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Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial.

ABSTRACT: Chronic low back pain (LBP) is a common condition, usually with the involvement of nociceptive and neuropathic pain components, high economic burden and impact on quality of life. Cebranopadol is a potent, first-in-class drug candidate with a novel mechanistic approach, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. We conducted the first phase II, randomized, double-blind, placebo- and active-controlled trial, evaluating the analgesic efficacy, safety, and tolerability of cebranopadol in patients with moderate-to-severe chronic LBP with and without neuropathic pain component. Patients were treated for 14 weeks with cebranopadol 200, 400, or 600 ?g once daily, tapentadol 200 mg twice daily, or placebo. The primary efficacy endpoints were the change from baseline pain to the weekly average 24-hour pain during the entire 12 weeks and during week 12 of the maintenance phase. Cebranopadol demonstrated analgesic efficacy, with statistically significant and clinically relevant improvements over placebo for all doses as did tapentadol. The responder analysis (?30% or ?50% pain reduction) confirmed these results. Cebranopadol and tapentadol displayed beneficial effects on sleep and functionality. Cebranopadol treatment was safe, with higher doses leading to higher treatment discontinuations because of treatment-emergent adverse events occurring mostly during titration. Those patients reaching the target doses had an acceptable tolerability profile. The incidence rate of most frequently reported treatment-emergent adverse events during maintenance phase was ?10%. Although further optimizing the titration scheme to the optimal dose for individual patients is essential, cebranopadol is a new drug candidate with a novel mechanistic approach for potential chronic LBP treatment.

SUBMITTER: Christoph A

PROVIDER: S-EPMC5761752 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial.

Christoph Annette A Eerdekens Marie-Henriette MH Kok Maurits M Volkers Gisela G Freynhagen Rainer R

Pain 20170901 9

Chronic low back pain (LBP) is a common condition, usually with the involvement of nociceptive and neuropathic pain components, high economic burden and impact on quality of life. Cebranopadol is a potent, first-in-class drug candidate with a novel mechanistic approach, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. We conducted the first phase II, randomized, double-blind, placebo- and active-controlled trial, evaluating the analgesic efficacy, safety, and tolerab ...[more]

PMID: 28644196

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Project description:BACKGROUND:Hypertonic dextrose injection (prolotherapy) is reported to reduce pain including non-surgical chronic low back pain (CLBP), and subcutaneous injection of 5% dextrose is reported to reduce neurogenic pain, hyperalgesia and allodynia. The mechanism in both cases is unclear, though a direct effect of dextrose on neurogenic pain has been proposed. This study assessed the short-term analgesic effects of epidural 5% dextrose injection compared with saline for non-surgical CLBP. METHODS:Randomized double-blind (injector, participant) controlled trial. Adults with moderate-to-severe non-surgical low back pain with radiation to gluteal or leg areas for at least 6 months received a single epidurogram-confirmed epidural injection of 10 mL of 5% dextrose or 0.9% saline using a published vertical caudal injection technique. The primary outcome was change in a numerical rating scale (NRS, 0 - 10 points) pain score between baseline and 15 minutes; and 2, 4, and 48 hours and 2 weeks post-injection. The secondary outcome was percentage of participants achieving 50% or more pain improvement at 4 hours. RESULTS AND CONCLUSIONS:No baseline differences existed between groups; 35 participants (54 ± 10.7 years old; 11 female) with moderate-to-severe CLBP (6.7 ± 1.3 points) for 10.6 ± 10.5 years. Dextrose participants reported greater NRS pain score change at 15 minutes (4.4 ± 1.7 vs 2.4 ± 2.8 points; P = 0.015), 2 hours (4.6 ± 1.9 vs 1.8 ± 2.8 points; P = 0.001), 4 hours (4.6 ± 2.0 vs 1.4 ± 2.3 points; P < 0.001), and 48 hours (3.0 ± 2.3 vs 1.0 ± 2.1 points; P = 0.012), but not at 2 weeks (2.1 ± 2.9 vs 1.2 ± 2.4 points; P = 0.217). Eighty four percent (16/19) of dextrose recipients and 19% (3/16) of saline recipients reported ? 50% pain reduction at 4 hours (P < 0.001). These findings suggest a neurogenic effect of 5% dextrose on pain at the dorsal root level; waning pain control at 2 weeks suggests the need to assess the effect of serial dextrose epidural injections in a long-term study with robust outcome assessment.

Project description:Inability to predict the therapeutic effect of a drug in individual pain patients prolongs the process of drug and dose finding until satisfactory pharmacotherapy can be achieved. Many chronic pain conditions are associated with hypersensitivity of the nervous system or impaired endogenous pain modulation. Pharmacotherapy often aims at influencing these disturbed nociceptive processes. Its effect might therefore depend on the extent to which they are altered. Quantitative sensory testing (QST) can evaluate various aspects of pain processing and might therefore be able to predict the analgesic efficacy of a given drug. In the present study three drugs commonly used in the pharmacological management of chronic low back pain are investigated. The primary objective is to examine the ability of QST to predict pain reduction. As a secondary objective, the analgesic effects of these drugs and their effect on QST are evaluated.In this randomized, double blinded, placebo controlled cross-over study, patients with chronic low back pain are randomly assigned to imipramine, oxycodone or clobazam versus active placebo. QST is assessed at baseline, 1 and 2 h after drug administration. Pain intensity, side effects and patients' global impression of change are assessed in intervals of 30 min up to two hours after drug intake. Baseline QST is used as explanatory variable to predict drug effect. The change in QST over time is analyzed to describe the pharmacodynamic effects of each drug on experimental pain modalities. Genetic polymorphisms are analyzed as co-variables.Pharmacotherapy is a mainstay in chronic pain treatment. Antidepressants, anticonvulsants and opioids are frequently prescribed in a "trial and error" fashion, without knowledge however, which drug suits best which patient. The present study addresses the important need to translate recent advances in pain research to clinical practice. Assessing the predictive value of central hypersensitivity and endogenous pain modulation could allow for the implementation of a mechanism-based treatment strategy in individual patients.Clinicaltrials.gov, NCT01179828.

Project description:ObjectiveMeta-analyses of analgesic medicines for low back pain often rescale measures of pain intensity to use mean difference (MD) instead of standardised mean difference for pooled estimates. Although this improves clinical interpretability, it is not clear whether this method is justified. Our study evaluated the justification for this method.MethodsWe identified randomised clinical trials of analgesic medicines for adults with low back pain that used two scales with different ranges to measure the same construct of pain intensity. We transformed all data to a 0-100 scale, then compared between-group estimates across pairs of scales with different ranges.ResultsTwelve trials were included. Overall, differences in means between pain intensity measures that were rescaled to a common 0-100 scale appeared to be small and randomly distributed. For one study that measured pain intensity on a 0-100 scale and a 0-10 scale; when rescaled to 0-100, the difference in MD between the scales was 0.8 points out of 100. For three studies that measured pain intensity on a 0-10 scale and 0-3 scale; when rescaled to 0-100, the average difference in MD between the scales was 0.2 points out of 100 (range 5.5 points lower to 2.7 points higher). For two studies that measured pain intensity on a 0-100 scale and a 0-3 scale; when rescaled to 0-100, the average difference in MD between the scales was 0.7 points out of 100 (range 6.2 points lower to 12.1 points higher). Finally, for six studies that measured pain intensity on a 0-100 scale and a 0-4 scale; when rescaled to 0-100, the average difference in MD between the scales was 0.7 points (range 5.4 points lower to 8.3 points higher).ConclusionRescaling pain intensity measures may be justified in meta-analyses of analgesic medicines for low back pain. Systematic reviewers may consider this method to improve clinical interpretability and enable more data to be included.Study registration/data availabilityOpen Science Framework (osf.io/8rq7f).

Project description:BackgroundChronic low back pain (cLBP) is a complex condition that is physically and psychologically debilitating, with vulnerable populations experiencing more severe outcomes. Physical therapy (PT) includes evidence-based treatments that can reduce disability, however the experience of PT can vary amongst different populations. Empirical evidence is largely based on majority samples that are predominantly white with high educational attainment. Little is known regarding how people from vulnerable groups (e.g. low income and racial minority) experience physical therapy treatment for low back pain.ObjectiveTo describe the experience of physical therapy in a predominantly low-income and minority population with cLBP.MethodsThis qualitative study was embedded within a randomized controlled trial for patients with cLBP in urban, underserved communities. We used a convenience sample to interview 12 participants from the 102 who participated in the PT arm of the trial and then performed thematic analysis to describe their experience.ResultsThree major themes emerged: 1) Empowerment through education and exercise; 2) Interconnectedness to providers and other patients; and 3) Improvements in pain, body mechanics, and mood. Divergent cases were few however centered around a lack of improvement in pain or an absence of connection with the therapist. Within the first theme a prevailing sub-theme emerged that aligned with Bandura's theory of self-efficacy: 1) Mastery of experience; 2) Verbal persuasion; 3) Vicarious experience; and 4) Physiological state.ConclusionsOur participants' insight highlighted the value of cognitive-emotional and interpersonal dimensions of PT. These may be particularly important components of PT in populations that have experienced systemic distrust in providers and disparities in services. Future work could use Bandura's model of self-efficacy to build a PT intervention comprised of fear-based movement exercises, interconnectedness, a strong therapeutic alliance, and mindfulness techniques.

Dataset Information

Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial.

Publications

Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial.

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