Methodological Issues in Conducting Pilot Trials in Chronic Pain as Randomized, Double-blind, Placebo-controlled Studies

Tominaga, Yushin; Koga, Hideyuki; Uchida, Naoto; Wanibe, Mikio; Hirose, Kenichi; Matsumura, Takehiko; Okamoto, Akiko; Richarz, Ute; Etropolski, Mila

doi:10.1055/s-0042-107669

Cited by 11 publications

(16 citation statements)

References 23 publications

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“…No difference was observed between placebo and treatment groups for the patient global impression of change and for responders at ≥30% and ≥50% pain reduction 58. These negative and disappointing findings have been ascribed to study design factors such as study underpower, heterogeneity of patients contributed in small numbers by 33 study centers in Japan, potential genetic factors and high numbers of uncontrolled concurrent medications; the authors reported also an unusually high placebo response probably due to large expectations generated in the patients from the 2:1 (treatment:placebo) enrollment design 58. Recently, in the context of a complex therapy including gabapentin 1800 mg/day, oxacarbazepine 600 mg/day and amytriptiline 20 mg/day, tapentadol 500 mg/day failed to relieve pain in a 68-year-old patient suffering from trigeminal PHN 76…”

Section: Introductionmentioning

confidence: 82%

“…In a subset of 13 PHN patients, tapentadol PR was not superior to placebo 58. Pain Numerical Rating Scale (NRS) declined from pretreatment to treatment week 12 from 7.0±1.4 to 5.0±2.9 in the placebo group and from 6.7±0.9 to 4.5±2.3 in the tapentadol group (mean reduction 2.0±2.4 and 2.2±2.2) 58. No difference was observed between placebo and treatment groups for the patient global impression of change and for responders at ≥30% and ≥50% pain reduction 58.…”

Section: Introductionmentioning

confidence: 84%

“…The last observation carried forward (LOCF) was used for imputing missing pain intensity data for the primary endpoints, which were then analyzed using the analysis of covariance (ANCOVA) on all patient populations (intention to treat [ITT]). In a subset of 13 PHN patients, tapentadol PR was not superior to placebo 58. Pain Numerical Rating Scale (NRS) declined from pretreatment to treatment week 12 from 7.0±1.4 to 5.0±2.9 in the placebo group and from 6.7±0.9 to 4.5±2.3 in the tapentadol group (mean reduction 2.0±2.4 and 2.2±2.2) 58.…”

Section: Introductionmentioning

confidence: 98%

“…Tominaga et al reported a 12-week (ie, ≤6-week titration plus maintenance periods), double-blind, placebo-controlled RCT on 31 patients treated with tapentadol extended release (ER) for PHN or DPN (mean dose 274.5±148.3 mg/day) 58. The last observation carried forward (LOCF) was used for imputing missing pain intensity data for the primary endpoints, which were then analyzed using the analysis of covariance (ANCOVA) on all patient populations (intention to treat [ITT]).…”

Section: Introductionmentioning

confidence: 99%

“…Pain Numerical Rating Scale (NRS) declined from pretreatment to treatment week 12 from 7.0±1.4 to 5.0±2.9 in the placebo group and from 6.7±0.9 to 4.5±2.3 in the tapentadol group (mean reduction 2.0±2.4 and 2.2±2.2) 58. No difference was observed between placebo and treatment groups for the patient global impression of change and for responders at ≥30% and ≥50% pain reduction 58. These negative and disappointing findings have been ascribed to study design factors such as study underpower, heterogeneity of patients contributed in small numbers by 33 study centers in Japan, potential genetic factors and high numbers of uncontrolled concurrent medications; the authors reported also an unusually high placebo response probably due to large expectations generated in the patients from the 2:1 (treatment:placebo) enrollment design 58.…”

Section: Introductionmentioning

confidence: 99%

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<p>Tapentadol for neuropathic pain: a review of clinical studies</p>

Freo¹,

Romualdi²,

Kress³

2019

JPR

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Neuropathic pain (NP) is an enormous burden for patients, caregivers and society. NP is a pain state that may develop after injury of the peripheral or central nervous system because of a wide range of diseases and traumas. A NP symptom component can be found also in several types of chronic pain. Many NP patients are substantially disabled for years. Due to its chronicity, severity and unpredictability, NP is difficult to treat. Tapentadol is a central-acting oral analgesic with combined opioid and noradrenergic properties, which make it potentially suitable for a wide range of pain conditions, particularly whenever a NP component is present or cannot be excluded. In randomized controlled trials, tapentadol has proved to be effective in relieving NP in diabetic peripheral neuropathy and in chronic low back pain. In observational studies, tapentadol reduced NP in chemotherapy-induced peripheral neuropathies, blood and solid cancers, and the NP component in neck pain and Parkinson’s disease. This narrative review aims to provide clinicians with a broad overview of tapentadol effects on NP.

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

<p>Tapentadol for neuropathic pain: a review of clinical studies</p>

Freo¹,

Romualdi²,

Kress³

2019

JPR

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Opioids for Chronic Noncancer Pain

Busse

Wang

Kamaleldin

et al. 2018

JAMA

494

216

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IMPORTANCE Harms and benefits of opioids for chronic noncancer pain remain unclear. OBJECTIVE To systematically review randomized clinical trials (RCTs) of opioids for chronic noncancer pain. DATA SOURCES AND STUDY SELECTION The databases of CENTRAL, CINAHL, EMBASE, MEDLINE, AMED, and PsycINFO were searched from inception to April 2018 for RCTs of opioids for chronic noncancer pain vs any nonopioid control. DATA EXTRACTION AND SYNTHESIS Paired reviewers independently extracted data. The analyses used random-effects models and the Grading of Recommendations Assessment, Development and Evaluation to rate the quality of the evidence. MAIN OUTCOMES AND MEASURES The primary outcomes were pain intensity (score range, 0-10 cm on a visual analog scale for pain; lower is better and the minimally important difference [MID] is 1 cm), physical functioning (score range, 0-100 points on the 36-item Short Form physical component score [SF-36 PCS]; higher is better and the MID is 5 points), and incidence of vomiting. RESULTS Ninety-six RCTs including 26 169 participants (61% female; median age, 58 years [interquartile range, 51-61 years]) were included. Of the included studies, there were 25 trials of neuropathic pain, 32 trials of nociceptive pain, 33 trials of central sensitization (pain present in the absence of tissue damage), and 6 trials of mixed types of pain. Compared with placebo, opioid use was associated with reduced pain (weighted mean difference [WMD], −0.69 cm [95% CI, −0.82 to −0.56 cm] on a 10-cm visual analog scale for pain; modeled risk difference for achieving the MID, 11.9% [95% CI, 9.7% to 14.1%]), improved physical functioning (WMD, 2.04 points [95% CI, 1.41 to 2.68 points] on the 100-point SF-36 PCS; modeled risk difference for achieving the MID, 8.5% [95% CI, 5.9% to 11.2%]), and increased vomiting (5.9% with opioids vs 2.3% with placebo for trials that excluded patients with adverse events during a run-in period). Low-to moderate-quality evidence suggested similar associations of opioids with improvements in pain and physical functioning compared with nonsteroidal anti-inflammatory drugs (pain: WMD, −0.60 cm [95% CI, −1.54 to 0.34 cm]; physical functioning: WMD, −0.90 points [95% CI, −2.69 to 0.89 points]), tricyclic antidepressants (pain: WMD, −0.13 cm [95% CI, −0.99 to 0.74 cm]; physical functioning: WMD, −5.31 points [95% CI, −13.77 to 3.14 points]), and anticonvulsants (pain: WMD, −0.90 cm [95% CI, −1.65 to −0.14 cm]; physical functioning: WMD, 0.45 points [95% CI, −5.77 to 6.66 points]). CONCLUSIONS AND RELEVANCE In this meta-analysis of RCTs of patients with chronic noncancer pain, evidence from high-quality studies showed that opioid use was associated with statistically significant but small improvements in pain and physical functioning, and increased risk of vomiting compared with placebo. Comparisons of opioids with nonopioid alternatives suggested that the benefit for pain and functioning may be similar, although the evidence was from studies of only low to moderate quality.

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Random-Effects Meta-analysis

Serghiou

Goodman

2019

JAMA

113

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Questions involving medical therapies are often studied more than once. For example, numerous clinical trials have been conducted comparing opioids with placebos or nonopioid analgesics in the treatment of chronic pain. In the December 18, 2018, issue of JAMA, Busse et al 1 evaluated the evidence on opioid efficacy from 96 randomized clinical trials and, as part of that work, used random-effects meta-analysis to synthesize results from 42 randomized clinical trials on the difference in pain reduction among patients taking opioids vs placebo using a 10-cm visual analog scale (Figure 2 in Busse et al). 1 Meta-analysis is the process of quantitatively combining study results into a single summary estimate and is a foundational tool for evidence-based medicine. Random-effects meta-analysis is the most common approach.Why Is Random-Effects Meta-analysis Used?Each study evaluating the effect of a treatment provides its own answer in terms of an observed or estimated effect size. Opioids reduced pain by 0.54 cm more than placebo on a visual analog scale in 1 study 2 ; this was the observed effect size and represents the best estimate from that study of the true opioid effect. The true effect is the underlying benefit of opioid treatment if it could be measured perfectly, and is a single value that cannot directly be known.If a particular study was replicated with new patients in the same setting multiple times, the observed treatment effects would vary by chance even though the true effects would be the same in each. The belief that the true effect was the same in each study is called the fixed-effect assumption, whereby the fixed effect is the common, unknown true effect underlying each replication. A metaanalysis making the fixed-effect assumption is called a fixed-effect meta-analysis. The corresponding fixed-effect estimate of the treatment effect is a weighted average of the individual study estimates and is always more precise (ie, it has a narrower confidence interval [CI] than that of any individual study, making the estimate appear closer to the true value than any individual study).However, medical studies addressing the same question are typically not exact replications and they can use different types of medication or interventions for different amounts of time, at different intensities, within different populations, and have differently measured outcomes. 3 Differences in study characteristics reduce the confidence that each study is actually estimating the same true effect. The alternative assumption is that the true effects being estimated are different from each other or heterogeneous. In statistical jargon, this is called the random-effects assumption. The plural in effects implies there is more than 1 true effect and random implies that the reasons the true effects differ are unknown.A random-effects assumption is less restrictive than a fixedeffect assumption and reflects the variation or heterogeneity in the true effects estimated by each trial. This usually results in a more realistic estimate of t...

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Methodological Issues in Conducting Pilot Trials in Chronic Pain as Randomized, Double-blind, Placebo-controlled Studies

Abstract: Both studies were associated with methodological issues, including populations with different disease entities, small sample sizes, use of concomitant analgesics, and possible placebo effect that may have led to the failure to differentiate between tapentadol ER and placebo.

Cited by 11 publications

References 23 publications

<p>Tapentadol for neuropathic pain: a review of clinical studies</p>

<p>Tapentadol for neuropathic pain: a review of clinical studies</p>

Opioids for Chronic Noncancer Pain

Random-Effects Meta-analysis

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