Chronic Pain Changes Your Brain in Areas Important for Reward and Emotion

The most effective class of drugs available for treating moderate to severe pain is opioid drugs, such as morphine, hydrocodone (Vicodin®) and oxycodone. Opioids have been used (and abused) for centuries with uses ranging from religious rituals to treatment of dysentery, however, their prominent use in treating moderate to severe pain in modern medicine will undoubtedly continue for the foreseeable future, due to the lack of alternative choices. Most experts would agree that despite the fears of addiction and the plethora of side effects that may limit use, opioid drugs are superior analgesics for the treatment of post-operative pain, traumatic injury-related pain, and cancer pain. However, their long-term use in management in chronic non-malignant pain is now being challenged, where concerns about safety and efficacy are debated.

Over the past 2 decades there has been a tremendous effort by basic scientists, biotechnology companies and the pharmaceutical industry to develop new drugs to alleviate pain. Various drug candidates made it from preclinical testing to clinical trials, only to have failed and consequently many companies have now abandoned their pain programs. Those new drugs that have made it to market are primarily restricted to spinal delivery, limited to use in terminal cancer patients, or are based on success of drugs with similar chemical structure (e.g. pregabalin, which was developed after the success of off-label use of gabapentin which rose to over 1 billion annual sales in the USA). Some analysts blame the lack of drug development for pain drugs in the trial design and/or the patient cohort (type of pain patient recruited for the trial). However, there is also a debate about whether the preclinical testing can capture pain.

Pain is a multidimensional experience comprised of sensory, cognitive, and affective (emotional) components, which are processed within discrete but interacting brain structures. It is well accepted that many chronic pain states, including those that result from spinal cord injury, are accompanied by dramatic sensory disturbances that result in pain hypersensitivity (allodynia – painful experience to something normally not painful and hyperalgesia – exaggerated response to something normally painful) and tonic (unprovoked) ongoing pain. Preclinical animal pain model testing captures the sensory component by measuring the time to respond to a painful stimulus. However, the emotional affective component, or how much the pain is ‘bothersome’ or unpleasant significantly impacts the quality of life of the sufferer. Most animal models of chronic pain typically rely on sensory/threshold measures of pain, but the emotional component of pain has been argued to be a greater measure of quality of life than its sensory component, and there is now a concerted effort to develop assays to capture this aspect of pain with the goal of better predictability of drug candidates. Capturing this aspect of pain is a challenge because you can’t ask a mouse or rat how it feels.

Future directions - How do we proceed? There is fascinating new research indicating that the “bothersome” unpleasant component of chronic pain engages parts of the brain called the limbic system. Within the limbic system are brain regions important for being able to experience something we like (rewarding) or something we try to avoid (aversion). The key point is that pain and reward are opposite processes, but are processed within overlapping or interacting brain structures - see Figure 1. This is important because stimuli that are rewarding such as food and pleasurable music DECREASE pain, and conversely pain can impair reward processing (pleasure). So chronic pain can cause an “anhedonic state” in which a person can’t experience pleasure from activities usually found enjoyable (e.g., exercise, hobbies, music, sexual activities or social interactions). In fact, chronic pain is second only to bipolar disorder as the major cause of suicide among all medical illnesses, further highlighting how devastating this condition is. The interplay between reward pathways and pain validate the importance of these brain areas, not only in why acute pain becomes chronic, but also the minimal effectiveness of opioid analgesics in treating many types of chronic pain (including that of neuropathic origin).

On-going Studies: Dr. Cahill and her research team recently identified that there is dysfunction of reward circuitry in an animal model of neuropathic pain. So, pain changes reward circuits. Reward (pleasure) decreases pain perception, so disrupting reward circuits may increase pain because it makes it more unpleasant. This is a major discovery, and the Cahill lab is now following up with research aimed at understanding the mechanisms responsible for the dysfunction of brain circuitry involved in emotion and reward in models of chronic pain. They are also preparing a proposal to seek pilot data for a clinical study aimed at novel therapies that will alleviate the emotional, affective component of pain. This is early stage research—the follow up to a fundamental discovery, so additional data are needed before a clinical study can be launched. The Cahill lab is seeking federal funding, but this is where private contributions could make a HUGE difference, allowing these scientists to collect the critical preliminary data that would allow a clinical study of novel therapies to address chronic pain.