Chronic pain has been called the nation's leading public health problem by the American Pain Society. Relentless pain interferes with quality of life, sleep, personal relationships, and economic security and is the cause of disability and depression for countless people worldwide.
- Up to 50 million Americans suffer from chronic pain.
- More than half of individuals with moderate to severe chronic pain have been suffering more than 5 years.
- An American Pain Society study in 1999 found that over 50% of individuals with chronic, non-cancer-related pain classify their pain as severe or very severe, and that fewer than half of these feel that their pain is adequately controlled by currently available medication.
Current medications are largely ineffective at treating a large portion of patients with chronic pain. With few exceptions, medications for the treatment of chronic pain were not initially developed for chronic pain, but rather for other diseases such as depression and epilepsy. Therefore, for many patients, the drugs' profiles limit their utility because of poor efficacy, significant central nervous system side effects (e.g., sedation), a short duration of action, and/or addictive properties. Avigen is prospectively developing drugs to treat chronic pain that have a good safety profile with limited central nervous system side effects, offer good efficacy by focusing on new mechanisms of action based on leading chronic pain research, provide long-lasting relief (especially through the night), and are non-addictive.
Acute vs. Chronic Pain
Acute pain occurs in disease or peripheral inflammation, and is a normal response to injury. It is an immediate and usually short-lived state, and the cause can usually be identified and treated. Chronic pain, in contrast, is continuous, persisting beyond the normal time for healing. It ranges from mild to severe and can last months or years - even for a lifetime. The cause is not always known, although it can be associated with disorders such as cancer, arthritis, diabetes, or various infections. Chronic pain may occur in the absence of known underlying disease or injury.
Neuropathic (neurogenic) pain results from nerve injury and can be particularly difficult to treat, and often becomes chronic. Neuropathic pain can distort signaling in the spinal cord such that even normal sensation is perceived as painful. In addition, spontaneous pain, exaggerated responses to otherwise mildly painful sensations, and widespread hypersensitivity extending beyond the area of original injury can become disabling. Chronic neuropathic pain affects up to one-third of individuals with diabetes, and is common after nerve damage caused by various cancer treatments, surgical procedures, trauma, accidental or therapeutic amputation, and as a complication of viruses which target the nervous system. such as herpes zoster (the cause of shingles) or HIV. Several hereditary conditions also are associated with neuropathic pain. While estimates of prevalence vary, more than 2 million North Americans are believed to be afflicted with neuropathic pain, and often are inadequately treated with available therapies.
Current Drug Treatment
Despite a common understanding among researchers in the field of the pathophysiology and molecular biology of the condition, patients with neuropathic pain are under-served. Current medications, including gabapentin, lidocaine, tramadol, antiepileptics, and tricyclic antidepressants, are largely ineffective at treating a large portion of patients with neuropathic pain. With few exceptions, such medications were not initially developed for pain, but rather other diseases such as depression and epilepsy.
Two major side effects of opioid use are tolerance and withdrawal. These undesirable side effects of opioids result in the reluctance of physicians to prescribe them, and the reluctance of patients to use them. However, the appropriate use of opioids can be beneficial, since relief from pain contributes significantly to the healing process. Avigen has discovered that AV411 may counteract opioid tolerance and withdrawal symptoms by blocking the activation of certain kinds of glial cells in the spinal cord. Together with our collaborators, Drs. Linda Watkins and Mark Hutchinson at the University of Colorado , Avigen has initiated preclinical studies to demonstrate this hypothesis. Initial results have been positive. With continued success these studies may provide guidance for the design of clinical trials to demonstrate these effects in humans.
Development of Chronic Pain
An increasing understanding of how chronic pain, particularly neuropathic pain, develops is necessary to guide development of new pain therapies. Researchers have begun to characterize physical changes in the nervous system that occur after nerve injury or disease. Such changes, including altered gene expression and nervous system inflammation, lead to abnormal processing of pain signals, and to intense pain that accompanies even normal sensation. Signaling pathways designed to facilitate a protective response to tissue injury become sources of chronic pathological pain.
The Role of Glia in Pathological Pain States
Groundbreaking research from several laboratories has identified cells that surround neurons, called glia, as important mediators of pathological pain states. Neurons have long been considered the sole cell types responsible for the development and maintenance of neuropathic pain. Glia traditionally have been disregarded as being little more than supporting cells for neurons. However, recent research has demonstrated that glia enhance the release of neurotransmitters that relay pain information to the spinal cord, and, even more striking, release substances that increase the excitability of pain-responsive neurons in the spinal cord. These substances, called pro-inflammatory cytokines, create and maintain exaggerated or pathological pain responses. Blocking the activation of glia reduces pro-inflammatory cytokines and reverses pathological pain. (Watkins and Maier, 2003) (Sorkin, book chapter, 2002) (see "Publications")
IL-10 and Pathological Pain
Leading research in the area of glial cell activation and its role in chronic pain is being conducted by Dr. Linda Watkins at the University of Colorado. Avigen is collaborating with Dr. Watkins to translate this research into clinical therapeutics.
Dr. Watkins' laboratory did the initial and most dramatic work to provide support that glial cell activation and the release of pro-inflammatory cytokines were indeed responsible for maintaining the chronic pain state. Dr. Watkins demonstrated that the potent anti-inflammatory cytokine interleukin-10 (IL-10), when injected in the region of the spinal cord where the activated glial cells reside, dramatically reverses the pain state in animal models of chronic pain. In fact, studies in animal models have shown that IL-10 prevents or reverses every pathological pain state examined, including pain induced by spinal inflammation, inflammatory neuropathy, traumatic neuropathy, and spinal trauma, without altering normal sensation.
While the use of IL-10 protein itself to treat pain is limited by its brief duration of action and its inability to get to nervous system tissue when given orally or by injection, it has opened the door to further developments. Dr. Watkins' research and the research of others who support the role of glial cells in chronic pain have led Avigen to pursue centrally acting glial attenuators as a treatment for chronic pain, including AV411, which is described in greater detail under "Pipeline