Topical Ketamine Formulations

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

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

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.

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

PHASE OF CARE: Active antitumor treatment

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. 

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.

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

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.

The purpose of this study was to evaluate a compounded topical gel containing baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO).
 

Participants were randomized to receive 1.31 g of a compounded gel containing 10 mg of baclofen, 40 mg of amitriptyline HCL, and 20 mg of ketamine versus an identical looking placebo gel. Instructions were to apply one level spoonful of gel topically to each area of pain, numbness, and/ or tingling, twice a day (in the morning and before bed), for four weeks duration. Participants were not allowed to treat more than four areas of pain, numbness, and/or tingling at a single time (i.e., a maximum of four spoonfuls of gel per application). A small subset of participants was asked to have blood drawn at the end of the four weeks to measure concentrations of drugs and their metabolites.

• A total sample size of 203 patients (62% female) were assigned to either an intervention group or control group.
• The mean age of the intervention group was 59.9 years (SD = 10.75) and 62.1 years (SD = 10.27) in the control group; the age difference was not statistically significant.
• Disease characteristics were not provided, although it was clear that the patients had cancer.
• About 90% of the participants were Caucasian with chronic neuropathic pain for more than three months in duration.

The study was conducted at 16 separate academic institutions in the United States.

Phase of care

• Active treatment  

Applications

• Late effects and survivorship
   

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

• The European Organisation for the Research and Treatment of Cancer QLQ-C30 to measure quality of life.
• The CIPN20 to measure peripheral neuropathy.
• The Brief Pain Inventory to measure pain.
• The Profile of Mood States to measure mood.
• The National Cancer Institute's Common Terminology Criteria for Adverse Events.

Significant improvements in neuropathy symptoms in the hand and functioning of the hands were identified. Results in the feet were not as marked. Systemic absorption was minimal. Analysis of change in sensory neuropathy showed an effect size of about 0.28 (Cohen’s d, p = 0.053) in favor of the intervention. For the measurement subscale for motor neuropathy, the effect size of the change from baseline was 0.38 (p = 0.021). When analyzed as an ordinal scale outcome variable of negative change, no change or positive change for neuropathy symptoms, no significant difference was found between groups. No differences were noted between groups in the mood, pain, or quality-of-life measures.

Topical application of baclofen, 40 mg of amitriptyline HCL, and 20 mg of ketamine may be a useful approach to treatment of neuropathic pain related to CIPN, particularly if pain in the hands exists.

A limitation of this research was that the authors could not get U.S. Food and Drug Administration approval for the doses they originally wanted to use because of limited data on systemic absorption.

 Nurses may consider use of this novel topical compound, but more data is needed before definite recommendations can be made.

To determine the effectiveness and safety of the topical application of a combined 2% ketamine and 4% amitriptyline (KA) cream for reduction of chemotherapy-induced peripheral neuropathy (CIPN) in patients who have completed chemotherapy

One week prior to enrollment, subjects completed a seven-day daily pain, numbness, and tingling diary over the past 24 hours. Subjects answered the question for any of the three symptoms in either their hands or feet. At enrollment, subjects were instructed to use a measuring device for application of 4 g of either KA or placebo cream twice daily to each area of hands or feet with any pain, numbness, or tingling. The seven-day daily pain, numbness, and tingling diary for pain over the past 24 hours, by numeric rating scale (NRS), was completed at three and six weeks after enrollment. A secondary analysis for pain using NRS was done at baseline, three, and six weeks.

• N = 458
• AGE = 18 years or older; range not defined
• MALES: 29%, FEMALES: 71%
• KEY DISEASE CHARACTERISTICS: 40% breast cancer, 27% gastrointestinal cancer, 9% hematologic malignancy, 3% head and neck cancer, 8% lung cancer, 7% gynecologic cancer, 5% genitourinary cancer
• OTHER KEY SAMPLE CHARACTERISTICS: 100% had previous chemotherapy, 85% had previous surgery, 48% had previous radiation therapy, and 53% had prior taxanes; no statistical difference in sample characteristics between groups
• INCLUSION: One month post-completion of chemotherapy; subjects with average seven-day pain, numbness, and tingling ratings of greater than 4; 18 years or older; KPS greater than 60; pain medications allowed if the dose was stable for two weeks prior to enrollment
• EXCLUSION: Pre-existing peripheral neuropathy resulting from something other than chemotherapy; prior neurologic procedures or topical treatment; clinical depression; medications: monoamine oxidase inhibitors, barbiturates, anticholinergic agents, sympathomimetic drugs, inhibitors CP450 2D6; open skin lesions in the region of cream application; creatinine greater than 2 mg/dL within 30 days prior to screening

• SITE: Multi-site 
• SETTING TYPE: Outpatient    
• LOCATION: University of Rochester Cancer Center Community Clinical Oncology Program

• PHASE OF CARE: Transition phase after active treatment 
• APPLICATIONS:  Elder care, palliative care

• Multi-center, phase III, double-blind, randomized, placebo-controlled clinical trial
  • Stratified into two treatment regimen groups: prior taxanes and nontaxane

• NRS (0 = not at all to 10 = as bad as you could imagine) for evaluation of any pain, numbness, and tingling in hands or feet
• Secondary analysis for pain in hands or feet was evaluated with an NRS  (0 = no pain to 10 = worst pain you can imagine) adapted from the MD Anderson Symptom Inventory.

No therapeutic effect was observed with the application of KA cream to the affected areas on hands or feet for reduction of pain, numbness, and tingling (p = 0.363). Secondary analysis for pain alone did not show a statistically significant difference between groups comparing means at 95% CI (KA cream, 4.64; placebo, 4.68). Patients in the treatment regimen group of prior taxanes, regardless of receiving study treatment with either KA or placebo, reported a reduction in pain, numbness, and tingling at six weeks (p = 0.042). No statistically significant adverse events were reported for the KA treatment group compared to the placebo group.

This study showed no therapeutic benefit for the topical application of KA cream for CIPN.

• Measurement validity/reliability questionable
• No separation for measurement of pain, numbness, or tingling in the primary analysis
• No standardized scale for symptom assessment of peripheral neuropathy was used (i.e., National Cancer Institute Common Toxicity Criteria) in the primary analysis
• Other limitations/explanation: Unknown type of prior chemotherapy for sample population other than taxanes; unknown surgical and radiation therapy anatomic sites; unknown patient sample age range and comorbidities

Further studies need to be done to investigate if any combination or separate topical compound targeting specific nociceptive pathways has a therapeutic benefit for CIPN.