Various technologies have been used in drug discovery and evaluation including combinatorial chemistry, high throughput screening, pharmacogenomics, and proteomics. More recently, brain imaging has provided novel insights into functional, anatomical, and chemical changes in the human condition that allow us to define new approaches that may assist current drug development efforts 12.

A number of findings suggest that our approach to the treatment of chronic pain (e.g., neuropathic pain, fibromyalgia) has been hampered by a lack of understanding of changes that occur subsequent to the onset of the condition at the level of the central nervous system (Figure 1). Amongst these are:

(i) A 'ceiling effect' of current analgesics for chronic pain, rarely exceeding a 30% efficacy level in controlled trials 3 or as defined by numbers needed to treat (NNT) or need to harm (NNH) 4.

(ii) Chronic pain may express itself as a consequence of other conditions. For example, chronic pain may arise after the onset of depression, even in patients without a prior pain history of depression 5.

(iii) Chronic pain patients are defined as 'difficult patients' in that they often have neuropsychological changes that include changes in affect and motivation or changes in cognition, all of which rarely predate their pain condition.

(iv) In some conditions such as complex regional pain syndrome (CRPS), manifestations of dysautonomia, movement disorders, and spreading pain (ipsilateral and contralateral) are all indicative of complex secondary changes in the CNS that follow a relatively trivial peripheral nerve injury 6.

(v) Chronic opioid therapy (e.g., methadone maintenance) results in a hyperalgesic state in both experimental and clinical pain scenarios 7 implying changes in central processing (e.g., alterations in modulatory systems).

(vi) Opioids, arguably the closest approximation to an ideal analgesic, fail to produce pain relief in all individuals, even at high doses. This implies the development of 'analgesic resistance', a consequence of complex changes in neural systems in chronic pain that complicates the utility of opioids for long term therapy 8.

Taken together, these clinical insights suggest a few important points related to pharmacological treatment for chronic pain. First, that pain therapy clearly still requires further research to define a basic understanding of the nature of the disease (particularly regarding CNS processing) that will allow improved analgesic agents in the human condition. Second, that single targets are probably not 'ideal' analgesics given the complexity of the disease affecting the peripheral and central nervous system. Third, a strategy for treating pain is required, given that it is a chronic disease with a dynamic process (e.g., evolution of co-morbid phenotypes such as anxiety or depression) that is not easily reversed in most patients, and alterations in brain anatomy (e.g., cortical thickness) can arise as a consequence of the disease. Recent insights gained from structural and functional imaging the central nervous system (CNS) have provided the groundwork for a novel approach to developing therapies for chronic pain.

Chronic pain is a multidimensional process that now must be considered as a chronic degenerative disease not only affecting sensory and emotional processing, but also producing an altered brain state. Therapeutic interventions should be reconsidered in this context. Several functional (Figure 2), neurochemical, and structural changes have now been defined in the CNS of humans using functional, chemical, and structural (Figure 2, 3, 4) neuroimaging techniques. These changes not only provide novel insights into the pathology of the disease but also opportunities for objective indices for therapeutic efficacy.

In the past, many drug treatments have focused on the peripheral nerve and dorsal horn. However, most drugs used in chronic pain have CNS effects. These drugs fall into three main categories: opioids, antidepressants, and anticonvulsants. Though not developed for treating pain using a rational mechanistic approach, nearly all of these drugs have been applied to chronic pain treatment. Even in the case of the opioids, subtle effects occur as a result of multiple subtypes of specific receptors (e.g., μ1, μ2 and μ3) or as a result of actions at multiple opioids receptor sites. In the case of antidepressants, the initial mechanism of action on monoamine oxidase (MAO) inhibition has been extended to possible inhibition of sodium channels 30. For the anticonvulsants, there has always been an association with probable efficacy in chronic pain, dating back to the use of carbamazepine in trigeminal neuralgia 31. Indeed, the cross domain therapeutic flow has been very fruitful in many cases, of which gabapentin is probably the most well known. Most anticonvulsants have or are also being tried as treatments for neuropathic pain states. While mechanistic approaches (that require careful evaluation of specific responses e.g., cold, heat, von Frey etc) to novel therapies have significant appeal, in practice these may be difficult to implement in busy clinical practice.

In nearly all cases, drugs used in neuropathic pain have actions on the CNS. These actions are not well defined in terms of specificity at the receptor/gene level or at specific regions within the brain. In addition, in most, if not all controlled trials drugs for chronic pain have a ceiling effect in their efficacy of approximately 30%.

What can we learn from our past? Few analgesics have been designer drugs (e.g., triptans for migraine), and most agents that have come into clinical use by serendipity, or 'parallelism' (e.g., many if not all anticonvulsants have a role in neuropathic pain). Either we are targeting only a small fraction of CNS processes in chronic pain dysfunction or we are not stopping a progressive underlying degenerative process with the current therapies. With respect to the first this may be considered in terms of systems function (e.g., emotional circuitry may be more important than sensory systems), non-neuronal systems involved in CNS function, or neural plasticity that continues to change over time. The latter feeds into the second issue. If chronic pain produces brain matter loss in regions of the brain (e.g., for example the dorsolateral prefrontal cortex) with associated consequences in altered neural function (e.g., cognitive, emotional), then our focus is very different or should be enlarged. In this context, we should now also be evaluating drugs that have better 'neuroprotective effects". The limited information from the use of NMDA inhibitors that are currently available (e.g., ketamine, memantine, methadone – seems to have a combined opioids/NMDA antagonist action) suggests that this may be the issue at hand.

Unusual drugs (i.e., outside of the purview of opioids, anticonvulsants, or antidepressants) provide novel insights into the chronic pain condition. There are a number of drugs candidates for chronic pain therapy that are examples pharmacological agents outside of the 'standard' trio of medications. These include, amongst others, toxins 32, antibiotics. (3334, neuroprotective agents 35, glial-modulating agents 3637, and centrally acting cannabinoids 38. Many of these have multiple known actions – for example, neurotoxins have anti-convulsant effects 39; cannabinoid type drugs may have an effect on cytokine modulation (40, on reward pathways 41, or they may be neuroprotective 42.

Two pharmacological models provide significant insights into the treatment of chronic pain: (i) drug induced changes in central sensitization in an experimental model of pain and (ii) the use of a novel therapy based on neurochemical and neurodegenerative changes in chronic pain.

Current evidence suggests that the perfect pharmacological therapeutic approach would be to: (a) provide early and prolonged pain relief; (b) have peripheral and central effects; (c) have neuroprotective effects; (d) protect against neurodegenerative effects; (d) enhance endogenous analgesic systems though receptor mediated or other mechanisms; and (e) modulate cytokine/immune responses. Such information may now be garnered from neuroimaging approaches potentially helping clinical development programs by enabling the objective evaluation of candidate therapeutics in clinical trials.

Some drugs may actually have a number of these effects in a single agent. Examination of cannabinoid action provides a useful example since it has a number of attributes that make it a useful model as a 'pain drug', as it is: (a) an endogenous mediator (e.g., endogenous receptors); (b) analgesic 44; (c) a neuroprotectant 45; and (d) an immune modulator 4647.

The human condition is not a controlled experimental condition. Unfortunately, many patients seek treatment for pain many months or years after its onset. There are two groups of patients that could benefit from early intervention – diabetics and postoperative patients – who together comprise a significant number of neuropathic pain patients. Treating early with drugs that inhibit or slow down a degenerative process associated with pain may provide long-term effects. While there are patient compliance issues since there may not be an immediate benefit, current evidence suggests that the longer the pain persists, the greater the level of alterations in chronic pain patients.

While neuroimaging clearly is not a stand-alone answer to improved pharmacotherapies for chronic pain, recent developments have provided novel insights through studies of the human brain in vivo in health and disease. We believe that the application of these insights will help focus therapeutic approaches in clinical trials. Some of these are discussed below.

The ability to evaluate functional, anatomical, and chemical changes in the human brain has provided new insights into the CNS processing of pain in the human condition and also how drugs such as analgesics may work 1. With respect to the latter, the fact that many analgesics do not provide excellent levels of pain relief indicates that multiple processes are at play in the chronic condition that need to be targeted by new pharmaoctherapies. Some of these targets are unexpected, based on insights garnered from neuroimaging and will almost certainly mould some of our thinking in defining new approaches to discovering analgesics for chronic pain.