A brand-new morphine derivative called Morphine-6-Glucuronide (M6G) is being developed by the biopharmaceutical company PAION. A UK company called Developm CeNeS specialized in the creation of drugs that affect the central nervous system (CNS).

The company's lead compound, M6G, is indicated for the management of moderate to severe pain following surgery. The M6G investigational new drug application that CeNeS submitted in April 2007 received approval from the US Food and Drug Administration.

A pivotal pan-European trial that was completed successfully demonstrated that, despite M6G's comparable analgesic effects to morphine, it significantly reduces nausea and vomiting.

The medication failed to significantly reduce the frequency or severity of nausea. However, PAION's post-acquisition meta-analysis of Phase II and Phase III clinical data confirmed M6G's analgesic effect and wider therapeutic margin in comparison to morphine. Presently, PAION is looking for a partner in the drug's development.

Opioids, such as morphine and morphine derivatives, are arguably the oldest class of pain-relieving drugs. They were discovered at the turn of the 19th century and underpin the management of severe post-operative pain. They are still the "gold standard" for treating severe pain, including pain following surgery and chronic pain caused by advanced disease.
Opioids, which originate from a poppy species, mimic the effects of naturally occurring opioids (endogenous opioids) by binding to receptors in the brain. One of the most potent opioids and most effective analgesics available today is morphine. However, it frequently has poor patient tolerability and is associated with a number of undesirable side effects. Nausea and vomiting, Sedation Drugs Development Market, and respiratory distress are among the side effects of morphine use.

There is a need for opioid derivatives with a better safety and tolerability profile for the many millions of surgical patients in Europe and the United States annually. To address this requirement, PAION's M6G was developed.

Compared to conventional morphine preparations in the post-operative setting, M6G has a similar analgesic efficacy but a significantly improved side effect profile, according to clinical studies. M6G reduces the burden of morphine side effects.

In Phase II studies, the incidence of adverse events was lower than that of morphine, providing early evidence for a decrease in the burden of side effects following treatment with M6G. When compared to the use of morphine to manage post-operative pain, for instance, in patients admitted for day-case gynecological surgery, the incidence of nausea and vomiting was reduced by more than fifty percent.

These encouraging early results have since been confirmed by larger Phase III trials. In a randomized, double-blind study comparing M6G to morphine in patients undergoing major orthopaedic surgery, the M6G treatment arm experienced a significant decrease in side effects. Patients who took M6G had a 50% lower rate of nausea and vomiting, as well as a significantly lower rate of respiratory depression and sedation.

Data from the Phase III European registration trial involving 500 patients undergoing open abdominal surgery (hysterectomy, major GI, bowel, and urological) now support these findings.
The results showed that M6G was equivalent to morphine in providing pain relief but associated with significantly lower rates of post-operative nausea and vomiting. These tests were designed to test for non-inferiority between M6G and morphine treatments with respect to analgesic efficacy and superiority with respect to side effect profiles. The severity of post-operative nausea and vomiting in the M6G treatment group decreased by 28% (p=0.018) and dry retching by 32% (p=0.044).

Patient-controlled analgesia (PCA) with either M6G or morphine was administered to all Phase III trial participants following an initial bolus dose of either drug.

Additionally, PAION is developing CNS 5161 for the treatment of neuropathic pain in addition to M6G. Chronic neuropathic pain is caused by damage to sensory nerves and frequently does not respond to opioid or non-steroidal anti-inflammatory drug (NSAID) treatment. It may consist of:

Post-herpetic pain Phantom limb syndrome following limb amputation Peripheral neuropathy Fibromyalgia CNS 5161 is a selective non-competitive N-methyl D-aspartate (NMDA) receptor antagonist that binds to a site within the NMDA receptor's ion-channel. Drug-induced nerve damage Drug-induced nerve damage In patients with chronic intractable neuropathic pain, initial, small-scale clinical trials have demonstrated efficacy and good tolerability.

Marketing commentary: The global CNS market is dominated by analgesic drugs. Opioids are a well-established class of painkillers and the standard of care for severe pain, including severe pain following surgery.

It is well-positioned to succeed because there is evidence that M6G has an improved side effect profile while maintaining the same level of efficacy as conventional morphine preparations. A significant factor in determining M6G's success will be securing a licensing agreement to market it with a major pharmaceutical company.