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Author Manuscript
Support Care Cancer. Author manuscript; available in PMC 2012 April 27.
NIH-PA Author Manuscript Published in final edited form as: Support Care Cancer. 2011 June ; 19(6): 833–841. doi:10.1007/s00520-010-0911-0.
A double-blind, placebo-controlled trial of a topical treatment for
chemotherapy-induced peripheral neuropathy: NCCTG trial
Debra L. Barton,
Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN, 55905 USA
Edward J. Wos,
Medcenter One Health System, Bismarck, ND, USA
Rui Qin,
Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN, 55905 USA
NIH-PA Author Manuscript Bassam I. Mattar,
Wichita CCOP, Wichita, KS, USA
Nathan Benjamin Green,
Missouri Valley Cancer Consortium CCOP, Omaha, NE, USA
Keith S. Lanier,
Providence Oncology and Hematology Care Clinic, Portland, OR, USA
James Dewitt Bearden III,
Spartanburg Regional Medical Center, Spartanburg, SC, USA
John W. Kugler,
Illinois CancerCare, Peoria, IL, USA
Kay L. Hoff,
Cancer Resource Center, Lincoln, NE, USA
Pavan S. Reddy,
Wichita CCOP, Wichita, KS, USA
Kendrith M. Rowland Jr,
NIH-PA Author Manuscript Carle Cancer Center, Urbana, IL, USA Mike Riepl,
Gateway Health Mart Pharmacy, Bismarck, ND, USA
Bradley Christensen, and
Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN, 55905 USA
Charles L. Loprinzi
Springer-Verlag 2010 Correspondence to: Debra L. Barton, [email protected].
Additional participating institutions include the following: Cedar Rapids Oncology Program CCOP, Cedar Rapids, IA 52403, USA(Martin Wiesenfeld, MD); Geisinger Clinic and Medical Center CCOP, Danville, PA 17822, USA (Albert M. Bernath, Jr., M.D.);Rapid City Regional Hospital, Inc, Rapid City, SD 57701, USA (Richard Charles Tenglin, M. D.); Sioux Community CancerConsortium, Sioux Falls, SD 57105, USA (Loren K. Tschetter, M.D.); Toledo Community Hospital Oncology Program (Paul L.
Schaefer, M.D.); Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, MN 55416, USA (Patrick J. Flynn, M.D.);Mayo Clinic, Scottsdale, AZ 85259-5404, USA (Tom R. Fitch, M.D.); and Hematology/Oncology Centers of the Northern Rockies,Billings, MT 59101, USA (Benjamin Marchello, M.D.).
Barton et al.
Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN, 55905 USA Debra L. Barton: [email protected] NIH-PA Author Manuscript Background—Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic
symptom that has no proven pharmacologic treatment. The purpose of this double-blind
randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this
Methods—Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg,
and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to
determine its effect on numbness, tingling, pain, and function. The primary endpoint was the
baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks.
Results—Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO
arm over placebo in both the sensory (p=0.053) and motor subscales (p=0.021). The greatest
improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in
the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated
with the BAK-PLO and no evidence of systemic toxicity.
Conclusion—Topical treatment with BAK-PLO appears to somewhat improve symptoms of
NIH-PA Author Manuscript CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research isneeded with increased doses to better clarify the clinical role of this treatment in CIPN.
CIPN; Topical gel; BAK-PLO Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect ofmany chemotherapeutic agents including vincristine, paclitaxel, cisplatin, and oxaliplatin[1–7]. The incidence of CIPN can be variable, ranging from 0% to 70% of patients receivingchemotherapy, but commonly occurs in 30–40% of patients. There are a number of factorsthat can influence the incidence of CIPN, in particular, patient age, dose intensity,cumulative dose, duration of therapy, administration of other neurotoxic agents, and pre-existing conditions such as diabetes and alcohol abuse [2, 3, 8–13]. Many symptoms ofCIPN may resolve completely for some patients. However, CIPN is only partly reversible inother instances. In the worst instances, it does not appear to be reversible at all and can even NIH-PA Author Manuscript increase over time [13].
CIPN can be extremely painful and/or disabling, causing significant loss of functionalabilities and quality of life [14]. Neurotoxic chemotherapeutic agents may cause structuraldamage to peripheral nerves, resulting in aberrant somatosensory processing of theperipheral and/or central nervous system [7]. This resultant peripheral neuropathy canpotentially affect both small fiber axons (temperature and pin prick) and large fiber sensoryaxons (vibration and proprioception) [14]. A common clinical course begins with tingling orparesthesias and dysesthesias, often located in the toes and fingers. These symptoms canthen spread proximally to affect both lower and upper extremities in a characteristic "gloveand stocking" distribution [15]. The pain associated with CIPN has not been adequatelycharacterized nor clinically quantified. Sensory perceptions of patients are varied and caninclude reports of severe pain, shooting pain, burning sensations, numbness, tingling,increased response to painful stimuli, sensitivity to touch, and/or a combination of all ofthese sensations. It is not currently known whether all of these sensations (such as Support Care Cancer. Author manuscript; available in PMC 2012 April 27.
Barton et al.
numbness, tingling, burning pain, allodynia, and hyperalgesia) have similar physiologiccharacteristics or trajectories. Until more is known, all possible symptom experiences should NIH-PA Author Manuscript be evaluated both clinically and in research.
Current management strategies
There is no proven standard treatment to prevent or treat CIPN at this time [13], althoughpreliminary data suggest that infusions of calcium and magnesium may reduce CIPN relatedto oxaliplatin, and studies are ongoing to evaluate this treatment for neuropathy related totaxanes [16]. Current prevention strategies mainly consist of chemotherapy dose reductionor lower dose intensities, particularly in those patients who are at higher risk to developneurotoxic side effects. Patients who develop peripheral neuropathy while actively receivingneurotoxic chemotherapy often receive decreased doses or discontinuation of theirchemotherapy treatment all together [6]. This strategy, decreasing chemotherapy dosing orcessation of treatment, can potentially impact tumor response, prognosis and, therefore,overall survival.
Several agents have been evaluated for the treatment of CIPN, mostly on the basis of theirability to impact diabetic or other forms of neuropathy [17–19]. Adjuvant analgesics,including tricyclic antidepressants and anticonvulsants, are among a few of these. To date,none of these agents, such as nortriptyline [20], gabapentin [21], or lamotrigine [22], have NIH-PA Author Manuscript been found effective for treating CIPN in randomized, controlled trials. Otherpharmaceutical agents such as amifostine [23] and glutamine [24] are theorized to behelpful, but randomized controlled trials have not yet been completed to evaluate theireffectiveness.
Physiology of analgesia and neuropathic pain
One of the limitations in developing effective prevention or treatment strategies for CIPN isthe lack of knowledge about the exact pathophysiology and trajectory of the development ofCIPN. Strategies to understand the physiology of CIPN have utilized the science forneuropathic pain, which is admittedly only one element of CIPN symptoms. There areseveral potential physiologic mechanisms theorized [25, 26]. One of these involves thedepletion of substance P, a neurotransmitter that affects small diameter sensory afferentnerves. Depleting substance P might be able to quiet the noxious activation of these nervesand decrease pain. There are numerous potential physiologic targets for neuropathic painthat may relate to CIPN. These include modulating voltage-gated sodium channels,inhibiting NMDA, turning on alpha 2-ADRENERGIC receptors and GABA (in particularGABA-B) receptors, and inhibiting histamine, to name only a few [25–27]. Agents NIH-PA Author Manuscript exhibiting one or more of these mechanisms of action are available and can be used eitherorally or topically [27, 28].
Since neuropathic pain is complex and several physiologic pathways may be implicated, oneapproach to treating chemotherapy-induced neuropathy or neuropathic pain would be toemploy agents with multiple mechanisms of action for treatment [28]. Combining severalpharmacological agents with different mechanisms of action orally, however, could result inintolerable sedation and side effects, due to cumulative effects of analgesics agents. Onestrategy, to allow multiple agents with different mechanisms of action while minimizingintolerable side effects, is to use a topical approach for analgesia. The use of topicalamitriptyline in combination with ketamine for diabetic neuropathy, postsurgical/posttraumatic neuropathic pain with allodynia, hyperalgesia, pinprick hyperesthesia [29–31],or postherpetic neuralgia [32] has been described.
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Topical agents, that are locally absorbed, have been described in the literature related to pain[29, 33]. Pharmacokinetic data over 96 h in 36 healthy adults found topical 4% amitriptyline NIH-PA Author Manuscript and topical 2% ketamine to have systemic concentrations well below that of systemicallyadministered agents [33]. The permeability of a compound is due primarily to theconcentration in the vehicle and its ability to cross the stratum corneum of the skin [34].
Therefore, it is theoretically possible that pain medications can be given in combinations toprovide complementary mechanisms of action to have efficacy at the local level without theunwanted systemic toxicities. It is also quite possible that topical analgesics can have animpact on a wider range of CIPN symptoms than just neuropathic pain.
This current trial was developed to evaluate three topical analgesic agents for their effect onCIPN. These agents, baclofen, amitriptyline HCL, and ketamine, were chosen specificallybecause of their unique but complementary mechanisms of action [28–37]. Baclofen is aGABA receptor agonist [35, 36], amitriptyline HCL affects adenosine A receptors [29–31]and sodium channels and ketamine inhibits NMDA receptors [29–31, 37]. Therefore, thereare three different pathways invoked that may provide additive or synergistic relief ofneuropathy symptoms. The triple agent gel was developed by a compounding pharmacist inNorth Dakota and has been used in clinical practice to relieve symptoms of peripheralneuropathy from various etiologies. Based on published data showing the efficacy of topicalamitriptyline and ketamine for neuropathic pain as well as positive outcomes in clinical NIH-PA Author Manuscript practice for CIPN with this triple agent gel, a clinical trial was developed to formallyevaluate the combination of baclofen, amitriptyline, and ketamine.
The purpose of this study was to conduct a randomized placebo-controlled clinical trial toevaluate a topical baclofen, amitriptyline HCL, and ketamine (BAK) gel to alleviateneuropathic pain, numbness, and/or tingling of CIPN. Secondary goals included theevaluation of function, general pain, and toxicity.
Materials and methods
Patients who had received, or were currently receiving, neurotoxic chemotherapy and hadnumbness, tingling, or pain associated with peripheral neuropathy for at least the previousmonth were eligible for this study. Participants had to rate their numbness/tingling/pain at alevel of at least four out of ten on a 0–10 scale where zero was no neuropathy and ten wasworst possible neuropathy. Also required was a life expectancy of at least 4 months and aserum creatinine less than 1.5 times the upper limits of normal. Neuropathy had to be limitedto the hands and/or feet where the topical gel could be applied. Participants could not have a NIH-PA Author Manuscript history of peripheral neuropathy from other causes nor pre-existing allergies to baclofen,amitriptyline, or ketamine. They could not be concurrently treated with any agent withsuspected efficacy for neuropathy, such as anticonvulsants or tricyclic antidepressants.
Participants must not have had a history of coronary artery disease. Written informedconsent for participating in this trial was obtained for each patient, which was monitored bylocal institutional review boards as required by US federal regulations. Participants werestratified based on current versus only previous neurotoxic chemotherapy exposure, use ofopioids or oral pain medication, baseline pain ratings, and whether they had previously triedpharmacologic treatment for their neuropathy. Randomization was done using dynamicallocation to balance marginal distributions of the stratification factors [38].
Participants were randomized to receive 1.31 g of a compounded gel containing 10 mg ofbaclofen, 40 mg of amitriptyline HCL, and 20 mg of ketamine versus an identical appearing Support Care Cancer. Author manuscript; available in PMC 2012 April 27.
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placebo gel. Instructions were to apply one level spoonful of gel topically to each area ofpain, numbness, and/or tingling, twice a day, in the morning and before bed, for 4 weeks NIH-PA Author Manuscript 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). Asmall subset of participants was asked to have blood drawn at the end of the 4 weeks tomeasure concentrations of drugs and their metabolites. Drug assignments to individualpatients were accessible only by the North Central Treatment Group randomization office,study pharmacists, and the study statisticians. The BAK and placebo gel were compoundedat Gateway HealthMart Pharmacy Laboratory in Bismarck, North Dakota. AnInvestigational New Drug Application was obtained for this trial, and the Food and DrugAdministration specified the doses of the agents that were approved to be used in this study.
These doses were lower than initially proposed, due to the lack of data on systemicabsorption of this triple combination. Potency of the gel was evaluated every 3 months outto 1 year by Eagle Analytical. Full potency was sustained in the gel for each active agentthroughout the 1-year period. The study was registered according to current US federalregulations. Funding for this study was provided through the National Cancer Institute'sCCOP program.
The primary end point for the study was the changes in the sensory neuropathy subscale asmeasured by the European Organization for Research and Treatment of Cancer QLQ- NIH-PA Author Manuscript CIPN20 (CIPN-20) [39] instrument from baseline to 4 weeks. The CIPN20 is a fairly new20-item questionnaire evaluating various aspects of CIPN. It has three subscales assessingsensory (nine items), motor (eight items), and autonomic (three items) symptoms andfunctioning with each item measured on an ordinal 1–4 scale (1, not at all; 4, very much).
The sensory subscale contains nine items, which cover the experience of numbness, tingling,and burning/shooting pain in the fingers/hands and the toes/feet (six questions). Theremaining three questions ask about problems standing or walking due to difficulty feelingthe ground, difficulty distinguishing between hot and cold, and difficulty hearing. The motorsubscale asks about function such as being able to hold a pen, open jars, climb stairs, andcramping. The autonomic subscale evaluates erectile dysfunction, dizziness, and vision.
Participants completed this questionnaire at baseline, before starting the study gel, and at 4weeks. The EORTC QLQ-CIPN20 has been used in patients with cancer receiving a varietyof chemotherapies and has been shown in pre-testing to have internal consistency reliabilitybased on Cronbach's alpha coefficients of 0.82, 0.73, and 0.76 for the three subscales,respectively [39].
Other measurement instruments utilized in this trial include the Profile of Mood States(POMS) [3, 40], the Brief Pain Inventory [41], and the sensory neuropathy subsection of the NIH-PA Author Manuscript NCI Common Terminology Criteria, version 3.0. Single numeric analogue questions [42–44] regarding the presence of numbness/tingling/pain (all included in one question) as wellas various potential side effects, such as drowsiness, dry mouth, dizziness, constipation,nausea, headaches, and skin irritation, were also included. Participants rated the severity ofthese symptoms on a 0 to 10 scale, with 10 being the most severe. Adverse events wereevaluated through the patient-reported questions mentioned above as well as being gradedthrough the NCI Common Terminology Criteria, version 3.0. Toxicities specifically gradedduring the 4 weeks of the study included rash, constipation, dry mouth, confusion, anddepressed level of consciousness.
The scoring algorithm for the parent instrument, the EORTC QLQ-C30, was applied forlinearly converting items and subscales of CIPN-20 to 0–100 scales so that a high scorecorresponds to better condition or less symptom. The primary analysis was to comparechanges from baseline at 4 weeks for the sensory neuropathy subscale of the CIPN-20.
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Effect size using Cohen's d was calculated using the mean difference between the arms forthe subscale divided by the standard deviation. Supplementary analysis included changes NIH-PA Author Manuscript from baseline at 4 weeks for the motor neuropathy and autonomic subscale of the CIPN-20,the POMS, single-item neuropathy question, and the Brief Pain Inventory. The change frombaseline at 4 weeks for the numeric analogue scale and self-report toxicities was alsocompared between arms. A two-sided two-sample t test or Wilcoxon rank-sum test with analpha of 0.05 was used for the primary statistical analysis. Wilcoxon rank-sum tests and chi-square tests were used for baseline patient characteristics. Descriptive statistics with 95%confidence intervals based on two-sample t test were used for secondary analyses due totheir exploratory nature. Sixty-four patients per arm provided 80% power to detect a halfstandard deviation difference between arms, which is considered a moderate effect size.
Two hundred and eight patients were enrolled into this study from February 22, 2008 toOctober 23, 2008 by 16 NCCTG institutions. There were five patients who withdrew fromthe study before starting study medication, leaving 101 patients in the BAK arm and 102patients in the placebo arm. Baseline characteristics of the study population are listed inTables 1 and 2, while the flow of participants is illustrated in the CONSORT diagram in Fig.
1. There were 26 participants in the BAK arm and 27 in the placebo arm who did not NIH-PA Author Manuscript provide primary endpoint data. In the BAK arm, 11 refused due to experiencing an adverseevent and 15 refused for non-specified reasons. In the placebo arm, eight refused due to anadverse event, one patient died, and 18 refused for non-specified reasons.
The primary analysis of the changes from baseline at 4 weeks for the sensory neuropathysubscale showed a trend in favor of the active arm, with the mean and SD of 8.1 (15.05) forthe BAK arm and 3.8 (15.52) for the placebo arm, with an effect size of about 0.28 for theactive arm over placebo (p= 0.053). For the motor neuropathy subscale, the mean changefrom baseline and SD were 7.1 (13.72) for BAK arm and 1.8 (14.05) for placebo arm, for aneffect size of about 0.38 over placebo (p=0.021). The change in the autonomic subscale wasnot significantly different between the two study arms. These data are shown in Table 3.
Further exploratory analyses were done looking at individual items of the sensory and motorneuropathy subscales, looking at the changes from baseline. In terms of the original 1–4scale (Figs. 2 and 3), there were three areas that were improved with the BAK treatmentwithout adjusting for multiple comparisons. These were tingling in fingers/hands, shootingor burning pain in fingers/hands, and the ability to hold a pen. Trends of improvement fromBAK treatment were seen for several other items. In general, the benefits of therapy tendedto be more impressive in the upper extremities, as opposed to the lower extremities.
NIH-PA Author Manuscript The sensory neuropathy change from baseline measured by the CTCAE was evaluated viatwo different ways due to the ordinal nature of toxicity data. Assuming equal intervalsbetween grades, we have observed a marginally significant difference between the treatmentand placebo arms (p=0.054). However, when we collapsed the change from baseline aspositive change, no change, and negative change, analyzing as an ordinal scale (which islikely a more valid assumption), there was no significant differences between arms (p=0.195). The single-item neuropathy question mean change from baseline at 4 weeks in theBAK arm was 11.2 (SD, 20.53) and 6.3 (SD, 23.60) in the placebo arm. Neither the BriefPain Inventory nor the POMS were significantly different between the two study arms.
No significant differences in toxicities were observed between the BAK arm and the placebothroughout the 4 weeks of the study. These data are shown in Table 4 for the CTC gradedtoxicities and Table 5 for the self-report side effects.
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Blood was drawn during the double-blind phase on a small subset of participants (N=8) toevaluate systemic absorption. None of the four people taking placebo had detectable levels NIH-PA Author Manuscript of any of the components of BAK. Of the four participants on active drug, two hadundetectable levels of all three agents, one had barely detectable levels of amitriptyline thatwere not near therapeutic levels but no detectable ketamine or baclofen, and one had lowtherapeutic levels of baclofen but undetectable levels of amitriptyline and ketamine.
This study demonstrated that BAK gel resulted in a trend toward more improvement insensory neuropathy and a statistically significant improvement in motor neuropathy asmeasured by the EORTC QLQ-CIPN20. Though there were some statistically significantoutcomes, the overall effect size was not large. While these results provide some support forthe pre-study hypothesis that the BAK gel can decrease CIPN, the data from it fall short ofconvincingly proving this hypothesis.
There are a couple reasons that might explain why a more potent effect was not observedand why further study is needed. This study was developed based on the clinical experienceof compounding pharmacists in North Dakota. Initially, based on clinical experience, thestudy proposed using 60 mg of amitriptyline HCl, 30 mg of ketamine, and 30 mg ofbaclofen. Due to insufficient data supporting the lack of systemic absorption, the Food and NIH-PA Author Manuscript Drug Administration required the use of lower doses in this trial, which resulted in thedosing described in this manuscript. This lower dose may explain why more benefit was notseen.
A similar dose–effect issue may explain why the hands seemed to derive more benefit thanthe feet. Since one level spoonful was instructed to be applied to each area of neuropathy, itis possible that the feet were relatively underdosed based on surface area. In addition, itcould be argued that the hands would likely have received a higher dose than the feet as thehands would have been used to rub the gel onto the feet, but not vice versa. Since separatequestions for hands and feet are included in the sensory subscale, the under-dosing related tothe feet could have impacted the effect size.
In addition, this group of agents was compounded in a pluronic lecithin organogel (PLO)gel, which was thought to be the best medium for topically absorbed agents. There werereports from the institutions participating in this trial that patients had difficulty workingwith the PLO gel and getting it to absorb into their skin. Therefore, future studies may wishto consider using a different liposomal transdermal base, such as Lipoderm, which may beeasier for participants to rub into their skin.
NIH-PA Author Manuscript It was not surprising that the autonomic subscale of the CIPN-20 measure was not positivelyimpacted with the BAK treatment. The three items that comprise this subscale relate tosystemic neuropathy troubles: erection (for males), dizziness, and vision. First, patients onthis trial were only required to have neuropathy in their extremities. Therefore, it is likelythat participants in this trial were not having difficulties in these areas. In addition, thissupports that the study drugs were not systemically absorbed to any significant degree.
It is noteworthy that positive results on the Brief Pain Inventory similar to those forshooting/burning pain were not achieved. This is likely because the Brief Pain Inventorydoes not include language specific to neuropathic pain, while the CIPN20 uses the term"shooting/burning pain." About 25% of the participants in each arm did not provide data that enabled computation ofthe primary endpoint. As participants could be eligible for this study with advanced disease, Support Care Cancer. Author manuscript; available in PMC 2012 April 27.
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going in and out of treatment, and experiencing any number of health problems, thispercentage of non-evaluable patients is consistent with this situation.
NIH-PA Author Manuscript As there are no other known effective treatments for the relief of established neuropathysymptoms from chemotherapy, the signal of potential benefit provided by these data warrantfurther study of this combination of topical baclofen, amitriptyline, and ketamine,specifically evaluating a higher dose of the agents in a more user-friendly compoundingbase.
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinicand was supported in part by Public Health Service grants CA-25224, CA-37404, CA-63848, CA-35195,CA-37417, CA-35448, CA-35267, CA-63849, CA-35113, CA-35103, CA-35415, CA-35431, and CA124477. Thecontent is solely the responsibility of the authors and does not necessarily represent the views of the NationalCancer Institute or the National Institute of Health.
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NIH-PA Author Manuscript NIH-PA Author Manuscript Fig. 1. CONSORT diagram
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NIH-PA Author Manuscript NIH-PA Author Manuscript Fig. 2. Sensory subscale of the EORTC QLQ-CIPN-20; change from baseline, lower numbers are

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NIH-PA Author Manuscript NIH-PA Author Manuscript Fig. 3. Motor subscale of the EORTC QLQ-CIPN-20; change from baseline, lower numbers are

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NIH-PA Author Manuscript Black or African American Chemotherapy with neurotoxic agent Current use of opioids or other pain meds Duration of pain or neuropathy symptoms NIH-PA Author Manuscript >3 to 6 months Baseline numbness/tingling/pain category Previous peripheral neuropathy treatment Exposure to neurotoxic agents over lifetime NIH-PA Author Manuscript Support Care Cancer. Author manuscript; available in PMC 2012 April 27.
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Exposure to neurotoxic agents at baseline (participants may have been exposed to more
NIH-PA Author Manuscript than one agent)
Previous treatment only percent of patients
Concurrent treatment percent of patients
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EORTC QLQ-CIPN20 mean change from baseline; range, 0–100, higher numbers are
NIH-PA Author Manuscript Mean change from baseline
Difference (95% CI)
4.3 (−0.6, 9.3) Autonomic subscale 1.6 (−4.0, 7.1) NIH-PA Author Manuscript NIH-PA Author Manuscript Support Care Cancer. Author manuscript; available in PMC 2012 April 27.
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Maximum adverse events by arm related to central nervous system depression
NIH-PA Author Manuscript Low consciousness NIH-PA Author Manuscript NIH-PA Author Manuscript Support Care Cancer. Author manuscript; available in PMC 2012 April 27.
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Patient-reported side effects change from baseline at 4 weeks; range, 0–100, higher
NIH-PA Author Manuscript numbers are better
Side effect
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J Comp Physiol B (2004) 174: 223–236DOI 10.1007/s00360-003-0405-1 A. R. Cooper Æ S. Morris Haemoglobin function and respiratory status of the PortJackson shark, Heterodontus portusjacksoni, in responseto lowered salinity Accepted: 20 October 2003 / Published online: 8 January 2004 Springer-Verlag 2004 Abstract Haemoglobin function and respiratory status Keywords Respiration Æ Haemoglobin Æ Shark Æ

Arthropods in Cattle Dung on Canada's Grasslands Kevin D. Floate Agriculture and Agri-Food Canada, Lethbridge Research Centre 5403 - 1 Avenue South, P.O. Box 3000 Lethbridge, Alberta, Canada T1J 4B1 Abstract. Fresh cattle dung is a nutrient-rich habitat that is quickly colonized by a speciose and abundant assemblage of organisms. The ease with which this habitat is manipulated by using artificially formed pats (size,