Oxygenated glycerol triesters (OGTs) and menthol shown to provide better pain relief than mentholated cream alone

In light of concern regarding OTC pain relievers, topical analgesics present an important option for the treatment of acute and chronic pain.

Pain is one of the most undertreated healthcare problems in the world. It is also among the most common reasons for patients to seeking health care.

When it comes to treating pain, the goals depend on the nature of the pain:

  • For acute pain, the goal is safe, effective, and rapid analgesia that allows mobilization and healing to take place.
  • For chronic pain, the goals are to reduce pain, minimize side effects, improve physical and psychosocial function, and limit end organ-related consequences of chronic treatment.

Many patients treat their pain using over-the-counter (OTC) analgesics, such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) that carry considerable end organ risk. This risk is often proportional to the patient’s plasma levels, chronicity, and preexisting risk factors.

For example, chronic use of acetaminophen (paracetamol) has been associated with liver failure (at repeated supratherapeutic levels and possibly even at relatively low doses) and is one of the most common reasons for patients receiving hepatic transplantation.

Patients who are unaware of these risks may take in excessive amounts of acetaminophen and not realize the potential for harm. For instance, patients may not consider which OTC products contain acetaminophen, or they may have multiple prescriptions that result in high cumulative doses of acetaminophen.

NSAIDs are effective and widely used, but they are also associated with serious gastrointestinal, renal, and cardiovascular adverse events. Care must be taken when using OTC agents to manage persistent pain.

In light of concern over OTC pain relievers, topical analgesics present an important option for the treatment of acute and chronic pain.

Among several types of topical analgesics, creams containing menthol – a derivative of peppermint oil – have an initial cooling effect and then a localized warming effect secondary to increased localized blood flow.

Gate-Control Theory

Menthol for a long time has been considered a counter irritant, blocking pain signals sent by smaller nerve fibers by inducing signaling through larger nerve fibers, a theory known as the Gate-Control Theory. More recently, menthol has been shown to act on specific cold (thermoceptive) and menthol-sensing receptors in sensory neurons known as TRPM8, which is an ion channel that regulates sodium and calcium ions.

Regulation of these ions governs the action potential of a nerve and thus regulates its signaling. In addition, this effect on pain sensitivity seems to be dose-dependent, with low doses decreasing sensitivity to pain (increase pain threshold) and high doses inducing a feeling of cold and increased sensitivity.

Unlike menthol, the analgesic properties of oxygenated glycerol triesters (OGTs) are not well understood. One theory holds that OGTs’ ability to relieve pain may be due to its antioxidant and anti-inflammatory properties. It is thought that oxygenated glycerol triesters acts as a superoxide dismutase mimetic, scavenging free radicals and reducing the oxidative stress marker malondialdehyde, which has been associated with a number of pain conditions, including vascular pain, acute coronary syndromes, pain from pancreatitis, peripheral neuropathy, temporomandibular joint disease, fibromyalgia, acute abdominal pain, and primary dysmenorrhea.

In 2012 a study was undertaken to compare the effectiveness of a mentholated cream (MC) topical analgesic with a novel OGT oil topical analgesic that was commercially utilized in Europe and was recently made available in the United States (OxyRub_; Creomed, Naples, FL, USA). In formulating the research question, the investigators hypothesized that the addition of OGT to menthol would enhance the analgesic effect of a mentholated topical analgesic in the treatment for acute musculoskeletal pain. The study’s results confirmed that although the concentration of menthol was equal in both products being compared, the OGT product produced a significant additive analgesic effect.

The study abstract is below. The complete study is linked here.

A Randomized, Double-Blind Comparison Shows the Addition of Oxygenated Glycerol Triesters to Topical Mentholated Cream for the Treatment of Acute Musculoskeletal Pain Demonstrates Incremental Benefit Over Time

Robert Taylor Jr., PhD*; Tong J. Gan, MD†; Robert B. Raffa, PhD‡; Chris Gharibo, MD§; Marco Pappagallo, MD¶,**; Nicholas R. Sinclair, MD, PhD*; Charles Fleischer††; Aaron Tabor, MD‡‡


Background: Topical analgesics are important products in the armamentarium for pain relief.

Methods and Findings: This study compared a topical analgesic product containing menthol to the same product with the addition of oxygenated glycerol triesters (OGTs) (also called essential oxygen oil) in 66 healthy adult subjects with acute musculoskeletal pain. Patients were randomized in a single-center, double-blind study to receive mentholated cream (MC) only or MC containing OGTs.

Patients self-reported their pain intensity, lifestyle limitations, and evaluation of the mobility of the painful joint or muscle at baseline and three times daily over a seven-day course on a 100-mm visual analog scale (VAS). Patients in both groups experienced statistically significant pain relief on Day 8 over baseline, with the MC plus OGT-treated group reporting statistically significantly greater pain relief than the MC group (P = 0.016). In addition, patients treated with the combination product experienced an incremental decrease in pain during each of the 7 days of treatment in addition, and they had lower VAS scores and greater lifestyle and mobility improvements than the MC group. Both products were well tolerated with no serious adverse events reported and no signs of significant skin reactions in either group.

Conclusion: Based on this study, a MC containing OGTs is safe, effective, and provided significantly better pain relief than MC alone. The combination of oxygenated glycerol trimesters and MC provided significant pain relief and offered continued improvement in pain relief over time.

*NEMA Research, Naples, Florida; †Department of Anesthesiology, Duke University, Durham, North Carolina; ‡Temple University School of Pharmacy, Philadelphia, Pennsylvania; §Department of Anesthesiology and Pain Medicine, New York University School of Medicine; ¶New Medical Home for Chronic Pain, New York, New York, U.S.A.; **US Medical Intelligence, Grunenthal, Aachen, Germany; ††Always Healthcare, Naples, Florida; ‡‡Physicians Laboratories, Inc., Kernersville, North Carolina, U.S.A.

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