Volume 35, Issue 4 , Pages 420-429, April 2008
Tetrodotoxin for Moderate to Severe Cancer Pain: A Randomized, Double Blind, Parallel Design Multicenter Study
Article Outline
Abstract
Cancer pain is a serious public health issue and more effective treatments are needed. This study evaluates the analgesic activity of tetrodotoxin, a highly selective sodium channel blocker. This randomized, placebo-controlled, parallel design study of subcutaneous tetrodotoxin, in patients with moderate or severe unrelieved cancer pain persisting despite best available treatment, involved 22 centers across Canada. The design called for tetrodotoxin administered subcutaneously over Days 1–4 with a period of observation to Day 15 or longer. All patients could enroll into an open-label extension efficacy and safety trial. The primary endpoint was the proportion of analgesic responders in each treatment arm. Eighty-two patients were randomized, and results on 77 were available for analysis. There was a nonstatistically significant trend toward more responders in the active treatment arm based on the primary endpoint (pain intensity difference). However, analysis of secondary endpoints, and an exploratory post hoc analysis, suggested there may be a robust analgesic effect if a composite endpoint is used, including either fall in pain level, or fall in opioid dose, plus improvement in quality of life. Most patients described transient perioral tingling or other mild sensory phenomena within about an hour of each treatment. Nausea and other toxicities were generally mild, but one patient experienced a serious, adverse event, truncal and gait ataxia. This trial suggests tetrodotoxin may potentially relieve moderate to severe, treatment-resistant cancer pain in a large proportion of patients, and often for prolonged periods following treatment, but further study is warranted using a composite primary endpoint.
Key Words: Cancer pain, analgesic, controlled clinical trial, tetrodotoxin
Introduction
More than 10 million people in North America are diagnosed with cancer every year, and between 75% and 90% of patients with metastatic or advanced stage cancer will experience significant cancer-related pain.1 In hospitalized patients, 79% experience pain, with 46% experiencing severe pain despite the fact that the majority of patients are adequately medicated with analgesics.2 Moreover, treatment of cancer can cause pain. Chemotherapy-induced peripheral neuropathy occurs in about half of patients receiving some types of chemotherapy.3 Over half of the patients undergoing surgery for breast cancer will develop chronic pain.4 These data indicate that cancer-related pain is a prevalent and serious public health issue despite existing analgesic approaches.
Many valuable nondrug and drug interventions are available to help patients with cancer to experience relief of pain. However, these strategies are not always effective and can be associated with dose limiting toxicity. Contributing to the incidence of unrelieved pain is the high frequency of adverse effects produced by analgesics. For instance, 42% of patients with cancer receiving regular opioids develop clinically significant adverse effects, such as cognitive impairment and hallucinations, and most patients develop constipation or nausea and vomiting.5, 6
Unrelieved pain often results in decreased quality of life, impaired function, and reduced productivity. Suffering from unrelieved pain may lead to suicide.7, 8 The personal, social, and economic impact of untreated pain is enormous.9 Effective treatment of cancer-related pain remains both a high priority and an ongoing challenge in clinical practice.10
Tetrodotoxin (TTX) is a naturally occurring sodium channel blocker, which is found in several species of tetraodon pufferfish, notably of the Fugu genus. TTX is also found in a variety of other marine animals including the globefish, starfish, sunfish, stars, frogs, crabs, snails, and the Australian blue-ringed octopus. Animal studies have shown that TTX exhibits a strong analgesic effect.11, 12, 13 Sodium channels are found on most nociceptive pain fibers; the mechanism by which TTX exerts its analgesic effect is thought to be related to its sodium channel blocking properties but the exact mechanism remains to be elucidated.14
A Phase 2, open-label, multicenter study of TTX in severe cancer-related pain was recently completed.15 The study involved administration of TTX two or three times daily for four consecutive days followed by a period of observation. Seventeen of 31 treatments resulted in clinically meaningful reduction in pain intensity, and relief of pain persisted for up to two weeks or longer. Somatic, visceral, or neuropathic pain could all respond, and various dimensions of neuropathic pain as defined by the Neuropathic Pain Scale16 also could respond. The dose of 30
μg intramuscularly twice daily was the highest well-tolerated dose within that study.
We further assessed the role of TTX in cancer-related pain in a large, multicenter, placebo-controlled clinical trial.
Methods
Trial Design
This multicenter, randomized, double-blind, placebo-controlled, parallel design trial evaluated the efficacy and safety of TTX in patients with stable but inadequately controlled moderate to severe pain associated with cancer.
The primary objective of the study was to compare the efficacy of subcutaneous (s.c.) TTX treatment vs. placebo in reducing the intensity of cancer-related pain. Secondary objectives were to (1) estimate the onset of analgesic response to s.c. TTX; (2) estimate the time to and period of peak analgesic response of s.c. TTX; (3) determine the duration of analgesic response associated with s.c. TTX treatment; (4) determine whether or not s.c. TTX reduces the need for breakthrough medication; and (5) determine whether or not s.c. TTX improves physical and emotional functioning, that is, improves quality of life, in patients with inadequately controlled cancer-related pain. An exploratory objective was to generate preliminary information about the specificity of TTX's analgesics action for neuropathic, visceral, and somatic pain.
The study lasted at least three weeks from start of screening to the end of analgesic response. Patients were screened for the study and entered a 5 to 7 day baseline period within 28 days of screening (Fig. 1). Following the baseline period, patients were admitted to the hospital (inpatients) or visited the site's outpatient care facility on a daily basis. They were randomized on Day 1 to receive study drug or placebo for four days. After the treatment period, all patients were seen again on Days 5, 8, and 15 for further safety and efficacy evaluations, and then every two weeks until pain returned.
Fig. 1
Study design.
The following parameters were assessed: neurological examination (screening and Days 1–4), vital signs (screening, baseline, and Days 1–5, 8, 15 and thereafter at the end of study), oxygen saturation (screening), 12-lead ECG (screening, Days 1–4, 15 and thereafter at the end of study), clinical chemistry tests, hematology and coagulation, urinalysis, pregnancy (screening, Day 15, and thereafter at the end of study); pain characterization of the three most bothersome pains and pain characterization (cancer type, primary cancer site, pain etiology, identification of component-specific pain, neuropathic or not) at screening and baseline. Review of concurrent medications, including opioid or other medications for pain, was assessed daily. Patient diaries and BPI were assessed daily from baseline until Day 15, and weekly thereafter until pain return. Patient impression of change was assessed on Days 5, 8, 15, and at the end of study. Adverse events were recorded daily.
Study Population
Men or women over 18 years of age with relatively stable but inadequately controlled, moderate-to-severe cancer-related pain of at least two weeks duration, were eligible. Pain intensity as assessed by Question #3 of the Brief Pain Inventory (BPI) (worst pain in past 24hours) was scored as 4 or 5 (moderate) or 6 out of 10 or greater (severe) pain.17 Average baseline pain intensity as measured by BPI#3 had to be ≥4 to be eligible for the study. Patients had a life expectancy greater than three months in the opinion of the site investigator and had the ability to communicate with the investigator, to comply with the requirements of the study and also willingness to provide written informed consent. Exclusion criteria included: planned initiation of chemotherapy, radiotherapy, or bisphosphonates within 30 days prior to randomization; use of systemically administered local anesthetics; history of CO2 retention; second or third degree heart block or prolonged QTc (corrected QT interval of the electrocardiogram, e.g. QT interval divided by the square root of the preceeding R-R interval; prolonged is > 0.45 seconds) interval on screening ECG; known hypersensitivity to puffer fish toxin; lactation; or being at risk of pregnancy. This study was approved by the scientific and ethical review boards of all participating institutions and conducted in accordance with Good Clinical Practice Guidelines. Written, informed consent was obtained from all patients.
Assessment Methods
Given the complexity of cancer pain and the possibility of a differential response of different kinds of pain to the study drug, a panel of efficacy variables was studied to maximize the sensitivity of detecting a response to treatment, consistent with the published IMMPACT (Initiatives on Methods, Measurements, and Pain Assessments in Clinical Trials) guidelines.18 Pain intensity, quality, and analgesic response were assessed using descriptors 1–8 of the BPI,17 the six descriptors of the McGill Pain Questionnaire (MPQ),19 the 10 descriptors of the Neuropathic Pain Scale (NPS) when applicable,16 the 0–10 visual analog scale, and a patient diary, which included the characterization and assessment of pain intensity (0–10 scale) of the three most bothersome pains, the review of concurrent medication, and patient impression of change (seven-point scale— four being no change, greater being an increase in pain and lower being relief of pain). Changes in quality of life were assessed with the seven pain-related interference descriptors of BPI#9 (Items “A–G”). Adverse events were recorded according to type and severity, and a judgment was made regarding the association with the treatment drug (causality).
Efficacy Analysis
The primary efficacy analysis was to assess the proportion of responders, defined as a patient having a mean reduction in pain intensity of greater or equal to 30% from baseline during the early postinjection period (Days 5–8) for the late postinjection period (Days 9–15), as assessed by the patient's global pain intensity measures for either the daily worst pain intensity (BPI#3) or daily average pain intensity (BPI#5), or any of the patient's most bothersome pains. Mean opioid analgesic dose (in morphine equivalents) during the same period must be less than 125% of the mean baseline period use, to be as confident as possible that improvement of pain was not simply due to an increase in the opioid dose.
The following variables were selected for secondary efficacy analysis response: duration of relief, period of peak analgesic response and time to peak of analgesic response, summed pain intensity difference (daily worst pain, daily average pain); these variables were assessed with the BPI#1–8 descriptors, the MPQ, and the NPS. Quality of life was evaluated assessing pain interference with physical (BPI 9A, general mobility; 9C, walking ability; and 9D, normal work) and emotional functioning (BPI 9B, mood; 9E, relation to other people; 9F, sleep; and 9G, enjoyment of life). In addition, the patient's global impression of pain was used as a secondary efficacy analysis. Finally, breakthrough and baseline medication were recorded daily in the patient's diary.
Statistical Plan
All patients were to be included in the analysis based on the study drug group to which they were randomized, according to the intent-to-treat principle. The intent-to-treat analysis approach for efficacy (primary) was performed in subjects who received at least one dose of study medication and who had at least one efficacy evaluation.
The primary efficacy analysis was performed to compare the proportion of patients who were responders to TTX with the proportion of patients who were responders to placebo. Comparison of the proportion of responders in each treatment group was made using the Mantel–Haenszel procedure, stratifying for baseline pain pathophysiology (neuropathic component vs. no neuropathic component), severity of baseline pain (moderate vs. severe). The response as assessed by the secondary endpoints, and the differences between the proportion of responders to TTX and to placebo, were evaluated using the Pearson Chi-squared test with the ad hoc correction of Yates. Data are presented as mean±SD.
Results
Twenty-two centers across Canada participated in the study. In total, 82 patients were randomized, of whom five were excluded because they did not complete the four-day treatment or efficacy could not be evaluated. Toxicity data were available on 81 patients, and analgesic outcome data were available on 77 patients who fulfilled intent-to-treat criteria and were included in the final analysis. Table 1 outlines the demographic characteristics of the study population.
Table 1. Demographic Characteristics and Baseline Values of Pain Intensity
| Tectin (n=41) | Placebo (n=41) | |
|---|---|---|
| Age (years) | 59.7±15.1 | 55.7±10.7 |
| Gender | 25M/16F | 21M/20F |
| Race | 38 Caucasians | 38 Caucasians |
| 3 Asians | 3 Orientals | |
| Pain type and severity | 23 severe neuropathic | 27 neuropathic: |
| 18 nonneuropathic: | 4 moderate | |
| 3 moderate | 23 severe | |
| 15 severe | 14 severe nonneuropathic | |
| BPI#3 | 7.81±1.34 | 7.41±1.20 |
| BPI#5 | 5.89±1.53 | 5.72±1.47 |
| CSP#1 | 7.56±1.45 | 7.01±1.32 |
| CSP#2 | 5.54±2.11 | 6.26±1.69 |
| CSP#3 | 4.78±2.64 | 5.04±1.68 |
The proportion of responders, as defined by a 30% or greater fall in pain with stable use of opioid during that period, was 16 of 38 patients in the TTX arm (42%) and 12 of 39 in the placebo arm (31%), P=0.425.
Among the secondary efficacy endpoints, the MPQ and NPS did not discriminate between TTX and placebo (MPQ: 14 responders of 31 to TTX and 10 of 27 to placebo, P=0.719) (NPS: 10 responders of 18 to TTX, and 11 responders of 18 to placebo, P=1.000). Using an endpoint of a ≥30% decrease of one or more descriptors of BPI#9, TTX (24 responders of 35) showed a superiority over placebo (14 responders of 35, P=0.031). Onset of analgesia was observed after 1–4 days of treatment, and average duration of analgesia with TTX was 19.5±14.3 days, and with placebo 18.0±12.9 days, ranging from 4 to 42 days (Fig. 2, Fig. 3).
Fig. 2
Average change in pain intensity after the subcutaneous administration of 30
μg bid of TTX or placebo for four days in 36 and 37 patients, respectively.
Fig. 3
Duration of analgesic response in the 14 patients who reported a ≥30% decrease in BPI#3, BPI#5, or in any of the three most bothersome pains.
Post Hoc Exploratory Analysis
Several patients and investigators reported a significant improvement in pain. We noted that more patients receiving TTX than patients receiving placebo indicated an improvement of one or more quality-of-life descriptors (BPI#9 Items A–G: physical functioning or emotional functioning). Therefore, we undertook an additional, post hoc exploratory analysis. The post hoc analysis was conducted in accordance with the recommendations of IMMPACT guidelines, recognizing the variety of endpoints that can provide evidence of a true analgesic response within clinical trials.18
Based on the experience gained with a TTX open-label study in cancer patients15 and IMMPACT guidelines,18 a primary composite endpoint was selected and a responder was defined as having either a fall in pain by 30% with stable opioid use or a greater than 50% decrease in opioid consumption, and also in both cases a 30% or greater improvement in either physical or emotional functioning domains of quality of life, as measured with the BPI interference items. The response of 77 intent-to-treat patients was evaluated and the differences between proportion of responders to TTX and to placebo were assessed using the Pearson Chi-squared test with the ad hoc correction of Yates. Statistical significance was set at P equal to or less than 0.05.
This post hoc analysis—with a responder experiencing either improvement of pain or significant fall in opioid use, along with improvement of quality of life—resulted in the appearance of a large treatment effect: 17 of 38 (45%) were responders to TTX and 8 of 39 (21%) were responders to placebo, and the difference in the proportion of responders was statistically significant (χ2=4.114, P=0.043). In three of the 17 responders to TTX (none in the placebo group), an analgesic response could be identified by a fall in their use of opioid with an improvement of quality of life but without any improvement in their raw pain scores. Further, four placebo responders, as initially defined, became nonresponders when response was defined as a decrease in pain (or decrease in opioid consumption) plus improvement of one or more descriptors of their quality of life. The percentage of treatment difference between TTX and placebo was 24%. Based on these data, the number of patients needed to treat with TTX to have one true responder beyond placebo effect (NNT) is approximately four. The MPQ and NPS did not discriminate between TTX and placebo post hoc analysis responders.
Of the patients randomized to TTX, 23 presented with predominant neuropathic pain and 15 with visceral or somatic pain. The responders were similarly distributed among both groups, that is, 44% of responders had predominantly neuropathic pain and 44% of responders had nonneuropathic pain. In the placebo group, 28 patients presented with neuropathic pain, of which 18% were considered responders, and 11 patients presented with visceral/somatic pain and 27% were considered as responders (Fig. 4).
Fig. 4
Distribution according to the randomization to TTX or placebo, the type of pain (neuropathic and nonneuropathic) and the response to TTX and placebo. The percentages listed in the figure reflect the percentage of responders in the indicated treatment group. For example, 18% of patients with neuropathic pain who were administered placebo, responded to the treatment according to the predetermined primary endpoint.
In a second exploratory post hoc analysis, the definition of responders was narrowed to include improvement in two domains of quality of life—improvement of at least one descriptor of interference with physical functioning (BPI#9 Items A, C, D) and one descriptor of interference with emotional functioning (BPI#9 Items B, E, G)—in addition to either 30% decrease in pain intensity or ≥50% reduction in analgesic medication. Using this definition of responder, 15 patients were classified as responders to TTX and six patients were responders to placebo (χ2=4.48, P=0.034). The percentage of treatment difference was 25%.
Safety
Physical examination, vital signs, oxygen saturation, QTc and other ECG parameters, neurological examination, clinical chemistry, and hematology measures were not affected by TTX. One patient who received active TTX was discontinued due to moderately severe but transient ataxia, a recognized toxicity of this agent. A second patient who received active TTX was withdrawn from the study due to the development of malignant epidural spinal cord compression that appeared on the fourth day of treatment within the trial. A third patient who received active TTX was discontinued due to the development of transient moderate dysphagia of 3½ hour duration on Day 1 that was thought to be probably related to study drug. There were two deaths during the course of the study, both in patients within the placebo arm. Overall, treatment-emergent adverse events were greater in the TTX arm than the placebo arm, but almost all were mild and related to tingling, numbness, or other transient sensory symptoms (Table 2).
Table 2. Safety Data
| All treatment emergent adverse events (based on safety data available on 81 patients) | ||
|---|---|---|
| Tectin, n=41; n (%) | Placebo, n=40; n (%) | |
| Number of patients with ≥1 AE during treatment | 38 (92.7) | 35 (87.5) |
| Number of AEs during treatment | 690 | 321 |
| Mild | 518 | 241 |
| Moderate | 130 | 53 |
| Severe | 42 | 27 |
| Number of patients with ≥1 AEs during treatment judged to be possibly, probably or definitely due to the treatment | 34 (82.9) | 28 (70.0) |
| Number of AEs during treatment judged to be possibly, probably or definitely due to the treatment | 570 | 216 |
| Mild | 442 | 173 |
| Moderate | 99 | 26 |
| Severe | 29 | 17 |
| Number of patients discontinued due to AE | 3 (7.3) | 0 |
| Number of patients who died due to a treatment-emergent AE | 0 | 2 (5.0) |
| Incidence and frequency of all treatment-related, treatment-emergent AEs | ||
|---|---|---|
| Body System; Preferred Term | Tectin; n=41 | Placebo; N=40 |
| Cardiac disorders | 1 (2.4) | 0 |
| Ear and labyrinth disorders | 1 (2.4) | 0 |
| Gastrointestinal disorders | 27 (65.8) | 13 (32.5) |
Discussion
The primary outcome of the study was a fall in pain level in the active treatment arm, and the data indicated despite a positive trend, there was no significant difference in the two treatment arms. Secondary outcomes, including quality of life, were consistent with an analgesic response being present. An exploratory post hoc analysis suggested that there is indeed a robust analgesic response to TTX, and that future analgesic studies in this population of patients should include measurement of multiple endpoints and a composite indicator of treatment effect as the primary outcome.
We conclude that a type II error occurred in the study as originally designed. Due to the complexities of the target population, often having unstable pain, rapidly progressive disease, multiple concomitant treatments, and several distinct pains, often of different mechanisms, the single endpoint of a fall in pain intuitively might not be the best choice. To reduce the risk of a type II error whereby a true treatment effect is not seen, our current experience suggests that future analgesic research in this population of patients with advanced cancer pain should define an analgesic responder by more than one covariate. Specifically, this should include a measure of pain intensity, predictors of quality of life, and use of analgesics. Indeed, this conclusion is in line with IMMPACT recommendations for chronic pain trials: several core outcome measures need to be documented to assess the analgesic effect of a drug.18
Preliminary studies with cancer patients15 and basic studies11, 12, 13 suggest that TTX has an analgesic effect that is of a markedly different mechanism than other analgesics: it has an accumulative effect until Day 4 or 5 of treatment followed by an analgesic effect that persists for up to two weeks or longer. In the current double-blind, randomized, placebo-controlled, parallel design study of cancer patients with moderate to severe pain, pain scores were not found to be significantly different between the active and placebo arms during early or late postinjection period, although there was a trend toward a difference between these two groups. However, the secondary endpoint, quality of life, was found to show a statistically significant and clinically meaningful improvement in patients who received active treatment. When quality-of-life descriptors (both physical and emotional functioning) are included in the definition of responder in an exploratory post hoc analysis, the analgesic effect of TTX appears to be more clearly delineated, for example, 15 responders (39%) to TTX and six responders (15%) to placebo (P=0.0343). These observations of an apparent clinical effect will be used to inform the design and statistical plan for a subsequent clinical trial of TTX in cancer pain.
The time course of the apparent analgesic response to TTX seen within this study had a similar pattern to what has been described previously: There was an additive analgesic effect until Day 4 or 5, the effect peaked around Day 10, and then became less after that time, wearing off two weeks or longer after the drug was first administered. This pattern of response to a sodium channel blocker has also been reported in several human and animal studies. Neuropathic pain patients have reported relief of pain lasting days or weeks after brief treatments with lidocaine and other sodium-channel blockers.14 In rats with tactile allodynia, intravenous lidocaine (15mg/kg) yielded 66% of the maximal possible effect on thresholds, and 21 days after lidocaine infusion, 30%–40% of the maximal possible effect persisted.20 In another study, a single intravenous infusion of lidocaine elicited a sustained elevation of paw withdrawal threshold developing slowly over 24hours after infusion and was maintained over the next 21 days.21 However, there is no widely accepted explanation for this dramatic, long-standing analgesic effect.14
Cancer-related pain is thought to arise from a wide range of pathophysiological mechanisms. If a sodium-channel blocker is effective for cancer-related pain, one might speculate that it could have a differential effect depending on how much of the pain is mediated through the sodium channels it blocks, and how much is mediated through other mechanisms. One small clinical trial suggested systemically administered lidocaine is not effective for cancer-related pain,22 however, a recent Cochrane review suggests there is indeed a meaningful analgesic response, particularly in neuropathic pain.23
In the current study, there was no apparent differential effect of TTX on neuropathic vs. nonneuropathic pain and there was no dimension of neuropathic pain that appeared to be uniquely sensitive to it. However, this cohort of patients had a wide range of different causes of neuropathic pain, caused by the cancer, chemotherapy, radiation therapy, or by other reasons such as shingles. Also, there were several discrete neuropathic pain syndromes within the cohort. There were not sufficient numbers of patients within any of these groups to be confident about a differential effect; however, the present study confirms the results of the open-label Phase 2 study, where it was apparent that patients with cancer-related pain of neuropathic origin as well of nonneuropathic origin could respond.15 Additional study would be needed to delineate a particular pain diagnosis that may be more likely to be responsive to TTX. Further, this is a cohort of heavily pretreated patients who had pain that was at least moderate in severity despite opioids, nonopioids, chemotherapy, radiation therapy, and other treatments.
Overall, 15% of patients with cancer-related pain responded to placebo. Among the six patients responding to placebo, four were classified as having neuropathic pain. The incidence of responders to placebo appears in the range of the values reported in the literature in this population and in subjects with neuropathic pain, that is, 10%–40%.24, 25, 26
The safety profile of TTX within this cohort appeared to be similar to that of what was observed within cancer patients with severe pain15 and also normal human volunteers27, 28, 29: The majority of patients had mild sensory side effects, primarily of tingling around the mouth or numbness, and most patients did not have additional toxicity. No QTc changes were recorded. Ataxia, which occurred in one study patient, has been well described with TTX and has been reported to always be reversible.
Cancer pain remains a serious public health issue. There is a high incidence of unrelieved cancer pain despite adequate treatment.1, 2 Such pain can be anticipated to have a negative impact on quality of life: 17% and 45% of patients with cancer-related pain express a strong or occasional desire for hastened death, respectively.30, 31 New therapeutic approaches to relieve cancer-related pain are greatly needed. A post hoc analysis of data in the current study suggests that 39% of the patients treated with TTX can experience a meaningful decrease in pain and an improvement in quality of life with acceptable adverse effects. Treatment with TTX results in a number needed to treat of 4.2, a value that compares with that of other analgesics currently used in cancer-related pain, for example, 4.4 for transdermal buprenorphine,32 2.6 for intravenous fentanyl,24 2.2–7.1 for gabapentin,26, 33, 34 and 1.8 for carbamazepine.35
This multicenter, placebo-controlled, parallel design trial demonstrated that parenteral TTX failed to result in clinically meaningful relief of pain in a heavily pretreated cohort of cancer patients with moderate to severe pain when only pain scores were assessed. However, analysis of secondary endpoints, and an exploratory post hoc analysis, suggested there may in fact be a robust analgesic effect. Further research in TTX for cancer pain is warranted. Also, future research in this population of patients should include a composite primary endpoint including fall in pain level, or fall in opioid dose, plus improvement in quality of life.
Acknowledgments
The authors wish to acknowledge the following investigators for their support and for accruing patients on the trial: P. Cano (Sudbury, Ontario), A. Chan (Thunderbay, Ontario), L.J. Clein (Regina, Saskatchewan), P. Daenick (Winnipeg, Manitoba), G.B. Dickson (Vancouver, British Columbia), S. Fox (Montreal, Quebec), G. Fyles (Kelowna, British Columbia), B. Gagnon (Montreal, Quebec), G. Girard (Sherbrooke, Quebec), R. Goel (Ottawa, Ontario), P. Hawley (Vancouver, British Columbia), H.M. Intrater (Winnipeg, Manitoba), J. Kooy (Penticton, British Columbia), D. Moulin (London, Ontario), K. Stakiw (Saskatoon, Saskatchewan), and S. Watanabe (Edmonton, Alberta). Also they wish to acknowledge the outstanding research nursing support from participating centers, particularly that of Carla Stiles, BN.
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This study was funded by WEX Pharmaceuticals Inc.
PII: S0885-3924(07)00744-0
doi:10.1016/j.jpainsymman.2007.05.011
© 2008 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Volume 35, Issue 4 , Pages 420-429, April 2008
