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17 Articles in Volume 20, Issue #3
20/20 with Dr. Suzanne Amato Nesbit: Clinical Pharmacy Roles and Disparities
A Clinician’s Guide to Treating Chronic Overuse Injuries
Adhesive Arachnoiditis: No Longer a Rare Disease
Analgesics of the Future: Cebranopadol as an Opioid Alternative
Ask the PharmD: What role do vitamin D supplements play in treating dysmenorrhea?
Behavioral Pain Medicine: Managing the Affective Components of Pain
Chronic Fatigue Syndrome: Naltrexone as an Alternative Treatment
Chronic Pain and Coronavirus
Connecting the Dots: How Adverse Childhood Experiences Predispose to Chronic Pain
Editorial: Why Are ER Opioids Out of Favor?
Fibromyalgia as a Neuropathic Pain Disorder: The Link to Small Fiber Neuropathy
How the COVID-19 Pandemic Is Transforming Pain Care
Hydroxychloroquine Use and Risk in the Management of Systemic Lupus Erythematosus
Management of Trigeminal Neuralgia in Multiple Sclerosis
Optimizing Care Using a Trauma-Informed Approach
Pediatric Pain Management: A Review of Clinical Diagnosis and Management
The Use of Low Dose Naltrexone in the Management of Chronic Pain

Analgesics of the Future: Cebranopadol as an Opioid Alternative

This investigational drug may be helpful in relieving pain associated with osteoarthritis, cancer, the lumbar region, diabetic neuropathy, and surgery.
Pages 19-23

The analgesic effects of highly selective mu-opioid receptor (MOR) agonists have been well established in clinical practice. The adverse effect profile of these medications, however, can limit the use of traditional opioids. Concerns surrounding poor tolerability and risk for tolerance, addiction, and respiratory depression have led clinicians and researchers to search for alternative agents that can provide similar efficacy for pain management without the known risks.

Recent development has focused on low-selectivity and multifunctional “mixed ligands” in attempts to attain the “opioid Holy Grail.”1 Single drugs with multiple mechanisms may provide the following advantages over using multiple drug products to achieve the same effect: reduced polypharmacy, smaller molecular size facilitates entry into the central nervous system when compared to bulkier bivalent drugs, more predictable pharmacokinetics, and the potential for lower side-effect profiles.2

Cebranopadol is one such mixed ligand that is currently in the clinical stages of development internationally by Grünenthal, a German pharmaceutical company. The US company Depomed, acquired the US and Canadian rights to cebranopadol in 2015. Since Depomed’s rebranding under the name Assertio, their continued involvement with the development of cebranopadol has been unclear. However, Grünenthal appears to support the continued development of this analgesic.

Cebranopadol is a novel, centrally acting, first-in-class analgesic with a unique mechanism of action that combines nociceptin/orphanin FQ peptide (NOP) receptor and opioid receptor agonism.2 The NOP receptor, previously named opioid receptor-like receptor-1 (ORL-1), is considered a non-classical member of the opioid receptor family as it shares structural and transduction similarities and anatomical localization with the classical MOR, delta-opioid (DOR), and kappa-opioid (KOR) receptors.2,3 However, the actions of the NOP receptor are not sensitive to morphine, the prototypical opioid agonist or naloxone, an opioid antagonist.2,3 NOP receptors are distributed widely throughout the central nervous system and the overall effect of agonist activation leads to a reduction in afferent neuronal excitability, a key pathway for pain transmission.3

The effect of NOP receptor activation appears to be site- and species-dependent as this system has demonstrated both antinociceptive (analgesic) and pronociceptive effects in animal studies.3 Of interest, rodent models have demonstrated that NOP receptor activation has been shown to counteract MOR agonist-mediated development of tolerance, addiction, and physical dependence.2,4,5

In vitro pharmacokinetic testing of cebranopadol has shown that it displays high affinity for NOP and opioid receptors in human receptor binding.6 Cebranopadol was found to be a full agonist (100%) at MOR and DOR, nearly a full agonist (90%) at NOP receptors, and a partial agonist (~70%) at KOR. Off-target receptor affinity is much lower than the affinity for intended targets (NOP and opioid receptors). Evaluation of drug-drug interactions using cytochrome P450 (CYP450) isozyme assays (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5) revealed that cebranopadol did not inhibit any of these isozymes at concentrations up to 250 nM. Furthermore, Phase 1 pharmacokinetic studies have demonstrated that cebranopadol is characterized by a late time to reach maximum concentration (Cmax = 4 to 6 hours) and a half-life of 24 hours, making it an attractive treatment option for chronic pain.6-8

The Data

Early clinical trials suggest safety and efficacy of cebranopadol for a variety of pain conditions, including acute post-operative pain, chronic osteoarthritis, chronic low back pain, cancer-related pain, and diabetic peripheral neuropathy (see Table I). Cebranopadol was studied post-operatively in patients undergoing bunionectomy surgery.9 Compared to placebo, cebranopadol dosed at 400 mcg and 600 mcg daily produced statistically significant reductions in pain intensity post-operatively. Cebranopadol 200 mcg, morphine 60 mg sustained release, and placebo resulted in similar times to first use of rescue medication (4.33, 4.22, and 4.10 hours respectively), while cebranopadol 400 mcg and 600 mcg doses resulted in a longer time until first dose of rescue medication, 8.93 and 8.22 hours, respectively.

Phase 2 studies examining the safety and efficacy of cebranopadol in osteoarthritis (OA) have not yet been published, however, the results of one study were located using the European Union (EU) Clinical Trials Register. In this randomized, double-blind study, cebranopadol 75 mcg, 200 mcg, and 400 mcg doses were compared to placebo in patients with OA of the knee.10 The primary outcome examined the change in average pain intensity from baseline after 4 weeks of treatment.

Cebranopadol 400 mcg was found to produce statistically significant results when compared with placebo (-1.1988 points on a numeric rating scale (NRS), P=0.0145). Cebranopadol 200 mcg showed a larger pain reduction than placebo, although results were not considered statistically significant. In contrast, cebranopadol 75 mcg performed numerically worse than placebo. The incidence of treatment emergent adverse events (TEAEs) increased with increasing cebranopadol doses, although the 75 mcg and 200 mcg doses resulted in similar rates of TEAEs as placebo (46.9%, 50.0%, and 40.6% respectively).

A randomized, placebo- and active-controlled Phase 2 trial was completed in patients with a clinical diagnosis of chronic moderate to severe low back pain of non-malignant origin (with or without a neuropathic component).11 Participants were randomized to 1 of 5 treatment arms: placebo, tapentadol prolonged-release (PR) 200 mg BID, and three cebranopadol arms (200 mcg, 400 mcg, and 600 mcg daily) for 14 weeks.

All three cebranopadol arms, as well as the tapentadol arm, produced statistically significant changes in pain from baseline when compared to placebo. Cebranopadol was not compared head-to-head with tapentadol using statistical analyses for efficacy outcomes. Another limitation of this study was that only 360 of 641 (56.2%) of the patients who were randomized completed the trial as planned. The highest dropout rates were in the cebranopadol arms, mainly related to TEAEs, with the most frequent being dizziness, nausea, somnolence, vomiting, constipation, fatigue, headache, and hyperhidrosis.

Studies examining the use of cebranopadol in diabetic polyneuropathy have not yet been published, however, the results from two studies were also located using the EU Clinical Trials Register. One study of 122 patients with DPN found no significant or clinically relevant improvement in pain intensity the cebranopadol arms (25 mcg, 75 mcg, and 200 mcg) vs. placebo.12 Another trial utilized a complex placebo- and active-controlled crossover design.13 Cebranopadol at doses of 80 mcg, 100 mcg, and 120 mcg daily showed clinically meaningful differences to placebo when looking at changes in average pain intensity after 5 days of treatment. Cebranopadol 100 mcg appeared to demonstrate a similar analgesic effect to morphine SR 60 mg. A third trial comparing cebranopadol to pregabalin and placebo has also been completed, however, the interpreted results of this trial are not publicly available at this time.14

Additionally, cebranopadol has been studied for treatment of cancer-related pain. The CORAL trial compared cebranopadol with morphine prolonged-release (PR) in patients with moderate-to-severe pain related to cancer.15 Noninferiority of cebranopadol with and superiority over morphine PR were demonstrated for the primary endpoint: the use of daily rescue medication (maximum of morphine immediate release 60mg/day) over the previous 2 weeks. Rates of adverse events were similar in both groups. The trial was, however, terminated early due to low accrual of patients. Patients who were successfully enrolled in the CORAL trial were then enrolled in the CORAL-XT study, which examined the safety of continued therapy with cebranopadol for up to 26 weeks.16 At least one TEAE was experienced by 64 of the 76 patients enrolled, however, the most frequent TEAEs [asthenia (27.6%), malignant neoplasm progression (26.3%), and decreased appetite (22.4%)] were most likely related to disease progression, rather than use of cebranopadol. Most TEAEs recorded were considered mild (36.6%) or moderate (45.4%) in intensity.

Over the course of the 26 weeks, the average pain level remained mild (3 out of 10 on an 11-point NRS) and the mean average pain intensity was only slightly elevated from baseline at the end of the study (0.8 points).

Cebranopadol drug-liking has also been studied in healthy human subjects with a history of recreational opioid use.17 While cebranopadol 200 mcg and 400 mcg were not different from placebo in drug likeability, a significant difference was observed when cebranopadol 800 mcg was compared to placebo. Both hydromorphone 8 mg and 16 mg doses resulted in significantly higher values of drug liking when compared to cebranopadol 200 mcg and 400 mcg doses. The effect of cebranopadol 800 mcg on drug liking was comparable with that of hydromorphone 8 mg, although effects were consistently delayed (approximately 3 hours post-dose) relative to hydromorphone (approximately 1.5 hours post-dose).


Based on the pharmacology and pharmacokinetics,
cebranopadol does appear to be a promising alternative to traditional opioids. The potential for reduced tolerance and dependence with NOP activation demonstrated in animal models, combined with a prolonged half-life and reduced likeability in human subjects make cebranopadol especially appealing for chronic pain management.2,4,5,8,16

Clinical trials have produced significant results for pain reduction in acute postoperative pain, chronic low back pain, and osteoarthritic pain, however, the data supporting the use of cebranopadol for DPN is currently lacking. We look forward to the publication of the results of the trials that have been completed but not yet published. Chronic use of cebranopadol up to 26 weeks appears to be safe, however, the high rates of TEAEs and participant dropout rate from the chronic low back pain study are concerning.11,17

The timeline for this drug's approval, both internationally and in the United States, is unclear. Further studies examining the safety, efficacy, and potential for abuse will be helpful in determining if cebranopadol can one day be considered the “Holy Grail” of opioids. For now, this investigational product may be considered a unique opioid product with intriguing implications for pain management. 


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Last updated on: September 8, 2021
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