Treatment Of Neuropathic Pain Conditions Research Articles

Psychological assessment and treatment of patients with neuropathic pain.

Studies on the psychological assessment and treatment of neuropathic pain conditions, including postherpetic neuralgia (PHN), diabetic neuropathy, complex regional pain syndrome, post spinal cord injury, post amputation, and AIDS-related neuropathy, are reviewed. Although limited information is currently available, the findings are consistent with the larger literature on chronic pain and indicate that the assessment of neuropathic pain needs to include measurement of multiple dimensions of quality of life. Mood, physical and social functioning, and pain-coping strategies such as catastrophizing and social support are all important domains. Clinical trials of psychological interventions have not been reported in the scientific literature. Case series of successful treatment of neuropathic pain are reported, primarily in the area of biofeedback. As with other chronically painful conditions, it is likely that cognitive-behavioral interventions will improve the quality of life in neuropathic pain conditions.

LOW‐DOSE LIDOCAINE REDUCES SECONDARY HYPERALGESIA BY A CENTRAL MODE OF ACTION

Sodium channel blockers are approved for intravenous administration in the treatment of neuropathic pain states. Preclinical studies have suggested antihyperalgesic effects on the peripheral as well as the central nervous system. The objective of this study was to determine mechanisms of action of low‐dose Lidocaine in experimental induced, secondary hyperalgesia. In a first experimental trial, participants (n = 12) received lidocaine systemically (a bolus injection of 2 mg/kg in 10 min followed by an intravenous infusion of 2 mg kg(−1) h(−1) for another 50 min). In a second trial, a modified intravenous regional anesthesia (IVRA) was administered to exclude possible central analgesic effects. In one arm, patients received an infusion of 40 mi lidocaine, 0.05%; in the other arm 40 mi NaCl, 0.9%, served as a control. In both trials capsaicin, 20 mu g, was injected intradermally and time course of capsaicin‐induced pain, allodynia and hyperalgesia as well as axon reflex flare was determined. The capsaicin‐induced pain was slightly reduced after systemic and regional application of the anesthetic. The area of pin‐prick hyperalgesia was significantly reduced by systemic lidocaine, whereas the inhibition of hyperalgesia was absent during regional administration of lidocaine. In contrast, capsaicin‐induced flare was significantly decreased after both treatments. We conclude that systemic lidocaine reduces pin‐prick hyperalgesia by a central mode of action, which could involve blockade of terminal branches of nociceptors. A possible role for tetrodotoxin resistant sodium channels in the antihyperalgesic effect of low‐dose lidocaine is discussed.

Low-dose lidocaine reduces secondary hyperalgesia by a central mode of action

Sodium channel blockers are approved for intravenous administration in the treatment of neuropathic pain states. Preclinical studies have suggested antihyperalgesic effects on the peripheral as well as the central nervous system. The objective of this study was to determine mechanisms of action of low-dose lidocaine in experimental induced, secondary hyperalgesia. In a first experimental trial, participants ( n=12) received lidocaine systemically (a bolus injection of 2 mg/kg in 10 min followed by an intravenous infusion of 2 mg kg −1 h −1 for another 50 min). In a second trial, a modified intravenous regional anesthesia (IVRA) was administered to exclude possible central analgesic effects. In one arm, patients received an infusion of 40 ml lidocaine, 0.05%; in the other arm 40 ml NaCl, 0.9%, served as a control. In both trials capsaicin, 20 μg, was injected intradermally and time course of capsaicin-induced pain, allodynia and hyperalgesia as well as axon reflex flare was determined. The capsaicin-induced pain was slightly reduced after systemic and regional application of the anesthetic. The area of pin-prick hyperalgesia was significantly reduced by systemic lidocaine, whereas the inhibition of hyperalgesia was absent during regional administration of lidocaine. In contrast, capsaicin-induced flare was significantly decreased after both treatments. We conclude that systemic lidocaine reduces pin-prick hyperalgesia by a central mode of action, which could involve blockade of terminal branches of nociceptors. A possible role for tetrodotoxin resistant sodium channels in the antihyperalgesic effect of low-dose lidocaine is discussed.

Opioid analgesics as noncompetitive N-methyl- d-aspartate (NMDA) antagonists

Much evidence points to the involvement of N-methyl- d-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure–activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak noncompetitive NMDA receptor antagonists in vitro has created much attention among clinicians, no clinical studies have been conducted to evaluate the applicability of these compounds in the treatment of neuropathic pain conditions.

A novel spinal action of mexiletine in spinal somatosensory transmission of nerve injured rats

Mexiletine is widely used for the treatment of neuropathic pain although its site(s) of action remain unclear. Here we have studied the effect of spinal administration of mexiletine (10–1000 μg) on the spontaneous and peripherally evoked responses of spinal neurones of nerve injured (selective ligation of spinal nerves L5-L6; SNL) rats. Sham controls for the surgical intervention were performed. A high proportion of the spinal neurones of SNL rats exhibited de novo spontaneous activity (mean frequency of firing 4±1 Hz), this activity was highly sensitive to spinal mexiletine ( F 5,55=2.5, P≤0.05). The spinal neurones of the sham operated rats exhibited negligible spontaneous activity. The electrically evoked Aβ-fibre neuronal responses of SNL and sham operated rats were not significantly influenced by spinal mexiletine. In contrast, the Aδ-fibre and C-fibre evoked neuronal responses of the SNL rats, but not sham operated rats, were significantly reduced by spinal mexiletine ( F 5,52=4.9, P≤0.001 and F 5,48=12, P≤0.0001, respectively). In addition, the mechanical punctate von Frey 9 and 50 g evoked neuronal responses of the SNL rats, but not sham operated rats, were significantly reduced by spinal mexiletine ( F 5,57=4.3, P≤0.002 and F 5,52=6.1, P≤0.001). This pharmacological study suggests that following nerve injury there is a novel mexiletine sensitive spinal substrate which contributes to Aδ-fibre and C-fibre, but not Aβ-fibre, somatosensory transmission. This central action may underlie some of the clinical efficacy of mexiletine in the treatment of neuropathic pain states.

NGF but Not NT-3 or BDNF Prevents the A Fiber Sprouting into Lamina II of the Spinal Cord That Occurs Following Axotomy

There is a stereotypical pattern of primary afferent terminations within the mature spinal cord; however, this pattern is not immutable. Peripheral axotomy causes A fibers to sprout into lamina II, a region from which they are normally excluded. We have investigated the role of neurotrophins in this response. Rats which had undergone sciatic axotomy were treated intrathecally with NGF, BDNF, or NT-3. A fibers were visualized using transganglionic labeling with cholera toxin B subunit; small fibers were visualized using CGRP immunostaining. NGF (12 μg/day for 2 weeks), but not NT-3 or BDNF, prevented both the axotomy-induced reduction in CGRP staining within lamina II and the sprouting of A fibers into this region. It is likely that the prevention of A fiber sprouting is a secondary consequence of NGF rescuing small fibers. This effect of NGF on dorsal horn sprouting has implications both for our understanding of the maintenance of CNS connectivity and for the treatment of neuropathic pain states.

Prolonged alleviation of tactile allodynia by intravenous lidocaine in neuropathic rats.

Lidocaine may be useful in the treatment of neuropathic pain states. The authors hypothesized that lidocaine would reduce tactile allodynia observed in a rat nerve injury model. In an effort to determine the site of drug action, effects after intravenous, intrathecal, and regional administration were compared. Rats underwent ligation of the left fifth and sixth lumbar spinal nerves. The 50% thresholds (g) for left hind paw withdrawal of awake rats to von Frey hairs were documented before, during, and after intravenous administration of lidocaine at programmed/documented pseudo-steady-state plasma concentrations, and correlated with measured plasma concentrations. Responses to lidocaine application intrathecally and regionally to the injured nerves were also recorded. In rats with tactile allodynia, intravenous lidocaine yielded 66 +/- 11% of the maximal possible effect on thresholds (100% = normal threshold), versus -1.3 +/- 2.7% for saline infusion. Twenty-one days after lidocaine infusion, 30-40% of the maximal possible effect persisted. Threshold increases depended on plasma concentration, rather than quantity of drug administered: rats receiving 15 mg/kg with higher plasma concentrations (1.2 +/- 0.1 micrograms/ml) showed significant allodynia suppression throughout 7 days of follow-up, whereas rats receiving 15 mg/kg at a slower rate with lower plasma concentrations (0.6 +/- 0.1 microgram/ml) did not. The EC50 for acute allodynia suppression was 0.75 microgram/ml. No such allodynia suppression was seen after intrathecal or regional administration of lidocaine despite transient neural blockade. Intravenous, but not intrathecal or regionally applied, lidocaine produces dose-dependent suppression of allodynia associated with nerve injury. The effects far outlast plasma concentrations of lidocaine. The mechanism of these prolonged effects is unknown.