Data interpretation in analgesic clinical trials with statistically nonsignificant primary analyses: an ACTTION systematic review.

UNLABELLED: Peer-reviewed publications of randomized clinical trials (RCTs) are the primary means of disseminating research findings. "Spin" in RCT publications is misrepresentation of statistically nonsignificant research findings to suggest treatment benefit. Spin can influence the way readers interpret clinical trials and use the information to make decisions about treatments and medical policies. The objective of this study was to determine the frequency with which 4 types of spin were used in publications of analgesic RCTs with nonsignificant primary analyses in 6 major pain journals. In the 76 articles included in our sample, 28% of the abstracts and 29% of the main texts emphasized secondary analyses with P values <.05; 22% of abstracts and 29% of texts emphasized treatment benefit based on nonsignificant primary results; 14% of abstracts and 18% of texts emphasized within-group improvements over time, rather than primary between-group comparisons; and 13% of abstracts and 10% of texts interpreted a nonsignificant difference between groups in a superiority study as comparable effectiveness. When considering the article conclusion sections, 21% did not mention the nonsignificant primary result, 22% were presented with no uncertainty or qualification, 30% did not acknowledge that future research was required, and 8% recommended the intervention for clinical use. PERSPECTIVE: This article identifies relatively frequent "spin" in analgesic RCTs. These findings highlight a need for authors, reviewers, and editors to be more cognizant of how analgesic RCT results are presented and attempt to minimize spin in future clinical trial publications.

Reporting of sample size calculations in analgesic clinical trials: ACTTION systematic review.

UNLABELLED: Sample size calculations determine the number of participants required to have sufficiently high power to detect a given treatment effect. In this review, we examined the reporting quality of sample size calculations in 172 publications of double-blind randomized controlled trials of noninvasive pharmacologic or interventional (ie, invasive) pain treatments published in European Journal of Pain, Journal of Pain, and Pain from January 2006 through June 2013. Sixty-five percent of publications reported a sample size calculation but only 38% provided all elements required to replicate the calculated sample size. In publications reporting at least 1 element, 54% provided a justification for the treatment effect used to calculate sample size, and 24% of studies with continuous outcome variables justified the variability estimate. Publications of clinical pain condition trials reported a sample size calculation more frequently than experimental pain model trials (77% vs 33%, P < .001) but did not differ in the frequency of reporting all required elements. No significant differences in reporting of any or all elements were detected between publications of trials with industry and nonindustry sponsorship. Twenty-eight percent included a discrepancy between the reported number of planned and randomized participants. This study suggests that sample size calculation reporting in analgesic trial publications is usually incomplete. Investigators should provide detailed accounts of sample size calculations in publications of clinical trials of pain treatments, which is necessary for reporting transparency and communication of pre-trial design decisions. PERSPECTIVE: In this systematic review of analgesic clinical trials, sample size calculations and the required elements (eg, treatment effect to be detected; power level) were incompletely reported. A lack of transparency regarding sample size calculations may raise questions about the appropriateness of the calculated sample size.

Meta-analysis of assay sensitivity and study features in clinical trials of pharmacologic treatments for osteoarthritis pain.

OBJECTIVE: To identify patient, study, and site factors associated with assay sensitivity in clinical trials of pharmacologic treatments for osteoarthritis (OA) pain. METHODS: We examined associations between study characteristics and the standardized effect size (SES) in a database of 171 publicly available randomized clinical trials of pharmacologic treatment for OA pain. The included trials 1) evaluated oral, topical, or transdermal treatments, 2) had treatment durations of ≥7 days, 3) used parallel-group or crossover designs, 4) included patients with OA of the knee, hip, and/or hand, and 5) were placebo controlled and double blind. Crossover trials were excluded, because complete information was available for only 2 of 20 treatment conditions. RESULTS: There was considerable heterogeneity in the SES among the examined trials. A multiple meta-regression analysis indicated that trials with shorter treatment period durations and those that did not permit concomitant analgesics had significantly greater assay sensitivity. In univariate analyses of efficacious treatments, trials conducted outside North America and those with a minimum baseline pain intensity score (as defined by the inclusion criterion) of ≥40 (0-100 scale) had a significantly larger SES, although these relationships were not significant in the multiple meta-regression analysis. CONCLUSION: The analyses examined potentially modifiable correlates of study SES and showed that longer treatment durations and allowing concomitant analgesics in randomized clinical trials of OA pain are associated with reduced assay sensitivity. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of false-negative outcomes in randomized clinical trials of efficacious treatments for OA pain.

Adverse event reporting in nonpharmacologic, noninterventional pain clinical trials: ACTTION systematic review.

Assessment of treatment safety is 1 of the primary goals of clinical trials. Organizations and working groups have created reporting guidelines for adverse events (AEs). Previous research examining AE reporting for pharmacologic clinical trials of analgesics in major pain journals found many reporting inadequacies, suggesting that analgesic trials are not adhering to existing AE reporting guidelines. The present systematic review documented AE reporting in 3 main pain journals for nonpharmacologic, noninterventional (NP/NI) trials examining pain treatments. To broaden our pool of nonpharmacologic trials, we also included trials examining acupuncture, leech therapy, and noninvasive stimulation techniques (eg, transcutaneous electrical nerve stimulation). We documented AE reporting at 2 levels of specificity using coding manuals based on the Consolidated Standards of Reporting Trials (CONSORT) harms reporting standards and Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) AE reporting checklist. We identified a number of inadequacies in AE reporting across the 3 journals. For example, using the ACTTION coding manual, we found that less than one-half of the trials reported specific AE assessment methods; approximately one-third of the trials reported withdrawals due to AEs for each study arm; and about one-fourth of the trials reported all specific AEs. We also examined differences in AE reporting across several trial characteristics, finding that AE reporting was generally more detailed in trials with patients versus those using healthy volunteers undergoing experimentally evoked pain. These results suggest that investigators conducting and reporting NP/NI clinical trials are not adequately describing the assessment and occurrence of AEs.

Reporting of primary analyses and multiplicity adjustment in recent analgesic clinical trials: ACTTION systematic review and recommendations.

Performing multiple analyses in clinical trials can inflate the probability of a type I error, or the chance of falsely concluding a significant effect of the treatment. Strategies to minimize type I error probability include prespecification of primary analyses and statistical adjustment for multiple comparisons, when applicable. The objective of this study was to assess the quality of primary analysis reporting and frequency of multiplicity adjustment in 3 major pain journals (ie, European Journal of Pain, Journal of Pain, and PAIN®). A total of 161 randomized controlled trials investigating noninvasive pharmacological treatments or interventional treatments for pain, published between 2006 and 2012, were included. Only 52% of trials identified a primary analysis, and only 10% of trials reported prespecification of that analysis. Among the 33 articles that identified a primary analysis with multiple testing, 15 (45%) adjusted for multiplicity; of those 15, only 2 (13%) reported prespecification of the adjustment methodology. Trials in clinical pain conditions and industry-sponsored trials identified a primary analysis more often than trials in experimental pain models and non-industry-sponsored trials, respectively. The results of this systematic review demonstrate deficiencies in the reporting and possibly the execution of primary analyses in published analgesic trials. These deficiencies can be rectified by changes in, or better enforcement of, journal policies pertaining to requirements for the reporting of analyses of clinical trial data.

Discrepancies between registered and published primary outcome specifications in analgesic trials: ACTTION systematic review and recommendations.

The National Institutes of Health released the trial registry ClinicalTrials.gov in 2000 to increase public reporting and clinical trial transparency. This systematic review examined whether registered primary outcome specifications (POS; ie, definitions, timing, and analytic plans) in analgesic treatment trials correspond with published POS. Trials with accompanying publications (n = 87) were selected from the Repository of Registered Analgesic Clinical Trials (RReACT) database of all postherpetic neuralgia, diabetic peripheral neuropathy, and fibromyalgia clinical trials registered at ClinicalTrials.gov as of December 1, 2011. POS never matched precisely; discrepancies occurred in 79% of the registry-publication pairs (21% failed to register or publish primary outcomes [PO]). These percentages did not differ significantly between industry and non-industry-sponsored trials. Thirty percent of the trials contained unambiguous POS discrepancies (eg, omitting a registered PO from the publication, "demoting" a registered PO to a published secondary outcome), with a statistically significantly higher percentage of non-industry-sponsored than industry-sponsored trials containing unambiguous POS discrepancies. POS discrepancies due to ambiguous reporting included vaguely worded PO registration; or failing to report the timing of PO assessment, statistical analysis used for the PO, or method to address missing PO data. At best, POS discrepancies may be attributable to insufficient registry requirements, carelessness (eg, failing to report PO assessment timing), or difficulty uploading registry information. At worst, discrepancies could indicate investigator impropriety (eg, registering imprecise PO ["pain"], then publishing whichever pain assessment produced statistically significant results). Improvements in PO registration, as well as journal policies requiring consistency between registered and published PO descriptions, are needed.

Assay sensitivity and study features in neuropathic pain trials: an ACTTION meta-analysis.

OBJECTIVE: Our objective was to identify patient, study, and site factors associated with assay sensitivity in placebo-controlled neuropathic pain trials. METHODS: We examined the associations between study characteristics and standardized effect size (SES) in a database of 200 publicly available randomized clinical trials of pharmacologic treatments for neuropathic pain. RESULTS: There was considerable heterogeneity in the SESs among the examined trials. Univariate meta-regression analyses indicated that larger SESs were significantly associated with trials that had 1) greater minimum baseline pain inclusion criteria, 2) greater mean subject age, 3) a larger percentage of Caucasian subjects, and 4) a smaller total number of subjects. In a multiple meta-regression analysis, the associations between SES and minimum baseline pain inclusion criterion and age remained significant. CONCLUSIONS: Our analyses have examined potentially modifiable correlates of study SES and shown that a minimum pain inclusion criterion of 40 or above on a 0 to 100 scale is associated with a larger SES. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of falsely negative outcomes in clinical trials of efficacious treatments for neuropathic pain.

Adverse event assessment, analysis, and reporting in recent published analgesic clinical trials: ACTTION systematic review and recommendations.

The development of valid and informative treatment risk-benefit profiles requires consistent and thorough information about adverse event (AE) assessment and participants' AEs during randomized controlled trials (RCTs). Despite a 2004 extension of the Consolidated Standards of Reporting Trials (CONSORT) statement recommending the specific AE information that investigators should report, there is little evidence that analgesic RCTs adequately adhere to these recommendations. This systematic review builds on prior recommendations by describing a comprehensive checklist for AE reporting developed to capture clinically important AE information. Using this checklist, we coded AE assessment methods and reporting in all 80 double-blind RCTs of noninvasive pharmacologic treatments published in the European Journal of Pain, Journal of Pain, and PAIN® from 2006 to 2011. Across all trials, reports of AEs were frequently incomplete, inconsistent across trials, and, in some cases, missing. For example, >40% of trials failed to report any information on serious adverse events. Trials of participants with acute or chronic pain conditions and industry-sponsored trials typically provided more and better-quality AE data than trials involving pain-free volunteers or trials that were not industry sponsored. The results of this review suggest that improved AE reporting is needed in analgesic RCTs. We developed an ACTTION (Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks) AE reporting checklist that is intended to assist investigators in thoroughly and consistently capturing and reporting these critically important data in publications.

Adherence to CONSORT harms-reporting recommendations in publications of recent analgesic clinical trials: an ACTTION systematic review.

Recommendations for harms (ie, adverse events) reporting in randomized clinical trial publications were presented in a 2004 extension of the Consolidated Standards of Reporting Trials (CONSORT) statement. Our objectives were to assess harms reporting in 3 major pain journals (European Journal of Pain, Journal of Pain, and PAIN®) to determine whether harms reporting improved following publication of the 2004 CONSORT recommendations, and to examine study factors associated with adequacy of harms reporting. A total of 101 randomized, double-blind, noninvasive pharmacologic trials were identified in the 2000-2003 (epoch 1) and 2008-2011 (epoch 2) issues of these journals. Out of 10 reporting recommendations, the mean number fulfilled was 6.08 (SD2.65). Although more harms recommendations were fulfilled in epoch 2 (m(2)=6.49, SD2.66) than in epoch 1 (m(1)=5.39, SD2.52; P=0.04), only the recommendation to report harms per arm was satisfied by >90% of trials in epoch 2, whereas <60% reported withdrawals due to harms. Several trial characteristics (study design, participant type, pain type, frequency of treatment administration, treatment administration method, sponsor, and number of randomized participants) were significantly associated with harms reporting. However, when trial characteristics and epoch were entered into a multiple regression analysis, only trials studying pain patients, those using oral treatments, and industry-sponsored trials were associated with better harms reporting. Despite some improvement in harms reporting, greater improvement is needed to provide informative, consistent reporting of adverse events and safety in analgesic clinical trials.

Serotonin stimulation of cAMP-dependent plasticity in Aplysia sensory neurons is mediated by calmodulin-sensitive adenylyl cyclase.

Calmodulin (CaM)-sensitive adenylyl cyclase (AC) in sensory neurons (SNs) in Aplysia has been proposed as a molecular coincidence detector during conditioning. We identified four putative ACs in Aplysia CNS. CaM binds to a sequence in the C1b region of AC-AplA that resembles the CaM-binding sequence in the C1b region of AC1 in mammals. Recombinant AC-AplA was stimulated by Ca(2+)/CaM. AC-AplC is most similar to the Ca(2+)-inhibited AC5 and AC6 in mammals. Recombinant AC-AplC was directly inhibited by Ca(2+), independent of CaM. AC-AplA and AC-AplC are expressed in SNs, whereas AC-AplB and AC-AplD are not. Knockdown of AC-AplA demonstrated that serotonin stimulation of cAMP-dependent plasticity in SNs is predominantly mediated by this CaM-sensitive AC. We propose that the coexpression of a Ca(2+)-inhibited AC in SNs, together with a Ca(2+)/CaM-stimulated AC, would enhance the associative requirement for coincident Ca(2+) influx and serotonin for effective stimulation of cAMP levels and initiation of plasticity mediated by AC-AplA.

Pharmacological characterization of an adenylyl cyclase-coupled 5-HT receptor in aplysia: comparison with mammalian 5-HT receptors.

We attempted to identify compounds that are effective in blocking the serotonin (5-hydroxytryptamine, 5-HT) receptor(s) that activate adenylyl cyclase (AC) in Aplysia CNS. We call this class of receptor 5-HT(apAC). Eight of the 14 antagonists tested were effective against 5-HT(apAC) in CNS membranes with the following rank order of potency: methiothepin > metergoline approximately fluphenazine > clozapine > cyproheptadine approximately risperidone approximately ritanserin > NAN-190. GR-113808, olanzapine, Ro-04-6790, RS-102221, SB-204070, and spiperone were inactive. Methiothepin completely blocked 5-HT stimulation of AC with a K(b) of 18 nM. Comparison of the pharmacological profile of the 5-HT(apAC) receptor with those of mammalian 5-HT receptor subtypes suggested it most closely resembles the 5-HT(6) receptor. AC stimulation in Aplysia sensory neuron (SN) membranes was also blocked by methiothepin. Methiothepin substantially inhibited two effects of 5-HT on SN firing properties that are mediated by a cAMP-dependent reduction in S-K(+) current: spike broadening in tetraethylammonium/nifedipine and increased excitability. Consistent with cyproheptadine blocking 5-HT stimulation of AC, cyproheptadine also blocked the 5-HT-induced increase in SN excitability. Methiothepin was less effective in blocking AC-mediated modulatory effects of 5-HT in electrophysiological experiments on SNs than in blocking AC stimulation in CNS or SN membranes. This reduction in potency appears to be due to effects of the high ionic strength of physiological saline on the binding of this antagonist to the receptor. Methiothepin also antagonized AC-coupled dopamine receptors but not AC-coupled small cardioactive peptide receptors. In conjunction with other pharmacological probes, this antagonist should be useful in analyzing the role of 5-HT in various forms of neuromodulation in Aplysia.