Wade S. Kingery

A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes

&NA; The purpose of this review was to identify and analyze the controlled clinical trial data for peripheral neuropathic pain (PNP) and complex regional pain syndromes (CRPS). A total of 72 articles were found, which included 92 controlled drug trials using 48 different treatments. The methods of these studies were critically reviewed and the results summarized and compared. The PNP trial literature gave consistent support (two or more trials) for the analgesic effectiveness of tricyclic antidepressants, intravenous and topical lidocaine, intravenous ketamine, carbamazepine and topical aspirin. There was limited support (one trial) for the analgesic effectiveness of oral, topical and epidural clonidine and for subcutaneous ketamine. The trial data were contradictory for mexiletine, phenytoin, topical capsaicin, oral non‐steroidal anti‐inflammatory medication, and intravenous morphine. Analysis of the trial methods indicated that mexiletine and intravenous morphine were probably effective analgesics for PNP, while non‐steroidals were probably ineffective. Codeine, magnesium chloride, propranolol, lorazepam, and intravenous phentolamine all failed to provide analgesia in single trials. There were no long‐term data supporting the analgesic effectiveness of any drug and the etiology of the neuropathy did not predict treatment outcome. Review of the controlled trial literature for CRPS identified several potential problems with current clinical practices. The trial data only gave consistent support for analgesia with corticosteroids, which had long‐term effectiveness. There was limited support for the analgesic effectiveness of topical dimethylsulfoxyde (DMSO), epidural clonidine and intravenous regional blocks (IVRBs) with bretylium and ketanserin. The trial data were contradictory for intranasal calcitonin and intravenous phentolamine and analysis of the trial methods indicated that both treatments were probably ineffective for most patients. There were consistent trial data indicating that guanethidine and reserpine IVRBs were ineffective, and limited trial data indicating that droperidol and atropine IVRBs were ineffective. No placebo controlled data were available to evaluated sympathetic ganglion blocks (SGBs) with local anesthetics, surgical sympathectomy, or physical therapy. Only the capsaicin trials presented data which allowed for meta‐analysis. This meta‐analysis demonstrated a significant capsaicin effect with a pooled odds ratio of 2.35 (95% confidence intervals 1.48, 3.22). The methods scores were higher (P<0.01) for the PNP trials (66.2±1.5, n=66) than the CRPS trials (57.6±2.9, n=26). The CRPS trials tended to use less subjects and were less likely to use placebo controls, double‐blinding, or perform statistical tests for differences in outcome measures between groups. There was almost no overlap in the controlled trial literature between treatments for PNP and CRPS, and treatments used in both conditions (intravenous phentolamine and epidural clonidine) had similar results.

Substance P signaling contributes to the vascular and nociceptive abnormalities observed in a tibial fracture rat model of complex regional pain syndrome type I.

&NA; Wrist and ankle fractures are the most frequent causes of complex regional pain syndrome (CRPS type I). The current study examined the temporal development of vascular, nociceptive and bony changes after distal tibial fracture in rats and compared these changes to those observed after cast immobilization in intact normal rats. After baseline testing the right distal tibial was fractured and the hindlimb casted. A control group was simply casted without fracturing the tibia. After 4 weeks the casts were removed and the rats retested. Subsequent testing was performed at 6, 8, 10, 16, and 20 weeks after onset of treatment. Distal tibial fracture or cast immobilization alone generated chronic hindlimb warmth, edema, spontaneous protein extravasation, allodynia, and periarticular osteoporosis, changes resembling those observed in CRPS. Hindlimb warmth and allodynia resolved much more quickly after cast immobilization than after fracture. Previously we observed that the substance P receptor (NK1) antagonist LY303870 reversed vascular and nociceptive changes in a sciatic section rat model of CRPS type II. Postulating that facilitated substance P signaling may also contribute to the vascular and nociceptive abnormalities observed after tibial fracture or cast immobilization, we attempted to reverse these changes with LY303870. Hindpaw warmth, spontaneous extravasation, edema, and allodynia were inhibited by LY303870. Collectively, these data support the hypotheses that the distal tibial fracture model simulates CRPS, immobilization alone can generate a syndrome resembling CRPS, and substance P signaling contributes to the vascular and nociceptive changes observed in these models.

The Analgesic Potency of Dexmedetomidine Is Enhanced After Nerve Injury: A Possible Role for Peripheral alpha2-Adrenoceptors

This study investigated the analgesic potency and site of action of systemic dexmedetomidine, a selective alpha2-adrenoceptor (alpha2 AR) agonist, in normal and neuropathic rats. Ligation of the L5-6 spinal nerves produced a chronic mechanical and thermal neuropathic hyperalgesia in rats. von Frey fibers and a thermoelectric Peltier device were used to measure mechanical and heat withdrawal thresholds over the hindpaw. Systemic dexmedetomidine dose-dependently increased the mechanical and thermal thresholds in the control animals (50% effective dose [ED50] 144 and 180 [micro sign]g/kg intraperitoneally [IP], respectively). Neuropathic animals responded to much smaller doses of dexmedetomidine with mechanical and thermal ED50 values of 52 and 29 [micro sign]g/kg IP, respectively. There was no difference between the control and neuropathic animals with respect to dexmedetomidine-evoked sedation, as determined by decreased grid crossings in an open-field activity chamber (ED50 12 and 9 [micro sign]g/kg IP, respectively). Atipamezole, a selective alpha2 AR antagonist, blocked the analgesic and sedative actions of dexmedetomidine in both the neuropathic and control animals. However, L-659,066, a peripherally restricted alpha2 AR antagonist, could only block the analgesic actions of dexmedetomidine in the neuropathic rats, with no effect in control animals. In conclusion, nerve injury enhanced the analgesic but not the sedative potency of systemic dexmedetomidine and may have shifted the site of alpha2 analgesic action to outside the blood-brain barrier. Implications: We tested the analgesic efficacy of the alpha2 agonist dexmedetomidine in normal and nerve-injured rats. The analgesic potency of dexmedetomidine was enhanced after nerve injury with a site of action outside the central nervous system. Peripherally restricted alpha2 agonists may be useful in the management of neuropathic pain. (Anesth Analg 1998;87:941-8)

Isoflurane and Nociception: Spinal α2A Adrenoceptors Mediate Antinociception while Supraspinal α1 Adrenoceptors Mediate Pronociception

Background The authors recently established that the analgesic actions of the inhalation anesthetic nitrous oxide were mediated by noradrenergic bulbospinal neurons and spinal &agr;2B adrenoceptors. They now determined whether noradrenergic brainstem nuclei and descending spinal pathways are responsible for the antinociceptive actions of the inhalation anesthetic isoflurane, and which &agr; adrenoceptors mediate this effect. Methods After selective lesioning of noradrenergic nuclei by intracerebroventricular application of the mitochondrial toxin saporin coupled to the antibody directed against dopamine &bgr; hydroxylase (D&bgr;H-saporin), the antinociceptive action of isoflurane was determined. Antagonists for the &agr;1 and &agr;2 adrenoceptors were injected at spinal and supraspinal sites in intact and spinally transected rats to identify the noradrenergic pathways mediating isoflurane antinociception. Null mice for each of the three &agr;2-adrenoceptor subtypes (&agr;2A, &agr;2B, and &agr;2C) and their wild-type cohorts were tested for their antinociceptive response to isoflurane. Results Both D&bgr;H-saporin treatment and chronic spinal transection enhanced the antinociceptive effects of isoflurane. The &agr;1-adrenoceptor antagonist prazosin also enhanced isoflurane antinociception at a supraspinal site of action. The &agr;2-adrenoceptor antagonist yohimbine inhibited isoflurane antinociception, and this effect was mediated by spinal &agr;2 adrenoceptors. Null mice for the &agr;2A-adrenoceptor subtype showed a reduced antinociceptive response to isoflurane. Conclusions The authors suggest that, at clinically effective concentrations, isoflurane can modulate nociception via three different mechanisms: (1) a pronociceptive effect requiring descending spinal pathways, brainstem noradrenergic nuclei, and supraspinal &agr;1 adrenoceptors; (2) an antinociceptive effect requiring descending noradrenergic neurons and spinal &agr;2A adrenoceptors; and (3) an antinociceptive effect mediated within the spinal cord for which no role for adrenergic mechanism has been found.

Capsaicin‐Sensitive Sensory Neurons Contribute to the Maintenance of Trabecular Bone Integrity

This investigation used capsaicin to selectively lesion unmyelinated sensory neurons in rats. Neuronal lesioning induced a loss of trabecular integrity, reduced bone mass and strength, and depleted neuropeptides in nerve and bone. These data suggest that capsaicin‐sensitive sensory nerves contribute to trabecular bone integrity.

A substance P receptor (NK1) antagonist can reverse vascular and nociceptive abnormalities in a rat model of complex regional pain syndrome type II.

&NA; Sciatic nerve section in rats evokes chronic hindlimb edema, pain behavior, and hyperalgesia, a syndrome resembling complex regional pain syndrome (CRPS II) in man. Furthermore, there is an increase in spontaneous protein extravasation in the hindpaw skin of rats after sciatic transection, similar to the increased protein extravasation observed in the edematous limbs of CRPS patients. Now we demonstrate that sciatic nerve section also generates chronic hindlimb warmth, distal articular tenderness, allodynia, and periarticular osteoporosis, sequelae of nerve injury resembling those observed in CRPS. We postulated that facilitated substance P signaling may contribute to these vascular and nociceptive abnormalities and attempted to reverse these changes with the long acting substance P receptor (NK1) antagonist LY303870. Hindpaw spontaneous extravasation was inhibited by LY303870. Systemic administration of LY303870 also reversed hindpaw edema and cutaneous warmth. Intrathecal, but not systemic administration of LY303870 reversed soft tissue and articular mechanical hyperalgesia in the hindpaw. Collectively, these data further support the hypothesis that the sciatic nerve transection model closely resembles CRPS and that substance P contributes to the spontaneous extravasation, edema, warmth, and mechanical hyperalgesia observed in this model.

The development of chronic mechanical hyperalgesia, autotomy and collateral sprouting following sciatic nerve section in rat

&NA; The development of mechanical hyperalgesia over the tarsometatarsal joints subsequent to chronic sciatic section was studied in rats. Mechanical thresholds began to drop within 7 days of sciatic section and continued to decline for 2–3 weeks, resulting in significant hyperalgesia over the original saphenous and sciatic border zones lasting up to 310 days. Contralateral hyperalgesia, which is seen in tissue injury mechanical hyperalgesia, failed to develop. Collateral sprouting of high‐threshold mechanoreceptors from the saphenous nerve into the denervated deep and cutaneous tissue was observed. The extent of cutaneous sprouting did not significantly correlate with the severity of hyperalgesia. The simultaneous uniform reduction of mechanical thresholds across all tarsometatarsal areas after chronic sciatic section is consistent with a central modulation of nociceptive afferent input. The severity and temporal development of the hyperalgesia strongly correlated with the extent of autotomy behavior. This animal model of chronic mechanical hyperalgesia following peripheral nerve section closely resembles a human neuropathic pain syndrome and may provide an experimental opportunity to advance our understanding of the neuropathology subserving chronic pain.

Effect of anti-NGF antibodies in a rat tibia fracture model of complex regional pain syndrome type I

&NA; Tibia fracture in rats evokes chronic hindpaw warmth, edema, allodynia, and regional osteopenia resembling the clinical characteristics of patients with complex regional pain syndrome type I (CRPS I). Nerve growth factor (NGF) has been shown to support nociceptive and other types of changes found in neuropathic pain models. We hypothesized that anti‐NGF antibodies might reduce one or more of the CRPS I‐like features of the rat fracture model. For our studies one distal tibia of each experimental rat was fractured and casted for 4 weeks. The rats were injected with anti‐NGF or vehicle at days 17 and 24 post‐fracture. Nociceptive testing as well as assessment of edema and hindpaw warmth were followed during this period. Molecular and biochemical techniques were used to follow cytokine, NGF and neuropeptide levels in hindpaw skin and sciatic nerves. Lumbar spinal cord Fos immunostaining was performed. Bone microarchitecture was measured using microcomputed tomography (μCT). We found that tibia fracture upregulated NGF expression in hindpaw skin and tibia bone along with sciatic nerve neuropeptide content. We also found nociceptive sensitization, enhanced spinal cord Fos expression, osteopenia and enhanced cytokine content of hindpaw skin on the side of the fracture. Anti‐NGF treatment reduced neuropeptide levels in sciatic nerve and reduced nociceptive sensitization. There was less spinal cord Fos expression and bone loss in the anti‐NGF treated animals. Conversely, anti‐NGF did not decrease hindpaw edema, warmth or cytokine production. Collectively, anti‐NGF reduced some but not all signs characteristic of CRPS illustrating the complexity of CRPS pathogenesis and NGF signaling.

Nitrous Oxide Produces Antinociceptive Response via α2Band/or α2CAdrenoceptor Subtypes in Mice

BACKGROUND Opiate receptors in the periaqueductal gray region and alpha2 adrenoceptors in the spinal cord of the rat mediate the antinociceptive properties of nitrous oxide (N2O). The availability of genetically altered mice facilitates the detection of the precise protein species involved in the transduction pathway. In this study, the authors establish the similarity between rats and mice in the antinociceptive action of N2O and investigate which alpha2 adrenoceptor subtypes mediate this response. METHODS After obtaining institutional approval, antinociceptive dose-response and time-course to N2O was measured in wild-type and transgenic mice (D79N), with a nonfunctional alpha2A adrenoceptor using tail-flick latency. The antinociceptive effect of N2O was tested after pretreatment systemically with yohimbine (nonselective alpha2 antagonist), naloxone (opiate antagonist), L659,066 (peripheral alpha2-antagonist) and prazosin (alpha2B- and alpha2C-selective antagonist). The tail-flick latency to dexmedetomidine (D-med), a nonselective alpha2 agonist, was tested in wild-type and transgenic mice. RESULTS N2O produced antinociception in both D79N transgenic and wild-type litter mates, although the response was less pronounced in the transgenic mice. Antinociception from N2O decreased over time with continuing exposure, and the decrement was more pronounced in the transgenic mice. The antinociceptive response could be dose dependently antagonized by opiate receptor and selective alpha2B-/alpha2C-receptor antagonists but not by a central nervous system-impermeant alpha2 antagonist (L659,066). Whereas dexmedetomidine exhibited no antinociceptive response in the D79N mice, the robust antinociceptive response in the wild-type litter mates could not be blocked by a selective alpha2B-/alpha2C-receptor antagonist. CONCLUSION These data confirm that the antinociceptive response to an exogenous alpha2-agonist is mediated by an alpha2A adrenoceptor and that there appears to be a role for the alpha2B- or alpha2C-adrenoceptor subtypes, or both, in the analgesic response to N2O.

Methylprednisolone prevents the development of autotomy and neuropathic edema in rats, but has no effect on nociceptive thresholds.

Corticosteroids are probably an effective treatment for some types of neuropathic pain and complex regional pain syndromes. This study examined the effects of systemic methylprednisolone (MP) on acute nociception and on pain behavior and hyperalgesia in normal and neuropathic rats. There was no dose-response to intraperitoneal MP (up to 12 mg/kg) for nociceptive thresholds to heat (Peltier) or mechanical (analgesy-meter and von Frey fibers) stimuli in normal rats. Chronic high dose MP (3 mg/kg per day for 21 days) also had no effect on acute nociceptive thresholds in normal rats. After sciatic nerve section in rats a saphenous nerve mediated hyperalgesia to heat and mechanical stimuli gradually developed over 21 days. High dose MP (3 mg/kg per day for 21 days) had no effect on this adjacent neuropathic hyperalgesia. When systemic MP was started immediately after bilateral sciatic and saphenous nerve transection there was a dose-dependent reduction in autotomy behavior. Substance P has been proposed as a mediator of neuropathic pain and edema. Single dose MP (12 mg/kg) slightly reduced the substance P mediated extravasation induced with electrical stimulation of the saphenous nerve. Chronic MP (3.4 mg/kg per day for 28 days) severely reduced the neurogenic extravasation induced with saphenous nerve stimulation. Sciatic sectioned rats developed hindpaw edema between 7 and 14 days after surgery, and this neuropathic edema did not develop in rats chronically treated with MP (3.4 mg/kg per day). These results demonstrate that corticosteroids did not affect nociceptive thresholds in normal or neuropathic hyperalgesic rats. Chronic steroid treatment did prevent the development of autotomy and neuropathic edema, and completely blocked neurogenic extravasation, findings consistent with the hypothesis that primary afferent substance P release mediates autotomy pain behavior and neuropathic edema. This may be a relevant model for examining the effects of corticosteroids on neuropathic pain and complex regional pain syndromes.