Investigational drugs targeting the prostaglandin E2 signaling pathway for the treatment of inflammatory pain

ABSTRACT

Introduction: Non-steroidal anti-inflammatory drugs (NSAID) are the most commonly used drugs for the treatment of pain, inflammation and fever. Although they are effective for a huge number of users, their analgesic properties are not sufficient for several patients and the occurrence of side effects still constitutes a big challenge during long term therapy.

Areas covered: This review gives an overview about the first and second generations of NSAIDs (COX1/2 non-selective, COX-2 selective), and their main side effects which gave still an urgent need for safer drugs and for the establishment of novel treatment strategies (improved safety, tolerability, patient convenience). The current developments of a possible third generation NSAID class comprise changes in the formulation of already approved drugs, combination therapies, dual cyclooxygenase-lipoxygenase inhibitors, NO- and H₂S-releasing NSAIDs, prostaglandin synthase inhibitors and EP receptor modulators, respectively. Literature search has been done with PubMed NCBI.

Expert opinion: Currently, there is no newly developed drug that is superior to the already approved selective and non-selective NSAIDs. Several novel approaches show promising analgesic efficacy but side effects are still an important problem. Solutions might be constituted by combination therapies allowing administration of lower drug doses or by individualized therapies targeting molecules apart from COX, respectively.

KEYWORDS:

• NSAID
• cyclooxygenase
• prostaglandins
• proton pump inhibitor
• side effects

Article highlights

• In spite of a number of available analgesics, several patients cannot be treated sufficiently.

• NSAIDs and coxibs are approved analgesics effective in inflammatory pain but sometimes associated with severe side effects in gastrointestinal, cardiovascular and renal systems.

• Coxibs in combination with proton pump inhibitors are currently the safest alternative for long-term treatment of pain patients.

• Modified NSAID formulations show some benefits but are also not devoid of side effects.

• NO- and H2S-coupled NSAIDs are new and promising developments but advanced clinical studies could not confirm superiority against approved NSAIDs so far.

• mPGES1 inhibitors and EP4 antagonists show potent antinociceptive effects but none of these compounds has reached advanced clinical development.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The manuscript received funding from the Deutsche Forschungsgemeinschaft (SFB 1039).