Can you comment on recent efforts to define and classify neuropathic pain more precisely?
The International Association for the Study of Pain has defined neuropathic pain as "pain initiated or caused by a primary lesion or dysfunction in the nervous system." While this definition certainly helps distinguish among various types of pain syndromes, it lacks precision for diagnosis. For example, how might a clinician prove nerve dysfunction exists? Currently available tools cannot easily define a nerve lesion when one actually exists. Patients with known so-called “small fiber” painful neuropathies may demonstrate normal findings on electrophysiological studies when other commonly used research tools such as quantitative sensory testing (QST) and epidermal skin biopsies demonstrate abnormalities.
Since normal or nociceptive pain is modulated and because peripheral as well as central sensitization may occur as part of normal nervous system behavior, it is challenging to distinguish abnormal (neuropathic) dysfunction from normal (physiologic) neuroplasticity. Responding to these and related challenges, an expert panel recently proposed that neuropathic be more precisely defined as arising as a direct consequence of a lesion or disease affecting the somatosensory system. The proposal includes a grading system of definite, probable, and possible neuropathic pain, reflecting the inherent ambiguity of the clinical presentation of pain and a need for improved diagnostic tools. Originally developed to clarify the diagnosis of pain, the proposed system remains a work in progress that in some respects has underscored the complexity of pain classification.
Is multidrug therapy commonly used for neuropathic pain? What pharmacologic combinations are most likely to be effective?
Although the prevalence of multidrug therapy for neuropathic pain has not been formally studied, my experience and that of my colleagues would suggest that it is the rule rather than the exception in pain clinics. This actually makes good sense since multiple pathophysiologic mechanisms are likely responsible for neuropathic pain. Results from numerous randomized placebo controlled studies would suggest that single therapeutic agents on average are likely to result in approximately 30% pain relief, increasingly accepted as clinically meaningful and certainly leaving room for improvement.
The pharmacologic combination which has been most widely studied is that of an alpha 2-delta agonist (gabapentin) and opioid (either morphine or oxycodone). Other combinations which might be considered would include an alpha 2-delta agonist with either a topical agent such as the 5% lidocaine patch or an SNRI agent such as duloxetine. Many other reasonable combinations could be considered, all of which require further evaluation in the clinic. Studies like those performed by Gilron (NEJM cite) have established a benchmark for evaluating the potentially additive benefits of combination therapies.
A recently published randomized trial (Yuan RY, et al. Neurology. 2009) demonstrates that botulinum neurotoxin A (BoNT/A) significantly reduced pain and improved sleep quality in patients with diabetic neuropathy. Is there additional evidence supporting the use of BoNT/A for neuropathic pain?
Jabbari and others have shown the benefit of subcutaneous injections of botulinum toxin type A in the management of spinal cord injury and additional studies have demonstrated its effective treatment of trigeminal neuralgia. A direct and sustained analgesic effect of botulinum toxin type A has recently been noted in chronic neuropathic pain by Ranoux and coworkers, who reported significant reductions in tactile allodynia and improvements in general activity. Although clinical anecdotes may support a role for botulinum toxin type A in the management of post herpetic neuralgia, to the best of my knowledge no published studies yet exist. Although not clearly a neuropathic pain state, there is increasing evidence that chronic daily headache may be effectively treated by botulinum toxin type A. BoNT has failed to achieve therapeutic benefits in patients with tension type headache, reflecting my own clinical experience, although I do use it in carefully selected patients with chronic daily headache.
What complementary and alternative modalities (CAM) or behavioral approaches have you found most effective for neuropathic pain?
The use of the supplement alpha lipoic acid has demonstrated effectiveness in the management of painful diabetic neuropathy. Motor cortex and deep brain stimulation as well as spinal stimulation have been used effectively for some patients with intractable neuropathic pain. Acupuncture, hypnotherapy and cognitive behavioral strategies may be considered but formal studies are lacking.
Similarly, well designed studies are needed to demonstrate whether CAM may provide additive analgesic benefit when used in combination with pharmacological and/or interventional modalities.
What investigational medications for neuropathic pain have shown promise?
While potentially exciting developments are underway, many clinical researchers have a measured, even cautious optimism when evaluating late stage compounds. Drug discovery and development is inherently complex, particularly for neuropathic pain. Among those in development presently are cytokine inhibitors, NMDA receptor antagonists, selective sodium channel antagonists, TRPV1 and TRPM8 receptor directed agents, ASIC channel antagonists, and new histaminergic receptor agents. Fueled by advances in combinatorial chemistry and nociceptive and inflammatory signaling, many of the molecules have demonstrated efficacy in animal models and small clinical trials. The final verdict is of course determined by results from large, randomized, blinded and controlled studies of patients with neuropathic pain. We shall see.
The Joint Meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee, which met June 29-30, 2009 to discuss steps to reduce acetaminophen-related overdoses and associated liver toxicity...
Bridget Martell et al presented an ambitious, systematic review of the effectiveness of opioid therapy in the treatment of chronic back pain.
Patient J.L. presented to pain management/neurology with complaints of low back pain and radiating right greater than left buttocks pain. Patient also complained of radiating right antero-lateral thigh pain, which occasionally radiated to antero-lateral lower leg.