title: Topical high molecular weight hyaluronan reduces radicular pain post laminectomy in a rat model.
abstract: BACKGROUND
  A controversy exists about the mechanism of causation of the post-laminectomy pain syndrome. Some believe that epidural scarring, and attendant spinal nerve and nerve root scarring and tethering to the disc or pedicle at the site of surgery contributes to post-laminectomy pain in such patients. However, clinical outcome studies on this question are inconclusive and the assertion remains controversial. Definitive studies to help resolve the question are needed. Previously our laboratory has reported on a preclinical post-laminectomy model that mimics the postoperative proliferative fibrotic response grossly, as well as by biochemical assessment of the collagen content within the spinal canal. The post-laminectomy fibrotic response was attenuated in that study by application of a topical antifibrotic (high molecular weight hyaluronan gel) or by insertion of an absorbable roofing barrier (0.2-mm-thick Macropore sheet material) over the laminectomy defect before wound closure. The question remains of relevance of the attenuation of the fibrotic response to post-laminectomy chronic pain syndromes.
  
  
  OBJECTIVE
  The purpose of this study is to evaluate the effect of therapeutic attenuation of proliferative scar within the spinal canal post laminectomy on the pain-related behavioral response in a preclinical rat model.
  
  
  METHODS
  An established L5-L6 rat laminectomy model with a unilateral L5-6 disc injury was employed to assess postoperative proliferative fibrosis of the L5 spinal nerves using quantitative biochemical hydroxyproline assessment of the collagen content in four experimental groups. These observations were correlated with gross descriptions of spinal nerve scarring or tethering. Associated manifestations of a sensory pain-related response in the L5 spinal nerve receptor area of the hind paws was studied using standard tactile allodynia assessment with the von Frey hair technique. The tactile allodynia findings were supplemented by weekly descriptors of behavioral pain manifestations.
  
  
  METHODS
  Bilateral laminectomies at L5 and L6 and a unilateral right disc injury (L5-6) were performed on 35 male adult Sprague-Dawley rats, weighing 400+ grams (approved by the VA Institutional Animal Care Use Committee). The study consisted of four groups: 1) normal nonoperative control; 2) a sham-operated group; 3) an untreated laminectomy-disc injury group; and 4) a laminectomy-disc injury treatment group in which 0.1 cc topical high molecular weight hyaluronan (HMW HA) gel was layered over the dura and into the laminectomy canal before closure. Before animals were entered into the study, they were checked for the presence of abnormal response to the tactile testing procedure of the L5 sensory receptor area. Animals exhibiting anomalous responses were excluded from the study. Behavioral testing for tactile allodynia was performed at weekly intervals post laminectomy beginning at 3 weeks. Pain-related behavior was characterized at weekly intervals. A behavioral test cage with a wire mesh floor allowed for tactile allodynia testing. Graduated von Frey hairs whose stiffness increased logarithmically from 0.41 to 15 g were used for tactile allodynia tests. The animals were killed 8 weeks postoperatively for analysis. The dissected spinal nerve and nerve root specimens were studied biochemically for hydroxyproline content to estimate total collagen in and around the L5 neural structures. Statistical analyses were performed using analysis of variance and a Fisher comparison t test.
  
  
  RESULTS
  The major observations on the untreated preclinical post-laminectomy rat model previously described by this laboratory were confirmed. All untreated animals developed a tail contracture concave toward the right (disc injury side) consistent with asymmetrical lumbar muscle spasm. Only one animal in the HA gel treatment group had a tail contracture. It was of mild degree and occurred in an animal that demonstrated slightly increased right L5 tactile sensitivity. Gross inspection of the dissected specimens demonstrated spinal nerve scarring and tethering to the disc and pedicle greater on the right than the left in untreated animals, findings that were markedly reduced in the treatment group. Collagen content of the L5 spinal nerve and nerve roots with attached scar were significantly lower in the HA gel treatment group than in the untreated laminectomy group (p=.0014). Pain behavioral testing of the L5 receptor area of the right hind paw in the untreated laminectomy group showed markedly increased sensitivity to tactile allodynia testing compared with the corresponding limb of the control group (p=.0001), to the corresponding limb of the sham group (p=.0001), and compared with the HMW HA gel treatment group (p=.0010). Comparisons of the pain behavioral data between the sham and the post-laminectomy HA gel treatment group and the control animals lacked statistical significance.
  
  
  CONCLUSIONS
  This study supports the concept of a relationship between perineural fibrosis and radicular neuropathy in the model described, and emphasizes the role of disc injury and spinal nerve retraction in the post-laminectomy fibrotic process. Furthermore, it shows promise for preliminary assessment of interventions with other anti-inflammatory agents, for characterization of the neurochemical profile of the post-laminectomy pain state, and for exploration of newer pharmaceutical agents potentially useful in the prevention or management of the post-laminectomy syndrome. Post-laminectomy scar is but one of many potential causes of the post-laminectomy pain syndrome. Furthermore, a cautionary note must be emphasized as in all studies using preclinical models, conclusions drawn from the studies cannot be extended directly to patients without confirmatory clinical follow-up studies.
authors.affiliation: Department of Orthopaedics, Veterans Administration San Diego Health Care System and University of California, San Diego, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Massie
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Schimizzi
authors.forename: Bill
authors.initials: B
authors.lastname: Huang
authors.forename: Choll W
authors.initials: CW
authors.lastname: Kim
authors.forename: Steven R
authors.initials: SR
authors.lastname: Garfin
authors.forename: Wayne H
authors.initials: WH
authors.lastname: Akeson
mesh_terms: D000287:Administration, Topical; D000818:Animals; D002921:Cicatrix / Q000473:pathology / Q000517:prevention & control; D005782:Gels; D006820:Hyaluronic Acid / Q000008:administration & dosage*; D007796:Laminectomy; D008159:Lumbar Vertebrae / Q000601:surgery; D008297:Male; D008970:Molecular Weight; D010147:Pain Measurement; D010149:Postoperative Pain / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013126:Spinal Nerve Roots / Q000473:pathology; D013127:Spinal Nerves / Q000473:pathology
chemical_list: D005782:Gels; D006820:Hyaluronic Acid