Conducting Pilot Trials for Chronic Pain: Methodological Issues
Chronic pain tends to be very difficult to manage because of its complex natural history, unclear etiology and poor response to therapy. It is characterized by the pain which persists despite adequate time for healing. Common sources of chronic pain include injuries, headaches, backaches, joint pain due to arthritis, sinus pain, tendinitis or injuries such as carpal tunnel syndrome. Chronic pain is also a feature of many types of advanced cancers. A number of symptoms can accompany chronic pain and can even arise as a direct result of the pain. These can include insomnia or poor quality sleep, irritability, depression and mood changes, anxiety, fatigue and loss of interest in daily activities. Pain can also trigger muscle spasms that can lead to soreness or stiffness.
Various drugs have been prescribed for chronic pain and many studies have also been conducted. To check the efficacy of tapentadol extended release for managing chronic pain, a large scale, randomized, controlled phase 3 studies have been conducted in patients with chronic osteoarthritis pain, low back pain and pain related to diabetic peripheral neuropathy (DPN). Results have been registered in United States and Europe. Whereas, in Japan, 2 pilot 12 week randomized, double blind, placebo-controlled phase 2 studies have been conducted with tapentadol ER to access chronic pain, DPN or peripheral herpetic neuralgia. These small exploratory studies were substantially under-powered and compared with the registered trials.
In these trials, patients in both studies were compared randomly to tapentadol or placebo for 12 weeks. Results indicated that primary efficacy endpoint of both studies were failed to differentiate between tapentadol ER and placebo and least-squares mean differences for tapentadol ER vs placebo were -0.1 in OA/LBP study and -0.1 in the DPN/PHN study. More than 80% of patients took concomitant analgesics during these studies. Results indicated that tapentadol was well tolerated.
On trial completion, it was observed that, both studies were associated with different disease entities, small sample size, use of concomitant analgesics and possible placebo effect that may have led to the failure to differentiate between tapentadol ER and placebo through methodological issues.