SHORT-TERM FORECAST FOR PAIN RESEARCH : FOCUS ON NEUROTECHNOLOGY

Prevalence and Economic Impact of Chronic Pain

Chronic pain is a disease that has reached endemic proportions irrespective of gender, social status, ethnicity or geographical location. In the United States, pain is a national health problem with over $150 billion/year in direct costs and lost productivity, whereas globally, pain secondary to nerve injury affects 170 to 270 million individuals 1. Hospitalized patients with intractable pain experience increased length of stay, longer recovery time and weakened immunity.

Pain is defined as chronic when lasting more than 6 months. In the absence of overt tissue damage, it is considered as abnormal or pathological 2. More than a sensory experience, pain engenders emotive and cognitive processes with significant behavioral consequences 3. A person suffering from long-term pain may be facing, in addition to physical agony, a somber forecast of losing one’s steady job and income, depression, sleep disturbance, deterioration in family relationships, and drainage of mental powers to deal with the pain… in short, it is a recipe for mental decline and social alienation.

In the face of incessant pain, the prospects of recovery lie in the hands of caregivers, which in Western societies equates with healthcare professionals. Herein lays the first hurdle the patient needs to overcome. A typical journey for someone with pathological pain may start in the clinic of a primary care physician, but is unlikely to yield an accurate diagnosis with an average of at least 5 referrals. People with chronic pain conditions are typically referred to one – or a combination of- the following specialists: neurology, orthopedic, anesthesia, neurosurgery, emergency medicine, gastroenterology, ear-nose-throat… whereas the most optimal path to adequate pain management should ideally start with a visit to the clinic of a board-certified pain management specialist.

Aside from the confusion surrounding the appropriate and timely referral of the pain patient, there’s the challenge of prescribing the right cocktail of pharmacotherapeutics, truly an art by itself, followed by physical therapy (if applicable) which ought to be concomitant with psychological therapy to better cope with some of the cognitive sequels of pain discussed above. In spite of a staggering healthcare cost, adding burden to the patient, insurers and tax payers, there is no guarantee of a cure. In some cases, patients are deprived of even a ‘worthy’ diagnosis, their pain labeled as ‘psychogenic’ or ‘exaggerated’. Surprisingly, objective diagnostic tools are lacking and verbal reporting by the patient remains the gold standard for pain diagnosis, with ensuing medico-legal issues and increased risks of misdiagnosis, unnecessary suffering and adverse side effects.

This, in a nutshell, is the harsh reality of chronic pain forcing some patients to commit suicide (yes, ‘Pain can kill’ 4).

Breakthrough technological advances with diagnostic and therapeutic potentials for pain

A report recently released by the Institute of Medicine of the National Academies concluded that “persistent pain can cause changes in the nervous system and become a distinct chronic disease” (see figure below, full report available online 5). The answer, it seems, lies in the central nervous system.

Looking at the future, innovation in the field of pain research is expected to come from an unfamiliar place: Neurotechnology. The nervous system is unique in its capability to utilize electricity for communication along nerve fibers, while being uniquely positioned to tolerate well, and effectively respond to, low-threshold electrical stimulation.

Thanks to recent breakthroughs in computational neuroscience and electrophysiological recording techniques, restoration of nervous system function has become feasible using neuroprostheses and brain-machine interfaces for motor disorders 6, or patient-controlled real-time feedback of brain function 7. Previously considered science fiction, it is now possible to harness the neuronal code from the brain of an individual with severe motor disability to control the motion of a robotic arm, or to communicate his/her thoughts by commanding a cursor on a computer screen 6.

Neurotechnology for pain management mainly refers to neuromodulation using deep brain stimulation (DBS, alternating current stimulation), transcranial direct current stimulation, or transcranial magnetic stimulation. In many respects, the field of pain research is still in the dark ages compared to state-of-the-art neurotechnology currently available for treating other forms of debilitating neurological disorders. After more than half-a-century, the exact mechanisms mediating the analgesic effects of neurostimulation techniques are uncertain, and devices being used are akin to an open-loop circuitry powered by a battery. Thus far, microstimulation in the nervous system is thought to trigger by one or several of the following events: ‘jamming’ of local hyperactive nociceptive circuitry, activation of analgesic structures, blockade of membrane ion channels such as voltage-gated currents 8, synaptic exhaustion, induction of early genes 9, 10, or even neurogenesis 11. Thorough understanding of neuromodulation phenomena requires further clinical testing in combination with well-designed animal experiments.

Although the classical DBS approach is to stimulate brain regions involved in modulatory systems known to initiate an endogenous morphine-like response (for example stimulation in the periaqueductal gray), experimental evidence suggests that the ‘pain circuitry’ in the brain can be directly targeted to reverse the hyperexcitability of neurons transmitting signals related to a painful stimulus, such as using high-frequency DBS in the sensory thalamic nucleus to inhibit sensitized neurons 12. Other options include motor cortex modulation with low-frequency stimulation, which is thought to release inhibition unto thalamic sensory neurons, at least in experimental animal models 13 (watch the video).

Video Legend:

A ‘mock’ patient with chronic pain. Data using electrophysiological recording of neuronal activity demonstrate abnormal burst activity in the sensory nucleus of the thalamus, whereas data using functional magnetic imaging suggest changes in cortical density, resulting in cortical thinning. Together, circuits in the cortex and thalamus communicate with each other, forming thalamocortical loops which oscillate at a defined frequency (or ‘rhythm’) under normal conditions. However, data using electroencephalography (EEG) demonstrate that this rhythm is disrupted under pain conditions and shifts to lower frequency domains. These findings carry diagnostic potentials for pain in the clinic (Courtesy of animal-LLC, http://animal-studio.com).

It is predicted that lessons learned from successful neurotechnologies will offer unprecedented opportunities for pain research in the near future. For example, it is envisioned that development of a sensor for the reliable detection of pain-related signals in the brain, coupled with a neuromodulation device for effective reversal of the pain ‘biomarker’, could yield a feedback closed-loop system for pain therapy, a novel concept that has already been validated clinically for the management of refractory epilepsy 14, 15. Ultimately, bearing in mind the multidimensional aspects of chronic pain and the host of co-morbid conditions associated with it would be necessary for advancing creative solutions to a neurological condition considered as the ‘holy grail’ of cognitive disorders.

Summary

hronic pain should be considered as a disease entity with poorly localized anatomical underpinnings within the nervous system 16. It is a multidimensional experience co-morbid with other psychological and cognitive states. For the healthcare provider, intractable pain poses the challenge of ineffective pharmacotherapy, compounded with absence of objective diagnostics. For Big Pharma industries, late stage failures of CNS therapeutics is blamed on lack of efficacy 17. Laboratory researchers, for their part, are also beginning to doubt the validity of existing animal models 18. Light at the end of the tunnel for patients and stake holders in pain research might come from an unlikely source, neurotechnology.

-Carl

Citations

1. ResearchandMarkets http://www.researchandmarkets.com/product/95248b/peripheral_neuropathy_and_neuropathic_pain.

2. Dworkin, R.H., et al. Evidence-based clinical trial design for chronic pain pharmacotherapy: a blueprint for ACTION. Pain 152, S107-115

3. McWilliams, L.A., et al. (2003) Mood and anxiety disorders associated with chronic pain: an examination in a nationally representative sample. Pain 106, 127-133

4. Liebeskind, J.C. (1991) Pain can kill. Pain 44, 3-4

5. InstituteofMedicine http://www.iom.edu/Reports/2011/Relieving-Pain-in-America-A-Blueprint-for-Transforming-Prevention-Care-Education-Research/Report-Brief.aspx.

6. Hochberg, L.R., et al. (2006) Neuronal ensemble control of prosthetic devices by a human with tetraplegia. Nature 442, 164-171

7. Cunningham, J.P., et al. (2011) A closed-loop human simulator for investigating the role of feedback control in brain-machine interfaces. Journal of neurophysiology 105, 1932-1949

8. Beurrier, C., et al. (2001) High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J Neurophysiol 85, 1351-1356

9. Benabid, A.L., et al. (2002) Mechanisms of deep brain stimulation. Mov Disord 17 Suppl 3, S73-74

10. Hammond, C., et al. (2008) Latest view on the mechanism of action of deep brain stimulation. Mov Disord 23, 2111-2121

11. Toda, H., et al. (2008) The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation. Journal of neurosurgery 108, 132-138

12. Iwata, M., et al. (2011) High-frequency stimulation in the ventral posterolateral thalamus reverses electrophysiologic changes and hyperalgesia in a rat model of peripheral neuropathic pain. Pain

13. Lucas, J.M., et al. (2011) Motor cortex stimulation reduces hyperalgesia in an animal model of central pain. Pain 152, 1398-1407

14. Ativanichayaphong, T., et al. (2008) A combined wireless neural stimulating and recording system for study of pain processing. Journal of neuroscience methods 170, 25-34

15. Venkatraman, S., et al. (2009) A system for neural recording and closed-loop intracortical microstimulation in awake rodents. IEEE transactions on bio-medical engineering 56, 15-22

16. Tracey, I., and Bushnell, M.C. (2009) How neuroimaging studies have challenged us to rethink: is chronic pain a disease? The journal of pain : official journal of the American Pain Society 10, 1113-1120

17. Arrowsmith, J. (2011) Trial watch: phase III and submission failures: 2007-2010. Nature reviews. Drug discovery 10, 87

18. Mogil, J.S., et al. (2010) The necessity of animal models in pain research. Pain 151, 12-17