Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects

June 8, 2006 Respected authors (with a special hello to Angela Mailis!)

Thanks for your work on a very difficult topic. I appreciate and agree with your comments that the studies you cite are problematic; they are too short to detect tolerance, addiction is not evaluated, etc. Furthermore, the studies are funded by the pharmaceutical companies, which may cause large biases as studies can be designed to show a favorable result – not difficult to do in the case of opioid research.

I believe there is another fundamental problem with opioid research for chronic non-cancer pain (CNCP). Opioids have a definite cognitive effect that is difficult to compare with either placebo or active placebo such as NSAIDs. They improve mood due to a euphoric effect, and even a nominal dose, such as of 5mg of oxycodone, is capable of producing this. After some time tolerance develops, and even a person using Q8h continuous release opioids will experience intermittent withdrawal, as well as smaller euphoric effects, during the peak and trough drug levels of their daily dosing. This has been my impression.

Under such conditions, patients will generally endorse benefit of opioids for the complex phenomena of CNCP, which may include psychogenic factors. Euphoria is equated with pain relief and greater wellbeing, and the dysphoria and pain of withdrawal is equated worse CNCP. Hence, patients are likely to say “I feel better when I take the opioids and worse when they wear off; hence they are helping my pain.”

Furthermore, it is often difficult to recall how bad their pain was while opioid free, and people on opioids for CNCP feel are likely to endorse and overall improvement even if they are worse off with the peaks and trough effects of their opioids. This may be because they cannot imagine a life without the opioids, since they now think that being without opioids would feel like their trough level of opioids – a state of withdrawal.

How else could the research be done? Firstly, I think that studies done with fentanyl patches, or a continuous infusion of opioids via pump would overcome some of these problems. The dose would have to be titrated so gradually that the patient would barely notice the nociceptive or psychogenic effects of the opioid. A suitable placebo would be necessary.

Secondly, in a trial comparing opioid in pill form to active placebo, perhaps the active placebo should contain one ingredient that gives nociceptive relief (i.e. an NSAID) and a second ingredient that has a calming but euphoric effect (i.e. a benzodiazepine such as a lorazepam, because it has a faster and more noticeable effect).

In traditional trials comparing oral opioids to placebo or NSAIDs, an objective and detailed assessment of “level of functioning” and overall “quality of life” are better primary outcomes than pain itself. Pain as a primary outcome measure is too skewed by the mechanisms I proposed above, and may have very little role in determining opioid effectiveness. For all of these measures of effectiveness, care must be taken to measure a study participant’s functioning/life-quality/pain at a single point in time. There should be nothing in the questioning method to that leads participants to compare how they were to their baseline levels. Psychologically, this could also lead patients to biased reporting.

Many thanks and all the best!

Dr. Tushar Mehta MD, CCFP

Substance Use Medical Service

St. Joseph’s Health Center

Toronto, Ontario

Conflict of Interest:

None declared