Treating Chronic Pain – Too Much of a Good Thing

Published - Written by Lester Leung

In medical school, learning to categorize pain into somatic (or inflammatory), visceral, and neuropathic categories based on a patient’s characterization of her symptoms is an inaugural step in a physician’s training. However, the treatment of pain is not a straightforward task, even for an experienced clinician. The mainstays of pain treatment, the non-steroidal anti-inflammatory drugs (NSAIDs) and opiates, each carry significant risks with their use. There is great interest, then, in discovering new mechanisms of pain reduction.

One theory in pain reduction focuses on the neutralization of nerve growth factor which has been found to be elevated in tissue inflammation (e.g., arthritis, pancreatitis) and which presumably increases nociception, the effectiveness of pain transmission through sensory nerves. Nerve growth factor activates two cell-surface receptors, tropomyosin-related kinase A (TrkA) and p75, which are thought to mediate inflammatory and neuropathic pain transmission, respectively. Up to this point, much about nerve growth factor remained a mystery: was the elevation of NGF simply a marker for exposure to painful stimuli, did NGF augment nociception, or was NGF directly involved in the process of sensing pain?

On September 28, 2010, the New England Journal of Medicine published the results from a Phase II randomized clinical trial by Lane et al. comparing the use of tanezumab, a monoclonal antibody targeting nerve growth factor, to placebo in 450 patients with osteoarthritis of the knee. The study, which demonstrated a mean reduction in pain of 45 to 62% in patients who received two intravenous doses of tanezumab as opposed to a 22% reduction in patients who received the placebo, showed that nerve growth factor is in the chain of causality leading to pain.

According to Elizabeth Phimister, Ph.D, a deputy editor at the NEJM, it was “interesting that targeting this one molecule had the effect it did.”

Surprisingly, this particular study demonstrated less severe short term adverse effects than NSAIDs and opiates: the most common side effects were headache, upper respiratory tract infection, and sensory disturbances (numbness or paresthesias). Nerve growth factor is a neurotrophin that maintains sensory and sympathetic neurons; the absence of this growth factor can result in apoptotic cell death. In this study, the peripheral nerve disturbances appeared to be transient, and there were no central nervous system effects detected. However, the long term consequences of NGF inhibition are very troubling. The U. S. Food and Drug Administration requested on June 23 that clinical trials involving tanezumab be suspended pending further review of reports that 16 patients in one Phase III trial developed worsening of their osteoarthritis requiring joint replacement.

In an accompanying editorial, Dr. John Wood of the Wolfson Institute of Biomedical Research at the University of London explains that the worsening of joint disease “was most likely caused by excessive wear and tear in the absence of joint pain.” This risk of neuropathic joint deformation and deterioration may offset the benefits of pain reduction and lead to greater morbidity and mortality.

This study highlights some of the challenges of managing chronic pain.  At this time, how do you approach the treatment of chronic inflammatory pain? What new strategies do you believe hold the most promise in the treatment of pain?