Vitamin E

Vitamin E

PEP Topic 
Peripheral Neuropathy
Description 

Vitamin E is a fat-soluble vitamin found in seeds, nuts, leafy vegetables, and vegetable oils. It is a type of antioxidant and helps prevent cell damage caused by free radicals (highly reactive chemicals). Vitamin E is being studied in the prevention and treatment of some types of cancer. Vitamin E has antioxidant properties and has been used as an oral or parenteral supplement and as a solution for topical application.  Vitamin E has been examined in management of diarrhea, mucositis, peripheral neuropathy, skin effects, cognitive impairment, and hot flashes.

Effectiveness Not Established

Research Evidence Summaries

Afonseca, S.O., Cruz, F.M., Cubero Dde, I., Lera, A.T., Schindler, F., Okawara, M., . . . Giglio, A. (2013). Vitamin E for prevention of oxaliplatin-induced peripheral neuropathy: A pilot randomized clinical trial. Sao Paulo Medical Journal, 131, 35–38.

doi: 10.1590/S1516-31802013000100006
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Study Purpose:

To evaluate if oral daily vitamin E is an effective agent in preventing oxaliplatin-induced peripheral neuropathy

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive either an oral placebo daily or 400 mg of oral vitamin E daily starting five days before their oxaliplatin-based regimen and continued until completion of the oxaliplatin-based regimen. Both groups received calcium 1 gram IV and magnesium 1 gram IV supplementation 30 minutes before and the same dose after the completion of 12 cycles of oxaliplatin infusions.

Sample Characteristics:

  • N = 32 (18 in the vitamin E group, 16 in the placebo group)  
  • MEAN AGE = 56 years in the vitamin E group; 57 years in the placebo group
  • MALES: 10 in the vitamin E group, 8 in the placebo group; FEMALES: 8 in the vitamin E group, 8 in the placebo group
  • KEY DISEASE CHARACTERISTICS: Equal distribution of colon cancer, rectal cancer, and advanced gastric cancer; metastatic colon cancer: three in the vitamin E group, zero in the placebo group
  • OTHER KEY SAMPLE CHARACTERISTICS: Eastern Cooperative Oncology Group score 0–1: equal distribution; FOLFOX, FLOX, and EOX regimens: equal distribution; diabetes: two patients in the vitamin E group, zero in the placebo group; previous chemotherapy, radiotherapy, and ETOH consumption: equal distribution
  • EXCLUSION CRITERIA: Patients with previous history of peripheral neuropathy or symptoms of peripheral neuropathy; patients receiving gabapentin, carbamazepine, amitriptyline, amifostine, or multivitamins

Setting:

  • SITE: Department of hematology and oncology
  • SETTING TYPE: University hospital  
  • LOCATION: Santo Andre, Sao Paulo, Brazil

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Adjuvant, advanced, and metastatic
  • APPLICATIONS: Elder care, palliative care

Study Design:

  • Prospective, phase II, randomized, double-blind pilot study

Measurement Instruments/Methods:

  • Common Terminology Criteria for Adverse Events (version 3) and gradation scales for oxaliplatin based on National Cancer Institute Common Toxicity Criteria in the assessment of chemotherapy-induced peripheral neuropathy to detect a 50% decrease in the incidence of peripheral neuropathy with a power of 0.8 and a type I error of 0.05

Results:

In evaluating the effectiveness of oral vitamin E 400 mg daily for prevention of oxaliplatin-induced peripheral neuropathy, this study sought to detect a 50% reduction in associated peripheral neuropathy. The results showed no significant decrease in the incidence of acute oxaliplatin-induced peripheral neuropathy comparing vitamin E and placebo groups (p = 0.43) and no significant difference in the grade (p = 0.45) or time to onset of peripheral neuropathy (p = 0.66) between groups. Incidence of vomiting, nausea, mucositis, fatigue, headache, vertigo, and bleeding observed between groups showed no statistical difference. Incidence of diarrhea was increased in the vitamin E group (p = 0.06).

Conclusions:

There is no difference in the incidence, grade, or time to onset of peripheral neuropathy when comparing vitamin E given at 400 mg orally daily or placebo in patients receiving 12 cycles of an oxaliplatin-based regimen (i.e., FOLFOX, FLOX, EOX).

Limitations:

  • Small sample (less than 100)
  • Measurement/methods were not well described. All time points for evaluation of peripheral neuropathy were not clearly stated. Any dose adjustment for the chemotherapy regimen or oxaliplatin dose, treatment delay, or missed treatment were not mentioned or addressed.
  • Other limitations/explanation: Both groups received calcium and magnesium supplementation that may have confounded results. The clinical effectiveness of vitamin E may not have been measured adequately. Dosing of vitamin E at 400 mg daily was based on only one previous clinical trial using cisplatin, not oxaliplatin. There may have been differences in peripheral neuropathy under the 50% measurement used that were not able to be evaluated.

Nursing Implications:

This small pilot study showed no benefit of vitamin E in preventing or reducing the onset or grade of peripheral neuropathy with oxaliplatin-based regimens over 12 weeks. Patients receiving vitamin E had increased signs and symptoms of diarrhea. Further nursing research is needed to evaluate the therapeutic value of vitamin E in this setting.

Argyriou, A.A., Chroni, E., Koutras, A., Ellul, J., Papapetropoulos, S., Katsoulas, G., . . . Kalofonos, H.P. (2005). Vitamin E for prophylaxis against chemotherapy-induced neuropathy: A randomized controlled trial. Neurology, 64, 26–31.

doi: 10.1212/01.WNL.0000148609.35718.7D
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Study Purpose:

Patients were enrolled to test vitamin E as prophylaxis against chemotherapy-induced peripheral neuropathy.

Intervention Characteristics/Basic Study Process:

Patients were randomly divided into groups assigned to receive chemotherapy treatment with (group I) or without vitamin E supplementation (group II). Group II served as control. Patients assigned to group I received alpha-tocopherol (i.e., vitamin E) orally at a dose of 300 mg per day twice daily during chemotherapy and as long as three months after chemotherapy was completed.

Sample Characteristics:

  • The total sample consisted of 40 patients treated with six courses of cumulative cisplatin, paclitaxel, or their combination regimens for a nonmyeloid malignancy.
  • The final sample size was 31.
  • Exclusion criteria included a history of neuropathy, systemic diseases such as diabetes, lupus, HIV, alcohol abuse, and those who had received chemotherapy in the past.

Study Design:

The study had a pilot, randomized, controlled, open label with blind assessment design.

Measurement Instruments/Methods:

The clinical evaluation of neuropathy was based on a modified Neurologic Symptom Score (NSS) and Neurologic Disability Score (NDS). NSS selected symptoms such as weakness, numbness, or pain, scoring as present (1) or absent (0). Clinical signs (i.e., cranial nerves function; joint position, pin prick, and vibration sensation; muscle strength and deep tendon reflexes) were assessed using a modified version of NDS ranging from 0 (no deficit) to 4 (absence of function/severest deficit). Electrophysiologic examination included motor conduction of ulnar and peroneal nerves. Measures were taken at baseline and repeated after the third and sixth cycles as well as three months after cessation by the same neurologist.

Results:

Vitamin E supplementation significantly decreased the incidence of neurotoxicity, with 25% of patients receiving Vitamin E experiencing chemotherapy-induced peripheral neuropathy compared to 73.3% in the control group.

Conclusions:

This pilot study with a small sample size and many variables assessed make achieving a statistically significant result by chance alone more likely.

Limitations:

Small sample size

Kottschade, L.A., Sloan, J.A., Mazurczak, M.A., Johnson, D.B., Murphy, B.P., Rowland, K.M., . . . Loprinzi, C.L. (2011). The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: Results of a randomized phase III clinical trial. Supportive Care in Cancer, 19, 1769–1777.

doi: 10.1007/s00520-010-1018-3
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Study Purpose:

The aim of the study was to evaluate the efficacy of Vitamin E for the prevention of chemotherapy-induced peripheral neuropathy.

Intervention Characteristics/Basic Study Process:

Patients who were to receive taxane or platinum-based chemotherapy were randomized to receive placebo or vitamin E 300 mg by mouth twice daily. Treatment was begun within four days of the first chemotherapy treatment and continued throughout treatment and for one month beyond completion of chemotherapy. Patient assessments were conducted at baseline, prior to each chemotherapy treatment, and at one and six months after chemotherapy.

Sample Characteristics:

  • The total sample consisted of 189 participants, 82% female and 18% male.
  • Sixty-one percent of the total sample were older than age 50 years.
  • Participants had multiple tumor types. Breast cancer was most common (61%).
  • Ninety-four percent were Caucasian. 
  • Fifty-eight percent were receiving taxane and the rest were receiving a platinum-based compound.
  • Patients were excluded if anticoagulatns, opiods, anticonvulsants, or other treatments were used for neuropathic pain.
     

Setting:

The study was conducted at multiple outpatient locations that were part of the North Central Cancer Treatment Group.

Phase of Care and Clinical Applications:

Phase of care

  • Active antitumor treatment

Study Design:

The study had a double blind,  randomized, placebo-controlled trial design.

Measurement Instruments/Methods:

  • NCI-CTCAE, version 3.0
  • Symptom experience diary
  • Neuropathic-specific questions
     

Results:

 No significant differences were noted between groups regarding study outcomes.

Conclusions:

The findings do not demonstrate an effect of Vitamin E oral supplements on peripheral neuropathy from chemotherapy.

Limitations:

  • Measurement and methods were not well described.
  • Measurement validity and reliability was questionable.
  • Use and frequency of the patient diary are not well described.
  • There were no objective measures of neuropathy. 
  • No recognized self-report questionnaire was used.

Nursing Implications:

 Findings do not support the use of Vitamin E to prevent chemotherapy-induced peripheral neuropathy. Nurses can guide patients regarding the evidence in this area.

Pace, A., Giannarelli, D., Galie, E., Savarese, A., Carpano, S., Della Giulia, M., . . . Cognetti, F. (2010). Vitamin E neuroprotection for cisplatin neuropathy: a randomized, placebo-controlled trial. Neurology, 74, 762–766.

 

doi: 10.1212/WNL.0b013e3181d5279e
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Study Purpose:

The aim of the study was to evaluate the neuroprotective effect of vitamin E in patients treated with cisplatin.

 

Intervention Characteristics/Basic Study Process:

Patients were randomized to either vitamin E 400 mg per day (α-tocopherol) or placebo. The vitamin E (or placebo) was started orally before chemotherapy and continued for three months after completion of cisplatin.

Sample Characteristics:

  • The study had a total sample of 108 patients. Forty-one were included in the analysis.
  • Mean age was 58 years, with a range of 28–74 years.
  • Patients had solid tumors and were in generally good health and receiving cisplatin therapy.

Setting:

The study was conducted at multiple outpatient sites: the National Cancer Institute in Rome and the National Neurologic Institute in Milan, Italy.

Study Design:

The study had a phase III randomized, placebo-controlled trial design.

Measurement Instruments/Methods:

  • Neurologic examination: Standardized history and assessment of pinprick and vibratory sensations, strength, and deep tendon reflexes.              
  • Total neuropathy score
  • Reidel-Seiffer tuning fork
  • Electrophysiologic examination

Results:

Neurotoxicity score was significantly lower in patients receiving vitamin E than in the placebo group (mean score of 1.4 versus 4.1; unpaired t test, p < 0.01). Neurotoxicity incidence differed significantly between groups (group 1, 1 of 17 participants; group 2, 10 of 24 participants; p < 0.01). Also, the relative risk of developing signs or symptoms of neurotoxicity was significantly lower in group 1 than group 2 (relative risk of 0.14, 95% confidence interval [0.02, 1],  p < 0.05). At follow-up, compared with baseline, mean sural and sensory median nerve amplitude values were significantly decreased in the control group (p = 0.02 and p = 0.008, respectively), while median nerve amplitude was unchanged and sural nerve amplitude was decreased, but not significantly, in patients receiving Vitamin E.

Conclusions:

Vitamin E may be helpful in reducing neurotoxic effects of cisplatin, but larger randomized trials are needed.

Limitations:

  • The study was limited by a small sample size (less than 100).
  • In addition, a large number of dropouts were reported.

Nursing Implications:

Cisplatin-induced peripheral neuropathy can be painful and also interfere with a patient’s quality of life; however, future research is needed with larger trials before Vitamin E is recommended. Also, drug interactions need to be considered.

Pace, A., Savarese, A., Picardo, M., Maresca, V., Pacetti, U., Del Monte, G., . . . Bove, L. (2003). Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. Journal of Clinical Oncology, 21, 927–931.

doi: 10.1200/JCO.2003.05.139
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Study Purpose:

This study evaluated the neuroprotective effect of vitamin E in patients with solid tumor malignancy treated with cisplatin chemotherapy.

Intervention Characteristics/Basic Study Process:

Patients were randomly assigned to either group 1, which received vitamin E supplementation during cisplatin chemotherapy, or to group 2, which received cisplatin chemotherapy alone. Vitamin E 300 mg per day was administered orally before cisplatin chemotherapy and continued for three months after the suspension of treatment.

Sample Characteristics:

  • A total sample of 47 patients was recruited. Twenty-seven completed the study.
  • Patients had a variety of solid organ malignancies.
  • Exclusion criteria included previous chemotherapy treatment or regimens including other neurotoxic drugs.

Measurement Instruments/Methods:

  • Assessment of neuropathic symptoms, pinprick, vibratory sensations, strength, and deep tendon reflexes.
  • A follow-up neurologic examination was performed by the same neurologists (not blinded to treatment status) after the three cycles of cisplatin treatment and after the cessation of chemotherapy. Neuropathic signs and symptoms were scored using a questionnaire designed for the detection of sensory disturbances (e.g., paresthesia, pain, and burning in feet or fingers) experienced by patients.
  • Nerve conduction velocity and the amplitude of potentials of the sensory median and sural nerves were assessed at baseline and at the end of treatment with vitamin E.
  • Plasma levels of vitamin E were measured by gas chromatography-mass spectrometry prior to chemotherapy.

Results:

Twenty patients dropped out of the study. Plasma levels of vitamin E were in the normal range and not significantly different between the two groups (8.06 and 7.17 mg/ml, respectively). Twelve of the 14 patients in the control group developed CIPN as compared to 4 of 13 patients who received vitamin E supplementation.

 

Conclusions:

Vitamin E supplementation significantly protects against cisplatin-induced peripheral neuropathy and reduces incidence and intensity of neurologic signs and symptoms.

Limitations:

  • The small sample size and differing tumor types included make comparisons difficult.
  • The small sample size can also make finding statistically significant results more likely by chance alone.

Systematic Review/Meta-Analysis

Albers, J.W., Chaudhry, V., Cavaletti, G., & Donehower, R.C. (2011). Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database of Systematic Reviews (Online), Feb. 16 (2), CD005228.

doi: 10.1002/14651858.CD005228.pub3
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Purpose:

Examine the efficacy of purported chemoprotective agents to prevent or limit neurotoxicity of cisplatin and related agents

TYPE OF STUDY: Combined systematic review and meta-analysis

Search Strategy:

DATABASES USED: Cochrane Neuromuscular Disease Group Specialized Register, Cochrane Central Register of Controlled Clinical Trials, MEDLINE, EMBASE, LILACS, and CINAHL

KEYWORDS: Extensive list provided in article appendix

INCLUSION CRITERIA: Quasi-randomized or randomized clinical trials whose participants received cisplatin (or related compounds) chemotherapy with or without a potential chemoprotectant and were evaluated zero to six months after completing chemotherapy using quantitative sensory testing (primary) or other measures, including nerve conduction studies or neurologic impairment rating using validated scales (secondary)

Literature Evaluated:

TOTAL REFERENCES RETRIEVED: Sixteen randomized trials were evaluated in the initial 2006 review. In the 2010 update, 11 additional randomized trials not among the 2006 review were identified.

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Cochrane method of evaluation for risk of bias done by two authors and finalized by consensus

Sample Characteristics:

  • N (studies) = 6
  • SAMPLE RANGE ACROSS STUDIES: 14–242
  • TOTAL PATIENTS INCLUDED IN REVIEW: 1,537 participants
  • KEY SAMPLE CHARACTERISTICS: Patients who received cisplatin chemotherapy

Conclusions:

Cisplatin is considered to have neurotoxic effects, with patients developing sensory neuropathy. Symptoms of pain, numbness, and tingling are observed mostly in the extremities from a distal to proximal distribution. The neuropathy experienced by patients may recover partially or may become permanent. Neuroprotective agents such as acetylcysteine, acetyl-L carnitine, amifostine, calcium and magnesium, growth factors, glutathione, ORG 2766, oxcarbazepine, and vitamin E have been tested. The five newly added randomized controlled trials included three chemoprotective agents not previously described in the 2006 review.

From the data examined in this updated review, inconclusive evidence exists for recommending any neuroprotective agent tested to prevent or limit the neurotoxicity of platinum chemotherapy.

Limitations:

While 1,537 participants were included in the 2010 update, few trials were amenable to meta-analysis. Clinical trials of neuroprotective agents are plagued by issues of study design, including small sample size, unclear randomization and blinding procedures, and lack of quantitative measures, especially conventional QST or electrophysiologic evaluation.

Hershman, D.L., Lacchetti, C., Dworkin, R.H., Lavoie Smith, E.M., Bleeker, J., Cavaletti, G., . . . American Society of Clinical Oncology. (2014). Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology, 32, 1941–1967.

doi: 10.1200/JCO.2013.54.0914
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Purpose:

STUDY PURPOSE: To provide evidence-based guidance on optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy in adult cancer survivors

TYPE OF STUDY: Systematic review

Search Strategy:

DATABASES USED: Ovid Medline (1946–April, week 2, 2013); EMBASE (1980–2013, week 16); AMED Allied and Complementary Medicine (1985–April 2013)

KEYWORDS: chemotherapy-induced peripheral neuropathy; adult cancer survivors; randomized clinical trials

INCLUSION CRITERIA: Adult cancer survivors with chemotherapy-induced peripheral neuropathy; randomized trials

EXCLUSION CRITERIA: Phase 1 trials; published in a language other than English; less than 10 patients; focused on radiation or stem cell transplant neuropathy; animal studies

Literature Evaluated:

TOTAL REFERENCES RETRIEVED = 1,252

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: An expert panel representing neurology, nursing, medical oncology, community oncology, pain research, and genetics met through teleconference and emails to review and develop the American Society of Clinical Oncology guidelines.

Sample Characteristics:

  • FINAL NUMBER STUDIES INCLUDED = 48
  • TOTAL PATIENTS INCLUDED IN REVIEW: Treatment studies: 780; prevention studies: 3,741

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment

Results:

Forty-two randomized clinical trials involved 19 various interventions for prevention of chemotherapy-induced peripheral neuropathy. These agents included anticonvulsants, antidepressants, vitamins, minerals, and other chemoprotectant drugs. Only six randomized clinical trials discovered six different drugs, such as antidepressants, anticonvulsants, and a topical gel, for the prevention of chemotherapy-induced peripheral neuropathy. The following are not recommended for use: acetyl-l-carnitine, amifostine, amitriptyline, calcium and magnesium, glutathione, nimodipine, ORG 2766, trans retinoic acid, rhuLIF, and vitamin E. Venlafaxine is not recommended for routine use in clinical practice. Although data support potential utility, evidence is not strong enough to suggest use. For treatment of chemotherapy-induced peripheral neuropathy, clinicians can offer duloxetine. No recommendation is made regarding ALC. Tricyclic antidepressants or gabapentin through trial use may be reasonable.  The panel felt that trying topical gel containing baclofen, amitriptyline, and ketamine would be reasonable. 

Conclusions:

No agents were recommended for the prevention of chemotherapy-induced peripheral neuropathy, but duloxetine is moderately recommended for the treatment of chemotherapy-induce peripheral neuropathy. Even though conclusive evidence is lacking to recommend tricyclic antidepressants such as nortriptyline, gabapentin, and a topical gel containing baclofen,amitriptyline, and ketamine for treatment of chemotherapy-induced peripheral neuropathy, the expert panel agreed that offering these agents based on treatment for neuropathic pain is reasonable. The panel also recommended that patients be counseled regarding the lack of evidence in treating chemotherapy-induced peripheral neuropathy with these agents.

Limitations:

  • Small, insufficient sample
  • Inability to compare studies because of different outcomes
  • Measurements and instruments used at different points in treatment

Nursing Implications:

Nurses are at the frontline in assessing patients who are receiving agents with the potential for chemotherapy-induced peripheral neuropathy. Nurses should be aware of the standard of care in treating this population. Many drugs prescribed have no evidence in preventing or treating these patients. However, with these American Society of Clinical Oncology guidelines, a role for duloxetine is clear and a role for tricyclic antidepressants is possible. Nurses need to be knowledgeable about this information to better inform patients.

Guideline/Expert Opinion

Stubblefield, M.D., Burstein, H.J., Burton, A.W., Custodio, C.M., Deng, G.E., Ho, M., . . . Von Roenn, J.H. (2009). NCCN task force report: Management of neuropathy in cancer. Journal of the National Comprehensive Cancer Network, 7(Suppl., 5), S1–S26.

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Purpose & Patient Population:

This study outlines the common antineoplastic agents known to cause neuropathy and provides information on incidence, onset dosages, the signs and symptoms, and general course and patterns of resolution. Agents identified include platinum compounds, vinca alkaloids, taxanes, bortezomib, ixabepilone, thalidomide, and lenalidomide. In addition to outlining the mechanisms of neuropathy development in cancer, the study discusses neurophysiologic and objective testing, noting that findings on electromyographic (EMG) and nerve conduction studies (NCS) can lag behind clinical symptoms. The study also identifies commonly used physician-based grading systems, including the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) and Eastern Cooperative Oncology Group (ECOG) systems, and notes that these two grading systems lack inter-rater reliability. Patient-based instruments for assessment include the Functional Assessment of Cancer Treatment (FACT) and the Patient Neurotoxicity Questionnaire (PNQ). The authors note that the routine assessment of pain secondary to neuropathy, using instruments such as the Brief Pain Inventory (BPI), is useful.

Guidelines & Recommendations:

Routine assessment should be conducted and continued throughout therapy. Key points in assessment that should be included are:

  • History, related comorbid conditions, alcohol use, symptoms, pain assessment, time course, and treatment delays or discontinuation from CIPN
  • Physical examination
  • Patient interview questions regarding sensation of numbness or tingling, pain, bothersome sensations, weakness, difficulty walking, falls, and interference with activities of daily living
  • Functional skills testing, such as straight-line walking, name writing, buttoning, pegboard tests, and timed pellet retrieval.

Proposed agents for prevention of CIPN identified include:

  • Agents with positive findings: vitamin E, calcium, magnesium, glutamine, glutathione, N-acetylcysteine, oxcarbazepine, xaliproden
  • Agents with negative findings: amifostine, nimodipine, Org2766, rhuLIF
  • Agents being tested in trials: vitamins B12, B6, acetyl-L-carnititne, alpha lipoic acid

Agents used for pain management:

  • Those with negative results in CIPN, including gabapentin, amitriptyline, notriptyline
  • Other agents commonly used include duloxetine, 5% lidocaine patch, opioids, tramadol

Current literature is inconclusive on the benefits of neurostimulation in treating CIPN. The authors note that evidence is scarce on efficacy of complimentary and alternative medicine (CAM) therapies and the need for appropriately powered and controlled studies in this area. However, acupuncture was identified as a promising adjunct option. The article also provides safety tips and issues for management of functional deficits in PIN, including situations in which to avoid or discontinue physical training, footwear selection, orthosis, and safety aspects of the household environment. Finally, the article addresses how autonomic neuropathy from chemotherapy occurs, but has not been well documented or studied.

Limitations:

  • Limitations include a significant lack of evidence regarding effective management and prevention in this area.
  • The review did not describe a search strategy or process to determine the quality of evidence used.

Nursing Implications:

The article provides a comprehensive review of current knowledge about CIPN and common approaches toward assessment, prevention, and management. The authors do not make specific recommendations for treatment, research to validate evaluation tools, and exploration of combinations and scheduling of pain medications. In addition, testing of the safety and effectiveness of therapeutic interventions and dietary supplements are needed.


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