Characteristics in patients with very early therapeutic response of condoliase chemonucleolysis for lumbar disc herniation.

INTRODUCTION: Treatment of lumbar disc herniation (LDH) using condoliase chemonucleolysis (CC) requires more time than surgery to demonstrate therapeutic effects. This study aimed to identify patients who show significant improvement in leg pain very early after CC and to determine pretreatment factors that can predict a very early therapeutic response. METHODS: The study included 52 patients who underwent CC for treatment-resistant LDH. Scores for low back and leg pain measured by a numerical rating scale were assessed at four time points (1 day, 1 week, 1 month, and 3 months after CC). Patients who reported subjective pain relief the day after treatment and further exhibited an improved straight leg raising (SLR) angle compared to pretreatment were classified as "very early responders (VER)". RESULTS: Of the 52 patients, 39 (75%) were VER, and 13 (25%) were non-VER. The VER showed earlier improvement in leg pain. The VER had a significantly higher proportion of positive SLR test patients (p = 0.01) and a significantly smaller pretreatment SLR angle compared to the non-VER (VER vs. non-VER: 40.6 ± 19.0 vs. 63.1 ± 16.9, p < 0.001). There were no significant differences in the level, type, and size of LDH and the disc regression rate between the two groups. CONCLUSIONS: Patients with a smaller pretreatment SLR angle are more likely to experience very early or early symptomatic relief, with a significant and sustained reduction in leg pain up to 3 months after CC treatment.

Chemonucleolysis in lumbar disc herniation: a meta-analysis.

PURPOSE: To carry out a systematic review and meta-analysis of the efficacy of chemonucleolysis in the treatment of lumbar disc herniation. METHODS: Clinical trials were selected from 3 electronic databases (The Cochrane Controlled Trials Register, MEDLINE, and EMBASE). Data were analyzed with the software STATA, using the meta command. RESULTS: Twenty-two clinical trials were eligible. For chemonucleolysis versus placebo, the summary risk ratio estimate for pain relief as outcome was 1.51 (95% CI: 1.27-1.80). The summary estimate was 1.07 (95% CI: 0.95-1.20) for the comparison between chymopapain and collagenase. Regarding chemonucleolysis with chymopapain versus surgery, the fixed-effect summary estimate of effect for pain relief was 0.93 (95% CI: 0.88-0.98) with surgery as the reference group. In this case, heterogeneity was statistically significant. CONCLUSIONS: Chemonucleolysis with chymopapain was superior to placebo and was as effective as collagenase in the treatment of lumbar disc prolapse. Results for studies comparing chemonucleolysis with surgery were heterogeneous, making it difficult to interpret the summary measure of effect.

Experimental studies on the effects of recombinant human matrix metalloproteinases on herniated disc tissues--how to facilitate the natural resorption process of herniated discs.

PURPOSE: Recently, MMP-7 and MMP-3 have been found to play a crucial role in the natural resorption process of herniated discs. We therefore examined the role of these recombinant human matrix metalloproteinases (rh MMPs) in the treatment of herniated discs. METHODS: (a) Surgical samples of herniated disc were cultured in the presence or absence of rh MMPs, and wet weight was measured 24h later. (b) The rh MMPs were administered into normal rabbit intervertebral discs, and after 1 week spine samples were stained with Safranin O. (c) The rh MMPs were administered into canine herniated discs in vivo. Myelography and MRI were performed prior to and 1 week after administration. Spine samples were examined histologically. Whole disc tissue was collected, total protein was extracted, and Western blot analysis was performed. RESULTS: (a) Proteoglycan degradation was found in MMP-7, MMP-3, and chymopapain-treated samples. MMP-7 and chymopapain-treated samples displayed a significant loss in wet weight (p<0.01). (b) Normal disc tissues after administration of rh MMP-7, MMP-3, and chymopapain showed an extensive loss of Safranin O staining. (c) The rh MMP-7-treated discs had a marked decrease in protruded herniation by MRI. Herniated discs after administration of MMP-7 and chymopapain showed a significant decrease in protruded mass 7 days after administration compared with saline-treated discs when evaluated by myelography (p<0.01). The rh MMP-7-treated discs displayed a clear loss of Safranin O staining in the nucleus pulposus. Proteoglycan expression was barely detectable in disc tissues after MMP-7 administration, whereas obvious expression was obtained in saline-treated or untreated disc tissues. CONCLUSIONS: Exposure to rh MMP-7 resulted in promising proteoglycan loss in human surgical samples, normal rabbit intervertebral discs, and natural canine herniated discs. Administration of rh MMP-7 may facilitate the resorption process of herniated discs.

Pharmacological management of back pain syndromes.

The symptom of back pain may be the result of many different pathologies. As such, patients with back pain require careful assessment to determine whether the cause is from the spine or other systems. For acute mechanical back pain, treatment is often symptomatic. Symptomatic treatment may include analgesics, anti-inflammatories and/or muscle relaxants. Patients may also need hypnotics in the short term to help them sleep at night. However, drug therapy should be reduced and stopped as soon as possible. Furthermore, too much bedrest may be counterproductive. Paracetamol (acetaminophen) is the standard treatment for transient back pain. More severe pain may require the addition of an opioid, such as codeine or dextropropoxyphene. Morphine and pethidine (meperidine) may be necessary in patients with back pain due to neoplastic disease or osteoporotic fracture. However, the opioid analgesics are associated with dependence, tolerance and adverse effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic efficacy comparable with paracetamol. Individual patients respond differently to different NSAIDs, and several agents may have to be tried. Long term therapy with NSAIDs is necessary in diseases with an inflammatory component such as ankylosing spondylitis. Calcitonin reduces bone resorption and bone blood flow, and has been suggested to have central analgesic effects. As such, it has been used successfully in patients with Paget's disease, osteolytic bone disease and osteoporosis. Bisphosphonates also inhibit osteoclastic bone resorption and may be useful in Paget's disease, osteolytic metastases and osteoporotic fractures. Other drugs which may be useful in relieving back pain associated with specific circumstances include the tricyclic antidepressants, anxiolytics, antiepileptic agents, corticosteroids, colchicine and chymopapain.

Increased glycosaminoglycan excretion after chymopapain injection of intervertebral discs.

The urinary excretion of glycosaminoglycans during the 24 hours after intradiscal injection of chymopapain was found to be greater than during the 24 hours before injection when comparison was made either on the basis of a complete 24-hour urine collection or by the use of a glycosaminoglycan/creatinine ratio. Each individual in a group of 14 patients showed this increase after injection. In contrast, no significant increase over the pre-injection levels was detected in serum glycosaminoglycans during the post-injection time periods for which blood samples were available.

Septic complications of chemonucleolysis.

The authors present two cases of septic complications after chemonucleolysis with chymopapain. One patient developed overt aortic valve failure. The second patient suffered an epidural abscess.

The chymopapain clinical trials.

The three published randomized clinical trials of chymopapain injection vs. placebo injection for the treatment of herniated lumbar discs are reviewed. Despite some differences, the similarities in selection criteria, technique, and outcome assessment are great enough to justify pooling the results to obtain an overall assessment of chymopapain efficacy. These pooled results suggest that the odds of successful outcome (at least some improvement in symptoms after injection) are 2.6 times as great with chymopapain injection as those after placebo injection. This corresponds to a 50% greater probability of success with chymopapain than with placebo or a 23% increase in the number of patients successfully treated with chemonucleolysis over those successfully treated with placebo. The fact that data from 234 patients evaluated in randomized clinical trials could resolve a controversy over therapeutic efficacy that the uncontrolled evaluation of over 20,000 patients could not answer suggests that the current controversy over the relative efficacy of chymopapain and discectomy should be studied in the same way. The difficulties of such a study are discussed.

Intervertebral disc infection after lumbar chemonucleolysis: report of a case.

Intervertebral disc space infection can be a serious and disabling complication of any procedure that affords entry for bacteria into the susceptible disc space. Most disc space infections occur after cervical or lumbar laminectomies. Discitis has been reported after myelography, lumbar puncture, paravertebral injection, and obstetrical epidural anesthesia. A case of septic discitis occurring after intradiscal therapy with chymopapain is presented. Patients who return for evaluation of recurrent spinal pain after chemonucleolysis, especially those with paravertebral muscle spasm, should be evaluated for the possibility of disc space infection by obtaining an erythrocyte sedimentation rate, peripheral white count, differential cell count, and plain roentgenograms. Radionuclide bone scans, although not specific, may provide further objective evidence leading to the diagnosis of an intervertebral disc space infection.

Microdiscectomy versus chemonucleolysis.

A retrospective analysis of 50 consecutive patients treated with chemonucleolysis and 50 treated with microlumbar discectomy was carried out. Similar clinical criteria for the diagnosis of "virgin" herniated lumbar discs were used. All patients had low back or radicular pain unrelieved by a minimum of 4 weeks of conservative therapy. Physical findings included a positive straight leg raising sign, weakness of the appropriate muscle groups, and a sensory loss or evidence of depressed reflexes. All had myelograms or computed tomographic scans demonstrating an extradural defect. Compensation cases were eliminated. Results demonstrated a 90% marked improvement in the microdiscectomy category and a 58% marked improvement in the chemonucleolysis group. Four per cent of the microdiscectomy patients were unimproved, and 18% of the chemonucleolysis group required a subsequent surgical procedure. The average postoperative hospital stay was 3 days for both groups. Because of the necessity for reoperations in the chemonucleolysis group, chemonucleolysis seemed less cost-effective than microdiscectomy.

Intradiscal pressure-volume response: a methodological contribution to chemonucleolysis. Preliminary results.

A new method is presented to verify whether a lumbar disc is degenerated prior to chemonucleolysis. This consists in rapid injection of a 0.3-ml bolus of saline into the center of the disc (through the needle employed for chemonucleolysis), under continuous recording of the intradiscal pressure changes caused by this volume load. If the intradiscal pressure falls below 600 mm Hg within 2 minutes after the injection, there is a high probability (p less than 0.001) that the disc is degenerated. This method has many advantages: it obviates additional injection of contrast medium prior to chemonucleolysis, it prevents inhibition of chymopapain by the contrast medium, it saves time, and it reduces the total amount of fluid injected during chemonucleolysis.

Late results of treatment of intervertebral disc disease with chymopapain.

The authors report a 12-year follow-up review of 33 patients treated with chymopapain (Discase) injection for intervertebral disc disease. This carefully controlled series of patients was treated under local anesthesia in the prone position. Only the single offending disc that correlated with the myelographic and clinical pathology (without the use of discography) was injected with Discase. Anaphylaxis is treated instantly at the first sign of disturbance, and no patients suffered shock. The percentage of patients who were completely cured or improved continues at about 70%. Aside from sensitivity, complications attributable to proper use of the enzyme remain at zero. Follow-up review of those patients over 10 years would indicate that there is no risk of delayed organ toxicity, no risk of carcinogenesis, and no apparent risk of first-generation teratogenesis.

Chemonucleolysis with chymopapain: results in 150 patients.

Chemonucleolysis with chymopapain has been advocated for the treatment of lumbar disc disease. When polled by a mail questionnaire, 150 consecutive patients who had undergone chemonucleolysis reported an overall success rate of only 40% and a failure rate of 60%. However, 57% of the patients were active or had only mild restriction of daily activities. Of those patients employed prior to injection, only 63% had returned to work. Those with workmen's compensation benefits fared considerably worse than those covered by third-party insurance (17% vs. 51% success). These results cast doubt on the long-term benefits of chymopapain in the treatment of lumbar disc disease.

Postchemonucleolysis discectomy versus repeat discectomy: a prospective 1- to 13-year comparison.

This long-term prospective study evaluates the clinical results of subsequent laminectomy in 103 consecutive patients who initially underwent chemonucleolysis (CNL) or laminectomy for lumbar disc herniation. Between 1981 and 1994, 53 patients who had received CNL initially and then underwent laminectomy and 50 patients treated initially with laminectomy underwent a repeat laminectomy. Clinical assessment at 6 weeks showed a success rate of 80.8% for post-CNL laminectomy and 78% for repeat laminectomy. At 6 months, the success rate for patients treated with CNL was 86% versus 78.7% for laminectomy. At 12 months, the overall success rate for the CNL group was 80.4% versus 83.3% for the laminectomy group, but in patients who had not obtained relief from the first procedure the success rate for the second procedure was higher for the post-CNL patients. A questionnaire was sent to all patients for 1- to 13-year follow-up review. The average follow-up period was 6.6 years for post-CNL laminectomy and 5.2 years for repeat laminectomy. The long-term success rate (81.8%) was higher in the post-CNL group compared to 64.4% in the repeat laminectomy group. Seven patients in the post-CNL group and nine in the repeat laminectomy group had undergone a third operation. When these originally successfully treated patients were reassigned after unsuccessful outcomes, the success rate for the CNL groups was 72.7%, versus 51.1% in the laminectomy group (p = 0.049). Employment rates were 80% for patients with CNL (21.8% changed jobs) and 76.3% for patients undergoing laminectomy (48.3% changed jobs) (p = 0.036). In conclusion, patients who underwent laminectomies after receiving CNL had significantly better long-term results than those who had repeat laminectomies.

Double-blind evaluation of intradiscal chymopapain for herniated lumbar discs. Early results.

The authors report 66 patients with signs, symptoms, and a myelographic abnormality of herniated lumbar disc, who were not responsive to conservative treatment. The discs were injected at random with either chymopapain or a placebo. Neither patient nor surgeon knew which agent was used until after the results had been tabulated. Unless early laminectomy was necessary for intractable pain, all patients were followed for 2 months or more. There was no statistically significant difference in incidence or quality of improvement between the two groups: chymopapain was successful in 58% while placebo was successful in 49% (p = 0.15). Early results from this study indicate that most, if not all, of the putative effectiveness of chemonucleolysis probably derives from a placebo effect.

Efficacy of chymopapain chemonucleolysis. A long-term review of 105 patients.

A 9- to 12-year follow-up review was conducted in 105 of 124 patients who were treated with chymopapain chemonucleolysis for herniated lumbar disc. The data were obtained from responses to a questionnaire. Seventy-nine patients (75.2%) reported marked improvement, six (5.7%) had slight improvement, and 20 (19.0%) had no improvement. Of the 87 patients not receiving workman's compensation, 70 patients (80.5%) had marked improvement; four (4.6%) had slight improvement; and 13 (14.9%) had no improvement. Of the 18 compensation cases, nine patients (50.0%) had marked improvement; two patients (11.1%) had slight improvement; and seven patients (38.9%) had no improvement. These results are comparable to those reported for surgical discectomy, and confirm that chymopapain chemonucleolysis is an alternative to surgery.

The long-term results of chymopapain chemonucleolysis for lumbar disc disease. Ten-year follow-up results in 268 patients injected at the Mayo Clinic.

The long-term clinical outcome is evaluated for 268 patients after chymopapain chemonucleolysis for radicular complaints referrable to documented intervertebral disc disease. The follow-up period for 92% of these patients was 10 years. No complications due to chymopapain toxicity were observed; 80.1% of patients were relieved of their presenting radicular leg pain and 75.1% were employed at a capacity equal to or more strenuous than before injection. Chemonucleolysis was demonstrated to be a safe and effective treatment modality, with long-term results that compare favorably with those of similarly selected patients undergoing open surgical procedures. In the patients whose chymopapain therapy failed, the outcome of subsequent open surgical procedures was not necessarily compromised by prior chemonucleolysis. A higher rate of failure and subsequent surgical intervention was seen in those patients with injections performed soon after an unsuccessful open procedure on the same side and at the same interspace, those with workmen's compensation or litigation pending, those with a history of work-related injury, those whose employment involved heavy manual labor or extensive driving, and those whose preinjection spine x-ray films indicated retrograde spondylolisthesis.

Injection of cymopapain into intervertebral discs. Preliminary report on 72 patients with symptoms of disc disease.

The author presents an evaluation of 72 patients given intradiscal chymopapain as the treatment for symptoms related to ruptured intervertebral disc. The rationale, criteria for patient selection, risks, and results are described. The author believes thatt this early follow-up suggests tha chymopapain may have a place in the treatment of symptomatic disc protrusions and extrusions.

Morphological alterations of the degenerated lumbar disc following chemonucleolysis with chymopapain.

Lumbar disc tissue from 10 patients who had previously undergone chemonucleolysis without success was studied by light and scanning electron microscopy. Seven patients had a sequestrated disc; three had large protrusions. As a control, material from 10 patients subjected to disc surgery without previous chemonucleolysis was studied in the same way. The control discs revealed the characteristic signs of degeneration: alteration of the collagen, microcystic areas, and giant chondromas. Changes following chemonucleolysis were restricted exclusively to the ground substance and characterized by a marked loss of basophilia in the cartilage matrix. There was no involvement of the anulus fibrosus, cartilage plate, or bone. Following chymopapain administration, scanning electron microscopy showed a naked collagen network devoid of ground substance.

Double-blind evaluation of chemonucleolysis for herniated lumbar discs. Late results.

Sixty-six patients with symptomatic herniated lumbar discs refractory to the usual conservative management were allocated at random into one of two treatment groups according to a double-blind protocol: 31 received chymopapain intradiscally (chemonucleolysis) and 35 received a placebo intradiscally. Symptoms remained significantly improved 1 year or more after injection for 55% of those treated with chymopapain and for 46% of those treated with placebo. The difference is not statistically significant. However, to discard chemonucleolysis on the basis of this one small clinical trial may be premature. Since continuing controversy has re-established a climate in which another double-blind study of chemonucleolysis is ethically feasible and scientifically desirable, we favor additional clinical trials under a tightly controlled protocol to help resolve the issue.

Correlation of radiological features to failure of lumbar intervertebral disc chemonucleolysis.

Chemonucleolysis was performed in 103 patients for lumbar disc prolapse. Multiple (two) interspaces were injected in only seven patients. Radiographically, all patients had myelographic or computerized tomography evidence of disc prolapse. Eighty-seven of 100 patients who were available for follow-up review had improved. Ten of 13 patients with persistent symptoms required a laminectomy. Altered spinal alignment was evident in five of the 13 patients with persistent symptoms: retrolisthesis in three and myelographic disc defect on the convex aspect of the scoliosis in two. Review of radiographic studies was carried out in an attempt to establish guidelines for patient selection so as to decrease the rate of failure in chymopapain treatment.