to a “brother or sister” interactive organ:

Liver/Gallbladder,
Spleen/ Stomach(digestive),
Heart/Pericardium,
Kidney/Bladder
Lung/ Large Intestine
And each individual is composed of both Yin and Yang and their manifestations of Blood and Qi

The substances are:

Yin, creating the structural components within the body and also creating body fluids, which in CIPN is the blood which is similar to western medicine,carrying nutrients to the body.

Yang is considered the metabolic fire needed in creating energy, and is considered similar to the idea of cellular mitochondria, and is essential to keep the body warm and is the source of Qi. Qi exists in multiple forms depending on an organ's needs. It could be the energy to breath, digest, detoxify or protect.
Disease then represents a potential imbalance in one or more organ systems,and treatment requires diagnosing both organ and the substance dysfunction to prescribe correctly.

Qi generates and moves blood and Blood nourishes the Qi, creating a mutual interaction between blood and Qi that must be integrated for successful treatment of peripheral neuropathy

When looking at CIPN treatment, commonly requires looking specifically at Yang, Qi, and Blood and their association with the movement of vital substances to the farthest areas of the body. Imbalance of any one of the three suggests, in CIPN, an inability to support and maintain nerve function.

Therapies using acupuncture and herbs involve recognizing and addressing all of these aspects. Traditional Chinese medicine in the U.S. commonly approaches acupuncture utilizing specific Meridian points, the vertical highways that travel up and down the body, to balance, restore, and integrate Qi and Blood. If unproductive, more complex acupuncture, but less familiar in TCM (Traditional Chinese Medicine) utilizes the Eight Extraordinary Vessels. These represent four acupuncture point pairs, a master and couple, that serve as reservoirs where an essential type of Qi can be stored and made available when needed.

These Extra Vessels can be represented by a metaphor from ancient times in China, represented by spring rains that were often excess and damaged the crops, while drought in the later summer and fall, left crops with inadequate water for support. As a method to control this situation and remedy this challenge, reservoirs were constructed to store the excess spring water, which could be released in times of shortage.

This expresses the concept of the Extra Vessels for acupuncture treatment. When imbalances occur within the body, they are understood as manifestations of excesses overactivity, or weaknesses causing reduced function, which can affect any organ system. The Extra Vessels offer an additional treatment possibility by assessing symptoms, and the unique Extra Vessel pulse patterns create a method of directing excessive energy away from an area or bringing energy to an area in need. In this manner, energy within the body can be better conserved and distributed where needed. This interaction is the domain of the Extra Vessels.

In CIPN, loss of feeling, pain, or muscular strength in the distant areas of the extremities reflects a need or weakness, and the Extra Vessels can augment the crucial energies and substances needed.

In addition, Auricular or ear acupuncture is considered a reflection of the body’s composite, a microsystem or map of its components, physical, metabolic and psychospiritual. Needling corresponding symptomatic areas on the map can be viewed as a means of accessing an individual’s mainframe computer through the laptop.

Chinese Herbal treatments of CIPN

Chinese herbal formulas act as the foundation of treatments for internal medicine diseases and, when associated with acupuncture, become an indispensable complement in treating chemotherapy-induced peripheral neuropathy.

The effectiveness of these formulas represents the interplay of several or more individual herbs, with each plant often composed of many different molecules, interacting with other similar multi-layered plant and mineral molecules. In Western molecular investigations, research requires the isolation of a single molecule or substance and measuring its effectiveness on a certain symptom or disease. It would be an impossible task to take a Chinese formula and catalog all the synergistic qualities brought to bear in a single formula. Chinese herbal formulas are composed of living materials that are used to match the correct pattern of disease and are specific recipes that can be compared to a chef also cooking a great recipe, always using fundamental principles and ingredients but adapting it to meet the needs of the clime and the time.

Herbal formulas generally were created, recorded and have been used in treatment for literally millenia. In Asia, Chinese medicine exists as an integral cultural component and was the only treatment modality available up until the modern era. So, while modern diagnoses did not exist, the patterns of symptoms can be understood and interpreted, allowing for herbal treatments that correspond with the Western viewpoint of the pathology or disease being seen.

Naming the formulas that can be used for CIPN requires an understanding of their clinical application as they can create side effects when used in the wrong context. Also, a practitioner seeing a patient for CIPN looks to not just treat the symptoms but also recognize there is a deeper origin or root cause for the problem’s development. That should be understandable in that not everyone gets CIPN, but those who do are affected by the chemotherapy, exposing an underlying predisposition to CIPN. Therefore, the goal is to treat the underlying root cause, as well as the branch, its manifestation, which is CIPN.

Herbal Formulas

Astragalus and Cinnamon 5 ( Huang Qi Gui Zhi Wu Wu Tang) and Tang-Kuei and Jujube (Dang-Kuei Si Ni San)

A small trial of 37 patients diagnosed with cold deficiency that had found western drugs ineffective or intolerable were started on these two formulas. Cold in the context of CIPN indicates symptoms of lack of warmth in the body, cold arms and legs and sluggish or slow movement of qi and blood in the extremities.

They are from the two classic foundational Chinese herbal texts written in 220 AD.

Astragalus and Cinnamon 5 formula strengthens the Qi, or tonifies it, and moves the Blood and Qi and alleviates numbness
Tang-Kuei and Jujube warms the meridians , dispels cold, and supports the circulation

This is applying herbal formulas to a specific diagnostic pattern in Chinese medicine, a cold constitution with symptoms of low energy and blood weakness is common to see in cancer and its treatment.

Goshajinkigan (Japanese) or Cyathula and Plantago - From the text, Kidney Pill from Formulas that Aid the Living derived in 1253 in China. In CIPN it assists in pertinent clinical manifestations of Kidney Yang (heat deficiency), cold lower body, and sensory numbness.

One recent study, in rodents, revealed specialized cells in the nervous system called astrocytes are a specific instigator of pacitaxel induced CIPN. These are a subset, in the nervous system, of glial cells whose function is associated with maintaining nervous system balance and protection. Pacitaxel activates these astrocytes to respond with an inflammatory response in the brain cortex which affects nerves of sensation ,adversely,causing increased pain sensitivity and pain to light touch. The use of Goshajinkigan inhibits this activation of the astrocytes. In the study, the herbal response reduced pain to light touch by 50% and overall pain sensitivity by 90%.

Integrative Naturopathic/Functional MedicineTreatments for Chemotherapy Induced-Peripheral Neuropathy

The research data using nutritional supplementation to reduce the effects of CIPN appear to have limited randomized clinical studies, while those available assessing and measuring improvement of CIPN have conflicting results, making the information more difficult to interpret.

Cryotherapy

A study that evaluated multiple reputable databases found 11 studies that compared cold therapy to controls in CIPN. Patients used frozen gloves or socks, with the recommendation to start 15 minutes prior to chemotherapy infusion and continue until 15 minutes after.

The data showed significant differences when measured mid-way through treatment and at the end of chemotherapy, showing that cryotherapy reduced sensory CIPN and improved quality of life.

However, the platinum drug Oxaliplatin, which is used in the treatment of pancreatic and colon cancers, can cause a side effect in which different body parts are extremely sensitive to cold, food, temperature, and iced drinks. It is called cold dysesthesia, and if it occurs, it is a potential cause of increased pain in CIPN when using cryotherapy.

Transcutaneous Electrical Nerve Stimulation (TENS)

A recent placebo-controlled study in May 2024 found that treatment with a TENS unit was effective for Pain in CIPN but had no effect on numbness or tingling.

Topical Agents for CIPN Pain

These agents have had studies and have some benefits for some people

Capsaicin in high concentrations has been shown effective for neuropathy pain. Neuropathy has been approved in Germany as a second-line treatment for CIPNs.

Lidocaine Patches have no studies specifically for CIPN but have shown benefits for neurologic pain. It is often used in older adults who cannot tolerate oral meds and should be considered for CIPN pain as a second-line treatment also.

Acetyl-L-Carnitine is an important supplement for the oxidation of free fatty acids, which is the breakdown of fatty acids to create energy. In animal studies it has been shown to help regenerate nerves and can reduce neurologic associated pain.

In humans, in the early 2000s, there were studies using oral doses that showed it as having the ability to prevent and treat CIPN, and it was used for many years in treatment. Newer studies, however, have found it ineffective in recent years and have shown that it may actually worsen CIPN. As a result, it is avoided in CIPN by practitioners.

Alpha Lipoic Acid (ALA)

Cancer chemotherapy causes the production of reactive oxygen species (ROS) in cancer cells, which contributes to their destruction.

ALA is a strong antioxidant that can reduce this oxidative reaction which can reduce the effectiveness of the chemotherapy. In addition, ALA also increases the production of glutathione which is also an antioxidant and is needed in the metabolism of chemotherapy drugs. Many oncologists are concerned that antioxidants can alter drug metabolism potentially increasing or decreasing the amount of chemotherapy given, both of which could change or alter the intended drug effects desired. Therefore, ALA should therefore be considered following the completion of chemotherapy for the treatment of CIPN.

Research and Studies

Studies in Germany in the 1960’s showed ALA improved symptomatic diabetic neuropathy, allowing government approval. This prompted evaluations for CIPN, which, in lab testing using cisplatin and pacitaxel to produce CIPN, showed it was effective in reducing neuronal damage.

In the early 2000s, there were clinical studies that evaluated the use of alpha lipoic acid in CIPN in patients specifically receiving cisplatin for cancer therapy. Two clinical studies indicated a reduction in neuropathy symptoms, but another clinical phase 3 study (2011) showed no significant reduction in neurologic symptoms.

Also, phase 2 studies using specifically oxaliplatin, in 2013 and 2015, with randomization of patients to treatment or controls, found no significant reduction in neuropathy.

L- Glutamine

For many years, the recommendation was to take large doses of glutamine, often up to 30 gms/day, for CIPN. Studies that reviewed the literature for random controlled studies, where clinical evidence showed there were minimal effects of the glutamine and no significant decrease in risk.

It is also important to know that while it is important as a component of the 20 amino acids needed for protein building. It can be obtained from dietary sources, meats, veggies, grains, nuts and tofu.

In cancer growth and progression, it can be used as a source to create energy when sugar is unavailable. So providing large amounts as a supplement can be supportive for cancer growth implying that there is usually adequate amounts in the diet, but if supplementation is needed it should be in small doses at short intervals

B Vitamins

Specific B vitamins are implicated in medical diseases.

B1, Low levels of Thiamine cause beriberi, which can cause loss of feeling in the hands and lower leg paralysis and rapid heart beat. It is commonly caused by poor diet, or excessive alcohol intake.
B6, Pyridoxine is often depleted from poor diet, medications: steroids and seizure drugs, some autoimmune diseases
B12, Cobalamin is often low from surgical removal of a section of the stomach or small intestine. It also is common in vegans as it is found in meat/fish proteins.

These vitamin deficiencies often occur in people with intestinal dysbiosis and leaky gut as nutrients of all types are not absorbed well. These vitamin levels can be measured to evaluate levels and if low may contribute to CIPN. Remember however, that these B vitamins are essential components as catalysts for metabolic reactions and are used by normal as well as cancer cells. So if your levels are adequate and you take supplementation cancer cells also can use them for their own cellular metabolism.

Vitamin E

Vitamin E is an antioxidant that helps prevent the production of reactive oxygen species(ROS), a loss of electrons when fats are oxidized, creating damaging free radicals. Many antioxidants reduce ROS through their involvement in detoxification, which can affect chemotherapy drug metabolism, but is not seen with Vitamin E.

It has been shown that Cisplatin or Carboplatin can reduce Vitamin E levels and that Vitamin E deficiency, unrelated to platinum drugs, can cause neuropathy.

Studies about the use of Vitamin E in CIPN are mixed.

In one study, Cisplatin decreased the incidence of CIPN and improved reflexes and sensory symptoms, while in another, Vitamin E appeared to reduce all grades of CIPN. However, when only double-blind controlled studies were evaluated, Vitamin E did not affect CIPN significantly. So, in that study, the recommendation was not to use it for prevention.

Since Vitamin E can affect platelet sticking, care should be used if a surgical procedure is planned or a clotting problem exists, so please discuss this with your practitioner.

Otherwise, while the data is less than robust, Vitamin E seems worthwhile to try, with guidance, if the Platinum drugs are being used.

Western medicine Recommendations

Western oncology offers few recommendations for CIPN. The American Society of Clinical Oncology, while suggesting there is preliminary supportive evidence for both Western and integrative treatments, their position is that the studies are not robust enough for the society to support recommending them.

There are also no FDA-approved pharmaceuticals for the treatment of CIPN, but some are used based on studies,

The use of antidepressant medications are commonly used for pain control. CIPN is a different situation, and few studies are available to support the combined 5-HT, serotonin and NE, norepinephrine reuptake antidepressants. These drugs have a dual action,and work to keep these neurotransmitters more available, which can suppress the transmission of painful stimuli to the brain from the body.

The American Society for Clinical Oncology recommends only the use of Cymbalta( Duloxetine) for CIPN, and a randomized study supports a greater decrease in CIPN pain than the placebo group.

Another study supports the use of Venlafaxine, Effexor, which is also a dual 5-HT, NE reuptake inhibitor that was shown to provide good relief of pain compared to controls.

Many other categories of antidepressants, especially Tricyclic antidepressants, have not shown evidence of improvement in CIPN.

It is also important if these drugs are prescribed to ask your provider about their side effects so as to be aware of what can occur. Also, these antidepressant drugs that are recommended for CIPN are not to be used in children or adolescents who may have CIPN from chemotherapy, as these drugs increase the risk of suicidal ideation in these age groups.

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