Duloxetine

Duloxetine

PEP Topic 
Peripheral Neuropathy
Description 

Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant. Antidepressants in general have been examined for treatment of depression in patients with cancer. Duloxetine specifically has been examined for its effect on pain and peripheral neuropathy.

Likely to Be Effective

Systematic Review/Meta-Analysis

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.

Research Evidence Summaries

Otake, A., Yoshino, K., Ueda, Y., Sawada, K., Mabuchi, S., Kimura, T., . . . Kimura, T. (2015). Usefulness of duloxetine for Paclitaxel-induced peripheral neuropathy treatment in gynecological cancer patients. Anticancer Research, 35, 359–363.

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Study Purpose:

To explore the potential efficacy of duloxetine for use against chemotherapy-induced peripheral neuropathy (CIPN) among patients with gynecologic cancers receiving paclitaxel

Intervention Characteristics/Basic Study Process:

The medical records of patients being treated with duloxetine were evaluated retrospectively. The severity of symptoms before and after duloxetine administration was evaluated according to documented patient responses as either responders (symptoms dropped more than 1 grade) or non-responders (patients had a stable or worsening grade of neuropathy). A maintenance dose of duloxetine at 20 mg per day was given in 18 cases, and 40 mg per day was given in seven cases. In 12 cases, duloxetine administration began during chemotherapy. In 13 cases, it was started after chemotherapy (in four of these cases, one year after the completion of chemotherapy).

Sample Characteristics:

  • N = 25  
  • MEDIAN AGE = 62 years (range = 40–77 years)
  • FEMALES: 100%
  • KEY DISEASE CHARACTERISTICS: Ovarian, corpus, and cervical cancers; all were receiving paclitaxel and carboplatin with or without epirubicin; median accumulated dose of paclitaxel was 1,805 mg per body; accumulated median dose of carboplatin was 3,368 mg
  • OTHER KEY SAMPLE CHARACTERISTICS: Prior to duloxetine, medications used in some patients included goshajinkigan, pregaabalin, vitamin B12, and SSRIs.

Setting:

  • SITE: Single-site    
  • SETTING TYPE: Outpatient    
  • LOCATION: Japan

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Multiple phases of care
  • APPLICATIONS: Palliative care 

Study Design:

Retrospective, observational trial

Measurement Instruments/Methods:

  • National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.0

Results:

56% of patients responded to duloxetine and 44% did not respond. An analysis of demographic, disease, and treatment-related variables showed no significant association between any of these factors and the effectiveness of duloxetine. Adverse events were mild, and duloxetine generally was well tolerated. Overall, older patients tended to be less responsive to duloxetine.

Conclusions:

The majority of patients responded to duloxetine, suggesting that in some patients, it can be helpful in managing the symptoms of CIPN.

Limitations:

  • Small sample (< 30)
  • Risk of bias (no control group)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Measurement validity/reliability questionable

 

 

Nursing Implications:

The findings of this study suggest that duloxetine may be helpful for some patients for the prevention and management of CIPN. However, it was not effective in all cases. The study's findings were limited by its design. Additional research studies exploring effective dosages, the types of CIPN that respond to duloxetine, appropriate timing, and effects of duloxetine on the full range of CIPN symptoms rather than just pain are needed.

Smith, E.M., Pang, H., Cirrincione, C., Fleishman, S., Paskett, E.D., Ahles, T., . . . Alliance for Clinical Trials in Oncology. (2013). Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial. JAMA: The Journal of the American Medical Association, 309, 1359-1367.

doi: 10.1001/jama.2013.2813
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Study Purpose:

Determine the effect of duloxetine on pain severity

Intervention Characteristics/Basic Study Process:

Patients were randomized to two study groups: group A subjects received 60 mg of duloxetine initially and then were crossed over to receive placebo and group B subjects initially received placebo and then were crossed over to duloxetine. The initial study period was five weeks. This was followed by a two-week washout period and then a final study period of an additional five weeks. Patients were assessed weekly. Use of other drugs that affect serotonin levels was not allowed. Concomitant use of other analgesics was allowed.

Sample Characteristics:

  • N = 141
  • MEAN AGE = 59 years (SD = 10.5 years)
  • MALES = 37%, FEMALES = 63%
  • KEY DISEASE CHARACTERISTICS: The majority of patients had gastrointestinal or breast cancer. All had received neurotoxic chemotherapy with taxanes or platinum compounds. 44% were considered high risk for peripheral neuropathic pain due to other conditions such as diabetes. All had at least grade 1 sensory pain on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v 3.0) and reported at least level 4 neuropathic pain on a 10-point scale for three or more months after completing chemotherapy.
  • OTHER KEY SAMPLE CHARACTERISTICS: 81% were Caucasian; 14% were black.

Setting:

  • SITE: Multi-site 
  • SETTING TYPE: Outpatient 
  • LOCATION: United States

Phase of Care and Clinical Applications:

PHASE OF CARE: Transition phase after active treatment

Study Design:

Double-blind, placebo-controlled, crossover, randomized controlled trial

Measurement Instruments/Methods:

  • Breif Pain Inventory (Short Form): Average pain severity was used as outcome.
  • Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx)
  • National Cancer Institute Common Terminology Criteria for Adverse Events (v 3.0)

Results:

Among patients who received duloxetine first, 59% reported some decrease in pain, 30% reported no change in pain, and 10% reported increased pain. Compared with placebo, there was a significant chance of receiving a 30% reduction in pain score (RR = 1.96, 95% CI 1.15-3.35) and a 50% reduction in average pain (RR = 2.43, 95% CI 1.11-5.30) with duloxetine. Analysis suggested a greater benefit in patients receiving platinums compared to those who received taxanes. Patients who received duloxetine in the second study period appeared to show greater reduction in average pain scores. Overall duloxetine treatment effect on pain was significant (p < .001). After initial treatment, 41% on duloxetine reported decrease in numbness and tingling in the feet versus 23% on placebo (p ≤ .05). This trend continued through the crossover period. In the duloxetine group, 11% dropped out due to adverse events, compared to 1% receiving placebo. More patients on duloxetine experienced nausea. Other adverse effects were similar between treatments. The most common adverse effects were fatigue and insomnia.

Conclusions:

Compared to placebo, duloxetine treatment had a significant effect on pain from chemotherapy-induced peripheral neuropathy. Duloxetine also had some positive effect on numbness and tingling symptoms in the feet but not in upper extremities.

Limitations:

  • Measurement validity/reliability was questionable.
  • Subject withdrawals were ≥ 10%.
  • Concomitant analgesics and changes in analgesics were not described.
  • It is unclear why an apparent greater effect on average pain with duloxetine occurred in the second study period for group B. 
  • There was an overall 19% drop-out rate.
  • A higher proportion of grade 3 toxicities occurred with duloxetine.
  • Only average pain, and pain interference during the initial study period, were compared, rather than comparison between the two study conditions. Why this was done is not clear..

Nursing Implications:

Findings show that duloxetine can be effective in reducing pain from chemotherapy-induced peripheral neuropathy. Duloxetine also was associated with more adverse events. Nurses will need to monitor for adverse events, particularly for patients who may already be experiencing sleep wake disturbance and fatigue.

Yang, Y.H., Lin, J.K., Chen, W.S., Lin, T.C., Yang, S.H., Jiang, J.K., . . . Teng, H.W. (2012). Duloxetine improves oxaliplatin-induced neuropathy in patients with colorectal cancer: An open-label pilot study. Supportive Care in Cancer, 20, 1491-1497.

doi: 10.1007/s00520-011-1237-2
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Study Purpose:

Evaluate the efficacy and tolerability of duloxetine in the treatment of chronic oxaliplatin-induced peripheral neuropathy

Intervention Characteristics/Basic Study Process:

Patients receiving 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) who had grade 1-2 neuropathy on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0) were given duloxetine at 30 mg/day and escalated to 60 mg/day for one week if there were no signs of drug intolerance. Patients were followed at two-week intervals for laboratory testing, assessment, and evaluation for adverse effects and symptom grading. The study lasted 12 weeks.

Sample Characteristics:

  • N = 30
  • MEAN AGE = 64.8 years (range = 34-83 years)
  • MALES = 56.4%, FEMALES = 43.6%
  • KEY DISEASE CHARACTERISTICS: All had colorectal cancer; 79.5% had stage IV disease.
  • OTHER KEY SAMPLE CHARACTERISTICS: 43% had grade 1 neuropathy at baseline, and 54% had grade 2 at baseline.

Setting:

  • SITE: Single site 
  • SETTING TYPE: Outpatient 
  • LOCATION: Taiwan

Phase of Care and Clinical Applications:

PHASE OF CARE: Active antitumor treatment

Study Design:

Single-group, prospective, open-label trial

Measurement Instruments/Methods:

  • Visual analog scale (VAS) for peripheral neuropathy pain (10 cm)
  • NCI CTCAE v3.0

Results:

VAS scores showed improvement in 63.3% of patients who continued on the study for 12 weeks, and 47.4% maintained a stable grade of neuropathy. 28% discontinued duloxetine because of intolerable adverse events, including dizziness, nausea, somnolence, restlessness, insomnia, and urinary hesitancy. No substantive changes in serum creatinine or hepatic enzyme levels occurred.

Conclusions:

For those patients who could tolerate escalating doses of duloxetine, it appeared to have some benefit in reducing peripheral neuropathy symptoms.

Limitations:

  • Small sample of < 100
  • Risk of bias (no control group)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Subject withdrawals ≥ 10%
  • 30% withdrew due to inability to tolerate the medication.

Nursing Implications:

Some antidepressants have been studied for their potential effect on chemotherapy-induced peripheral neuropathy. This study suggests that duloxetine may be helpful to some patients; however, the study was limited by a small sample size and open-label design. Thirty percent of the sample dropped out of the study within the first 12-week period due to side effects of the study medication, showing that many patients may not be able to tolerate the drug. Nurses caring for patients with or the potential for peripheral neuropathy symptoms and who are being treated with antidepressants need to assess for patient tolerance of these drugs. Further research is needed to establish the efficacy of antidepressants for peripheral neuropathy secondary to chemotherapy administration.


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