Misha-Miroslav Backonja

Evidence-based guideline: Treatment of painful diabetic neuropathy: Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation

Objective: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). Methods: We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: “What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?” Results and Recommendations: Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL.

Assessment: Use of epidural steroid injections to treat radicular lumbosacral pain Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Based on the available evidence, the Therapeutics and Technology Assessment subcommittee concluded that 1) epidural steroid injections may result in some improvement in radicular lumbosacral pain when assessed between 2 and 6 weeks following the injection, compared to control treatments (Level C, Class I-III evidence). The average magnitude of effect is small and generalizability of the observation is limited by the small number of studies, highly selected patient populations, few techniques and doses, and variable comparison treatments; 2) in general, epidural steroid injection for radicular lumbosacral pain does not impact average impairment of function, need for surgery, or provide long-term pain relief beyond 3 months. Their routine use for these indications is not recommended (Level B, Class I-III evidence); 3) there is insufficient evidence to make any recommendation for the use of epidural steroid injections to treat radicular cervical pain (Level U).

Individual Differences in the Effects of Perceived Controllability on Pain Perception: Critical Role of the Prefrontal Cortex

The degree to which perceived controllability alters the way a stressor is experienced varies greatly among individuals. We used functional magnetic resonance imaging to examine the neural activation associated with individual differences in the impact of perceived controllability on self-reported pain perception. Subjects with greater activation in response to uncontrollable (UC) rather than controllable (C) pain in the pregenual anterior cingulate cortex (pACC), periaqueductal gray (PAG), and posterior insula/SII reported higher levels of pain during the UC versus C conditions. Conversely, subjects with greater activation in the ventral lateral prefrontal cortex (VLPFC) in anticipation of pain in the UC versus C conditions reported less pain in response to UC versus C pain. Activation in the VLPFC was significantly correlated with the acceptance and denial subscales of the COPE inventory [Carver, C. S., Scheier, M. F., & Weintraub, J. K. Assessing coping strategies: A theoretically based approach. Journal of Personality and Social Psychology, 56, 267283, 1989], supporting the interpretation that this anticipatory activation was associated with an attempt to cope with the emotional impact of uncontrollable pain. A regression model containing the two prefrontal clusters (VLPFC and pACC) predicted 64% of the variance in pain rating difference, with activation in the two additional regions (PAG and insula/SII) predicting almost no additional variance. In addition to supporting the conclusion that the impact of perceived controllability on pain perception varies highly between individuals, these findings suggest that these effects are primarily top-down, driven by processes in regions of the prefrontal cortex previously associated with cognitive modulation of pain and emotion regulation.

A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain

ABSTRACT ABT‐594 is a neuronal nicotinic acetylcholine receptor (NNR) agonist that exhibits potent analgesic activity in preclinical models of acute, chronic, and neuropathic pain. The purpose of this phase 2, randomized, multicenter, double‐blind, placebo‐controlled study was to evaluate the safety and analgesic efficacy of ABT‐594 in patients with diabetic peripheral neuropathic pain (DPNP). A total of 266 DPNP patients were randomized 1:1:1:1 to receive placebo, ABT‐594 150 μg BID, ABT‐594 225 μg BID, or ABT‐594 300 μg BID. Patients were titrated to a fixed‐dose of ABT‐594 over 7 days and remained at this dose for another 6 weeks. Compared to placebo, all three ABT‐594 treatment groups showed significantly greater decreases on the average diary‐based 0–10 Pain Rating Scale (PRS) score from baseline to final evaluation, the primary efficacy measure (placebo, −1.1; 150 μg BID, −1.9; 225 μg BID, −1.9; 300 μg BID, −2.0). The proportion of patients achieving at least a 50% improvement in the average diary‐based PRS was greater in all three ABT‐594 treatment groups. However, adverse event (AE) dropout rates were significantly higher in all three ABT‐594 treatment groups (28% for 150 μg BID, 46% for 225 μg BID, and 66% for 300 μg BID) than for the placebo group (9%). Consistent with the expected side‐effect profile of NNR agonists, the most frequently reported AEs were nausea, dizziness, vomiting, abnormal dreams, and asthenia. This study establishes proof of concept for NNR agonists as a new class of compounds for treating neuropathic pain.

PAIN ASSESSMENT AND EVALUATION OF PATIENTS WHO HAVE NEUROPATHIC PAIN

Pain assessment and physical examination are the first crucial steps in diagnosis of neuropathic pain disorders because these are still solely diagnosed on clinical grounds. The physical examination should be conducted in such a way that all of the positive sensory phenomena, such as allodynia, hyperalgesia, hyperpathia, summation, and after-sensation are elicited. Other physical examination findings should corroborate the diagnostic impression of neuropathic pain. Specific pain diagnosis should then lead to more specific therapy.

The effect of continuous morphine analgesia on chronic thermal hyperalgesia due to sciatic constriction injury in rats

We employed hindfoot withdrawal latencies to radiant heat to assess the analgesic effect of prolonged morphine infusion on thermal hyperalgesia induced by chronic constriction injury (CCI) of the rat sciatic nerve. All CCI rats developed thermal hyperalgesia while sham-operated animals did not. Continuous systemic infusion of morphine dose-dependently reversed the thermal hyperalgesia in the CCI rats. In contrast, thermal hyperalgesia persisted in saline-treated CCI rats. Tolerance to morphines analgesic effect did not develop over a period of seven days of morphine infusion, which is considered long-term for animal models. These data suggest that morphine acts rapidly and effectively to reduce behavioral signs of hyperalgesia in rats with sciatic CCI, without the concomitant development of tolerance. Scheduled administration of morphine might be an appropriate treatment regimen for relief of neuropathic pain, and the infrequent use of opioids in equivalent human clinical pain syndromes due to fear of opioid unresponsiveness and tolerance might need to be re-evaluated.

Efficient assessment of neuropathic pain drugs in patients with small fiber sensory neuropathies

Abstract We sought to develop an enrichment crossover study design that would allow us to efficiently evaluate and compare promising candidate neuropathic pain drugs. We evaluated the efficacy of gabapentin or tramadol vs. active placebo (diphenhydramine) in subjects with biopsy‐proven painful idiopathic small fiber neuropathy (SFN) who were self‐reported gabapentin responders. Eligible subjects entered two single blind run‐in phases. In the first phase (Period A), subjects were treated with single blinded gabapentin at their prestudy dose followed by a second run‐in phase (Period B) in which they were treated with diphenhydramine active placebo. Subjects with ⩾3 pain and a ⩾30% increase in pain intensity in Period B compared to Period A were then randomized to a double‐blind three period cross over trial of gabapentin at pre study dosage, tramadol 50 mg QID and diphenhydramine 50 mg qhs. Of the 59 subjects enrolled, 41 subjects were excluded: Twenty‐three had an insufficient rise in pain intensity in Period B; eight had skin biopsies that did not confirm SFN. Eighteen subjects were randomized into the double‐blind, crossover phase. There was a significant treatment effect of gabapentin vs. diphenhydramine (p = 0.001) and tramadol vs. diphenhydramine (p = 0.018) by the before‐bed daily pain score averaged over the final 7 days of each treatment period. We conclude that gabapentin and tramadol were effective in the treatment of painful SFN and that this experimental enrichment paradigm is attractive to screen potential neuropathic pain compounds for efficacy in proof‐of‐concept studies.

Pain ratings at the thresholds are necessary for interpretation of quantitative sensory testing

Published databases of quantitative sensory testing (QST) for sensory thresholds provide a means for detecting deficits of the thermonociceptive sensory nervous system. These databases, however, do not assist in the assessment of neuropathic pain, which is characterized by pain or hyperalgesia, or both. We utilized the method of levels for innocuous thermal stimuli, warm and cool, and the method of limits for noxious thermal stimuli, hot pain and cold pain, to determine QST thresholds. Stimuli were applied to distal and proximal sites in the upper and lower limbs of 50 healthy volunteers, ranging in age from 19 to 59 years. Thresholds for innocuous and noxious stimuli in this study were similar to previously published results. The mean pain rating across all sites at thresholds for noxious heat and cold stimuli was 4.10, as rated on a 0–10 numeric scale. Suggestions are provided for combining threshold information for innocuous and noxious stimuli and related pain ratings for the evaluation of sensory nervous system function and, specifically, neuropathic pain.

Local anesthetics as adjuvant analgesics

Local anesthetics administered to block nerve conduction for surgical anesthesia and to provide analgesia in management of acute pain have become a standard of anesthesiology practice. These drugs have had an important role in the multimodality management of chronic pain as well, and this role is expanding since the revival of systemic administration. Local anesthetics are analgesics, albeit not in the traditional clinical and pharmacologic sense. Evidence suggests that intravenous administration is an effective treatment in chronic neuropathic pain syndromes. There is also evidence that intravenous local anesthetics can relieve acute pain. Furthermore, the novel idea that acute procedural and postprocedural pain control with local anesthetics could prevent the development of chronic pain syndromes, including chronic neuropathic pain syndromes, adds another important potential dimension to the role of local anesthetics in pain management.

Quantitative Sensory Testing for Spinal Cord Stimulation in Patients With Chronic Neuropathic Pain

Objective:  A prospective pilot study was conducted, attempting to identify objective tests that would help clinicians to assess the efficacy of spinal cord stimulation (SCS) trial preceding permanent device implantation.