New data presented for the first time at the 16th World Congress on Pain in Yokohama, Japan, have demonstrated potential advantages of the first in class analgesic co-crystal in acute pain over tramadol alone. Results from a Phase II study have shown that CTC (Co-Crystal of Tramadol-Celecoxib) 100 mg, 150 mg and 200 mg (which contain tramadol 44 mg, 66 mg and 88 mg, respectively) provided superior pain relief to tramadol (100 mg) in patients with moderate to severe pain after tooth extraction. Dose dependent pain relief with CTC was found to be associated with similar (CTC 200 mg), or better (CTC 50 mg, 100 mg and 150 mg) tolerability than tramadol 100 mg alone.1

These clinical benefits can be explained from the results of:

· Dissolution studies which have demonstrated a changed, potentially clinically beneficial release profile of celecoxib (by increasing its solubility) and tramadol (by lowering its peak concentration), with anticipated translation into optimised pharmacokinetics. 5
· A pre-clinical study in rats, which showed that ctcsusp (Co-Crystal of Tramadol-Celecoxib in a molecular ratio of 1:1 in suspension) provided synergy in a postoperative pain model without enhancing adverse effects 2
· Pharmacokinetic (PK) studies, which showed that co-crystallising tramadol and celecoxib into CTC led to a changed, potentially clinically beneficial PK profile for each active pharmaceutical ingredient (API) (tramadol and celecoxib) compared with commercially available tramadol and celecoxib given as an open combination.3 Administration of CTC was associated with a reduced tramadol peak plasma concentration, and a shorter time to reaching maximum peak plasma concentration of celecoxib 4

Together the available study data suggest that CTC may provide effective analgesia at lower doses of each component, with a potential for an improvement in tolerability, and earlier onset of pain relief compared to tramadol alone.3,4
CTC is a first in class analgesic co-crystal with a molecular ratio of 1:1 of tramadol hydrochloride and celecoxib. CTC has been developed to capitalise on the complementary mechanisms of action of the well-known analgesics tramadol and celecoxib. Co-crystallising both constituents into CTC optimises their pharmacokinetic characteristics compared with currently marketed tramadol, celecoxib, or their concomitant administration in open combination.

"We are very excited by the results of these CTC studies," said Mundipharma International Head of Medical Affairs for Pain, Dr Harry Smith. "By optimising the pharmacokinetic characteristics of tramadol and celecoxib in CTC, we have been able to demonstrate that CTC achieves effective analgesia at lower doses compared to tramadol, and with an improvement in overall tolerability," Dr Smith explained.

Acute pain benefits from a multimodal approach for effective pain treatment. 6 CTC represents a rational approach of combining well-established and efficacious analgesics, which act through complementary anti-nociceptive and anti-inflammatory pathways.

Intense acute pain afflicts millions of patients each year.6 Despite many advances in pain research over the last few decades, inadequate control of acute pain, for example in trauma patients and following surgery, is still a common problem.6, 7, 8, 9
Poor management of acute pain prevents patients from leading a normal life, and results in repeat visits to the emergency department or family doctor.6, 10
Poor pain management puts patients at risk of many different complications, creates needless suffering, and also significantly increases costs of care.7 There is good evidence to show that poorly managed acute pain can evolve into chronic disabling pain. For up to 20% of patients, poor management of acute post-operative pain could lead to severe chronic pain.7
Although opioids are the preferred treatment for most moderate to severe acute pain, their side effects can impede their use, and thus, their clinical effectiveness. Opioids in therapeutic doses may cause sedation, dizziness, nausea, vomiting, constipation, tolerance, and respiratory depression. 11

CTC has been specifically designed by merging two well-established analgesics into a new co-crystal structure with an optimised pharmacokinetic profile, thereby achieving effective pain relief at lower doses compared to tramadol alone, and with an improvement in tolerability.

"Mundipharma is committed to developing new treatments to help patients better manage their pain, which remains an area of continuing unmet need," said Dr Smith. CTC is already proving to be an important asset in the Mundipharma pain pipeline, with Phase III trials now underway," Dr Smith concluded.

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References
1. Videla S, López-Cedrún J, Burgueño M, et al. Co-Crystal of Tramadol-Celecoxib: efficacy and safety results from a dose-finding, randomised, double-blind, multicentre, Phase II clinical trial in patients with moderate-to-severe acute pain due to an oral surgical procedure. IASP 2016; Yokohama, Japan: Abstract 2315. Poster Number PW 293
2. Merlos M, Portillo-Salido E, Brenchat A, et al. Administration of Tramadol and Celecoxib in a 1:1 Molecular Ratio Produces Synergistic Antinociceptive Effects in Postoperative Pain Models: Preclinical Rationale for Clinical Development of Co-Crystal of Tramadol-Celecoxib. IASP 2016; Yokohama: Abstract 2312. Poster Number PW 290
3. Gascón N, Videla S, Lahjou M, et al. Pharmacokinetic profile of multiple doses of Co-Crystal of Tramadol-Celecoxib: findings from an open-label, 4-period, 4-sequence, crossover, Phase I clinical trial in healthy male and female volunteers. IASP 2016; Yokohama, Japan: Abstract 2313. Poster Number PW 291
4. Gascón N, Videla S, Lahjou M, et al. Single-dose pharmacokinetic profile of Co-Crystal of Tramadol-Celecoxib: findings from an open-label, 4-period, 4-sequence, crossover, Phase I clinical trial in healthy male and female volunteers. IASP 2016; Yokohama: Abstract 2314. Poster Number PW 292
5. Almansa C, Mercè R, Tesson N, et al. Discovery and characterisation of a first-in-class Co-Crystal of Tramadol-Celecoxib in development for the treatment of moderate to severe acute pain. IASP 2016; Yokohama, Japan: Abstract 2310. Poster Number PW 289
6. Sinatra R. Causes and consequences of inadequate management of acute pain. Pain Med. 2010; 11(12): 1859-71.
7. Global Year Against Pain. What is the problem? Available at: http://www.iasp-pain.org/files/Content/ContentFolders/GlobalYearAgainstPain2/AcutePainFactSheets/1-Problem.pdf. Accessed September 2016.
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9. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016; 17 (2): 131-57.
10. Mäntyselkä P, Kumpusalo E, Ahonen R, et al. Pain as a reason to visit the doctor: a study in Finnish primary health care. Pain. 2001; 89(2-3): 175-80.
11. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008; 11 (2 Suppl): S105-20.