Prospective randomized trial of chemonucleolysis compared with surgery for soft disc herniation with 1-year, intermediate, and long-term outcome: part II: the radiological outcome.

STUDY DESIGN: A prospective consecutive series of 100 patients computer randomized into 2 groups to have treatment by either chemonucleolysis or surgery. OBJECTIVE: To compare the radiological findings preoperatively with the clinical outcome between the groups at 1 year, 10 to 13, and 24 to 27 years of follow-up. SUMMARY OF BACKGROUND DATA: Chemonucleolysis was introduced in 1964 and became widely used. Its efficacy was proven by several randomized studies when compared with a placebo and surgery. However, it ceased to be manufactured in 2001. METHODS: One hundred consecutive patients were enrolled for the study and randomized according to age, sex, and disc level. Preoperatively, their anteroposterior, lateral lumbar spine, and lateral lumbosacral angle radiographs were obtained, and a myelogram was performed. At 10 to 13 years, 32 of the original patients (18 chemonucleolysis and 14 surgery) and at 24 to 27 years, 45 patients (24 chemonucleolysis and 21 surgery) were assessed by lateral lumbosacral angle radiographs. RESULTS: Using the myelographical findings, small, medium, and large herniations were digested by chymopapain with more of the failures being the larger ones. There was an equal degree of degenerative change as measured by disc height loss in the young and older age groups and the degree of degenerative change did not relate to outcome. The size of the defect did not relate to the degree of disc height loss. There was a slight loss of disc height over time in both groups. There was no difference in the loss of disc height between the treatments at any of the follow-up time points. CONCLUSION: Chemonucleolysis is as effective as surgery when assessed according to intention-to-treat analysis. The loss of disc height over time is the same in both groups. The authors think that restoration of its availability would be beneficial to patients. LEVEL OF EVIDENCE: 1.

Prospective randomized trial of chemonucleolysis compared with surgery for soft disc herniation with 1-year, intermediate, and long-term outcome: part I: the clinical outcome.

STUDY DESIGN: A prospective consecutive series of 100 patients computer randomized into 2 groups to have treatment by either chemonucleolysis or surgery. OBJECTIVE: To compare the complications and clinical outcome between the groups at 1 year, and at 10 to 13 and 24 to 27 years. SUMMARY OF BACKGROUND DATA: Chemonucleolysis was introduced in 1964 and became widely used. Its efficacy was proven by several randomized studies when compared with a placebo and surgery. The manufacturing of Chemonucleolysis was ceased in 2001. METHODS: One hundred consecutive patients were enrolled for the study and randomized according to age, sex, and disc level. They were followed up at 1 year with self-assessment questionnaires to establish if they were completely better, improved, the same or worse. At 10 to 13 years, 61 patients (32 chemonuceolysis and 29 surgery) and at 24 to 27 years, 45 patients (24 chemonucleolysis and 21 surgery) were self-assessed by questionnaire according to the Macnab criteria. RESULTS: Forty-eight patients were treated by chemonucleolysis and 52 by surgery. Ten patients treated by chemonucleolysis underwent surgery within 8 weeks. At 1 year, 10 to 13 years, and 24 to 27 years, 94%, 72%, and 63% of patients treated by chemonucleolysis had good or excellent results compared with 96%, 72%, and 67% of patients who underwent surgery, respectively. There was no difference in the clinical outcome between the treatments at any of the follow-up time points. There were 2 serious complications, 1in each treatment group. CONCLUSION: Chemonucleolysis is as effective as surgery when assessed according to intention-to-treat analysis, with reduced complications, and age has no bearing on the outcome. The authors think that restoration of its availability would be beneficial to patients. LEVEL OF EVIDENCE: 1.

Injection therapy and denervation procedures for chronic low-back pain: a systematic review.

Injection therapy and denervation procedures are commonly used in the management of chronic low-back pain (LBP) despite uncertainty regarding their effectiveness and safety. To provide an evaluation of the current evidence associated with the use of these procedures, a systematic review was performed. Existing systematic reviews were screened, and the Cochrane Back Review Group trial register was searched for randomized controlled trials (RCTs) fulfilling the inclusion criteria. Studies were included if they recruited adults with chronic LBP, evaluated the use of injection therapy or denervation procedures and measured at least one clinically relevant outcome (such as pain or functional status). Two review authors independently assessed studies for eligibility and risk of bias (RoB). A meta-analysis was performed with clinically homogeneous studies, and the GRADE approach was used to determine the quality of evidence. In total, 27 RCTs were included, 14 on injection therapy and 13 on denervation procedures. 18 (66%) of the studies were determined to have a low RoB. Because of clinical heterogeneity, only two comparisons could be pooled. Overall, there is only low to very low quality evidence to support the use of injection therapy and denervation procedures over placebo or other treatments for patients with chronic LBP. However, it cannot be ruled out that in carefully selected patients, some injection therapy or denervation procedures may be of benefit.

Interstitial matrix proteins determine hyaluronan reflection and fluid retention in rabbit joints: effect of protease.

Hyaluronan (HA) retention inside the synovial cavity of joints serves diverse protective roles. We tested the hypothesis that HA retention is mediated by the network of extracellular matrix proteins in the synovial lining. Cannulated rabbit knee joints were infused with HA solution with or without pretreatment by chymopapain, a collagen-sparing protease. Trans-synovial fluid escape rate was measured and, after a period of trans-synovial filtration, samples of intra-articular fluid and subsynovial fluid were analysed for HA to assess its trans-synovial ultrafiltration. In control joints, HA ultrafiltration was confirmed by postfiltration increases in intra-articular HA concentration (259 +/- 17% of infused concentration) and reduced subsynovial concentration (30 +/- 8%; n = 11). The proportion of HA molecules reflected by the synovium was 57-75%. Chymopapain treatment increased the hydraulic permeability of the synovial lining approximately 13-fold, almost abolished the trans-synovial difference in HA concentration and reduced the HA reflected fraction to 3-7% (n = 6; P < 0.001, ANOVA). Structural studies confirmed that chymopapain treatment depleted the matrix of proteoglycans but preserved its collagen. The findings thus demonstrate that HA ultrafiltration and synovial hydraulic permeability are determined by the network of non-collagen, extracellular matrix proteins. This may be important clinically, since protease activity is raised in rheumatoid arthritis, as are HA and fluid escape.

Transforaminal posterolateral endoscopic discectomy with or without the combination of a low-dose chymopapain: a prospective randomized study in 280 consecutive cases.

STUDY DESIGN: A prospective randomized study involving 280 consecutive cases of lumbar disc herniation managed either by an endoscopic discectomy alone or an endoscopic discectomy combined with an intradiscal injection of a low dose (1000 U) of chymopapain. OBJECTIVE: To compare outcome, complications, and reherniations of both techniques. SUMMARY OF BACKGROUND DATA: Despite a low complication rate, posterolateral endoscopic nucleotomy has made a lengthy evolution because of an assumed limited indication. Chemonucleolysis, however, proven to be safe and effective, has not continued to be accepted by the majority in the spinal community as microdiscectomy is considered to be more reliable. METHOD: A total of 280 consecutive patients with a primary herniated, including sequestrated, lumbar disc with predominant leg pain, was randomized. A clinical follow-up was performed at 3 months, and at 1 and 2 years after the index operation with an extensive questionnaire, including the visual analog scale for pain and the MacNab criteria. The cohort integrity at 3 months was 100%, at 1 year 96%, and at 2 years 92%. RESULTS: At the 3-month evaluation, only minor complications were registered. At 1-year postoperatively, group 1 (endoscopy alone) had a recurrence rate of 6.9% compared to group 2 (the combination therapy), with a recurrence rate of 1.6%, which was a statistically significant difference in favor of the combination therapy (P = 0045). At the 2-year follow-up, group 1 reported that 85.4% had an excellent or good result, 6.9% a fair result, and 7.7% were not satisfied. At the 2-year follow-up, group 2 reported that 93.3% had an excellent or good result, 2.5% a fair result, and 4.2% were not satisfied. This outcome was statistically significant in favor of the group including chymopapain. There were no infections or patients with any form of permanent iatrogenic nerve damage, and no patients had a major complication. CONCLUSIONS: A high percentage of patient satisfaction could be obtained with a posterior lateral endoscopic discectomy for lumbar disc herniation, and a statistically significant improvement of the results was obtained when an intradiscal injection of 1000 U of chymopapain was added. There was a low recurrence rate with no major complications. The method can be applied in any type of lumbar disc herniation, including the L5-S1 level.

Intradiscal therapies for discogenic pain.

Since the first injection of chymopapain in 1963, percutaneous intradiscal therapies have been used to treat discogenic back and leg pain. The percutaneous discectomy techniques treat contained disc herniations not by resecting the prolapsed disc material but rather through central decompression of the disc. By removing a small volume of tissue from the disc nucleus, a large reduction in overall disc pressure is achieved with consequent relief of neural compression. DISC Nucleoplasty and Dekompressor are the two leading percutaneous discectomy technologies currently. Although rigorous clinical testing of their efficacy is ongoing, there has now been a 40-year history confirming the concept of percutaneous disc decompression, and initial results are very promising. Discogenic low back pain can also arise from annular tears and other forms of internal disc derangement (IDD). Annuloplasty techniques, such as IntraDiscal Electrothermal Therapy (IDET) and discTRODE, have been developed over the past decade that thermally treat the lesions of IDD. Although the therapeutic mechanisms of thermal annuloplasty have yet to be fully elucidated, research studies demonstrate that the procedure can be effective for appropriately selected patients with degenerative disc disease characterized by discographically proven painful annular fissures. Other novel intradiscal therapies are emerging for percutaneous treatment of discogenic pain and await more widespread clinical evaluation.

Study of blood metabolism and urinary excretion of chymopapain following intradiscal injection using a high-sensitivity enzyme immunoassay.

To develop chymopapain-induced chemonucleolysis as an established treatment, it is necessary to determine the kinetics of chymopapain in blood and urine following intradiscal injection. To investigate the rate of blood metabolism and urinary excretion of chymopapain following intradiscal injection, we developed a high-sensitivity enzyme immunoassay for chymopapain. The sensitivity for this assay was 1 pg/tube (40 amol). After injecting chymopapain into the nucleus pulposus of humans, levels of blood chymopapain were measured by enzyme immunoassay. The level of chymopapain in blood decreased gradually, with a half-life of 2-3 days. The half-life for urinary excretion was a little longer, at 3 days. It was also found that chymopapain in blood was not present as a free molecule but formed a complex that had a molecular weight of about 120 kDa. These findings suggest that most chymopapain would not have activity in blood.

Interventional spinal procedures.

The interventional procedures for disk herniation and protrusion by percutaneous techniques are decompressive such as chemodiscolysis with chimopapain, nucleo-discectomy introduced by Onik, LASER discectomy, and recently nucleoplasty, and decompressive and direct antinflammatory such as chemiodiscolysis with an Oxygen-ozone mixture. These techniques have minimized the invasive nature of surgery and avoid or decrease complications like infection linked to surgery. Reducing intervertebral disc size by mechanical aspiration of a part of the disc or partially dissolving the herniation by drying reduces the conic pressure on the torn annulus and creates the space necessary for retropulsion whenever the circular fibres of the annulus regain a minimum capacity to contain the disc under tension. The proposed suggestion in these techniques is that a small change in volume produces large change in pressure. The success rates reported in different studies vary from 65 to 80% of excellent or good results with chemonucleolysis and aspiration. Vertebroplasty (VP) is done by percutaneous injection of acrylic cement (polymethylmetacrylate-PMMA) into the vertebrae under fluoroscopic and/or CT control to achieve an antalgic effect and stabilize the vertebral body. VP has been used for vertebral collapses caused by osteoporosis, long-term steroid treatment, aggressive symptomatic angiomas and lytic metastasis. The reported figures in literature are 80-95% of pain relief, within 7 days after procedure, commonly on the same day.

Spinal flexibility increase after chymopapain injection is dose dependent: a possible alternative to anterior release in scoliosis.

STUDY DESIGN: Experimental animal study. OBJECTIVES: To investigate whether the increase in spinal flexibility after chymopapain injection is dose dependent and determine the "optimal" dosage of chymopapain to increase spinal flexibility in a rabbit model. SUMMARY OF BACKGROUND DATA: Spinal instability after chymopapain injection may result in severe back pain. However, this undesired mechanical effect in treating disc herniation may provide a safe minimally invasive approach for anterior spinal release in scoliosis correction. METHODS: A total of 138 lumbar intervertebral discs from 46 New Zealand white rabbits were randomly injected with chymopapain at 6.25, 12.5, 25, 50, 75, and 100 picokatals (pKats)/0.05 mL/disc. The rabbits were killed 1 week after the injection, and the lateral bending stiffness of the spinal segments without posterior elements was determined. RESULTS: The lateral bending spinal stiffness showed no significant change after injection of 6.25 and 12.5 pKats/0.05 mL/disc but reduced significantly following chymopapain injection of 25, 50, 75, and 100 pKats (all P < 0.05 by post hoc least significant difference tests). While the lateral bending stiffness was lowest at the 100-pKats dose, there were no significant differences between the four higher dosages. CONCLUSION: The reduction in the lateral bending spinal stiffness after chymopapain injection is dose dependent, and an optimal dosage for spinal release existed; doses greater than the optimal dosage did not result in further significant decrease in lateral bending spinal stiffness.

[Study of preparation methods of polyclonal antibody of chymopapain].

OBJECTIVE: To study the preparation methods of polyclonal antibody of chymopapain with higher titre. METHODS: Three types of antigens-native chymopapain, chymopapain inactivated by H2O2 and inactivated by iodoacetic acid were injected into different male rabbits by hypodermic injections and by intravenous injection. The blood samples were obtained from veins in ear to test antisera after the 3rd injection, the used methods were Western blotting and ELISA. The data was analyzed by the SAS system. RESULTS: The antisera titre of two inactivated antigens were obviously higher than that of nature antigen (P < 0.05), while there was no significant difference between the two inactivated antigens. Intravenous injection can obviously increase the ability of immunoresponse and raise antisera titre rapidly. CONCLUSION: The inactivated antigens have better immunogenicity than native chymopapain. As compared with iodoacetic acid, using H2O2 was an economical and effective method. The combination method of hypodermic injections and intravenous injection can raise antisera titre effectively and shorten the period of antibody preparation.

The use of intra-articular Na-hyaluronate as a potential chondroprotective device in experimentally induced acute articular cartilage injury and repair in rabbits.

OBJECTIVE: This study examined if viscosupplementation from intra-articular administration of a commercially available form of hyaluronan (HA) could promote the restoration of proteoglycan (PG) depletion induced by chymopapain and then if the repair could be maintained once HA treatment was discontinued. METHODS: Animals received cartilage injury with intra-articular chymopapain (2.0 mg) followed by weekly treatment with intra-articular HA. HA treated animals were compared to injured animals with no treatment, contralateral untreated joints and joints from normal controls. The effect of intra-articular HA alone on articular cartilage was also examined. RESULTS: Serum keratan sulfate levels confirmed degradation of the cartilage PGs in the chymopapain-injected knees. Intra-articular chymopapain resulted in marked loss of PGs. There were no significant differences among the control groups (untreated control, HA/800 treatment only). HA treatment did not affect the loss of PGs caused by chymopapain after 42 days. However, in animals receiving chymopapain injury followed by weekly HA treatment for 42 days and then 42 days of free cage activity without HA, cartilage PG contents were significantly increased. Intra-articular HA alone had no effect on the articular cartilage. CONCLUSION: The results in the present study suggest a potential protective effect of HA on chymopapain-induced acute articular cartilage injury in rabbits that, in time, permits damaged cartilage to resynthesize matrix PGs after the HA treatment is discontinued.

Effect of oral glucosamine on cartilage and meniscus in normal and chymopapain-injected knees of young rabbits.

OBJECTIVE: To determine if oral glucosamine (GlcN) improves joint biology after acute damage by a protease. METHODS: The effect of 8 weeks of dietary GlcN (20 or 100 mg/kg/day) on knee joint cartilage was evaluated in 2.2-kg male NZW rabbits with and without damage introduced by intraarticular injection of chymopapain (CP). Cartilage was evaluated histologically and scored according to the Mankin scale. Analyses of total hydroxyproline and glycosaminoglycan (GAG) contents and reverse transcription-polymerase chain reaction (RT-PCR) analysis of selected genes were performed. RESULTS: After 8 weeks, there was no effect of GlcN on the GAG content of normal cartilage. Both levels of GlcN treatment significantly increased the sulfated GAG content in the cartilage of the medial femoral condyle in damaged and contralateral knees, but did not change the collagen content. In CP-injected knees, there was still some loss of surface proteoglycan (PG) that was not completely corrected by dietary GlcN. Even after 8 weeks, levels of messenger RNA (mRNA) detected by RT-PCR showed changes indicative of damage and repair, such as elevated type II collagen mRNA, and these levels were not influenced by GlcN treatment. Meniscal GAG content was increased in the contralateral knee of rabbits receiving high-dose GlcN, but was decreased in those receiving no GlcN or low-dose GlcN. Neither diet nor treatment affected the meniscal collagen content. CONCLUSION: These results suggest that oral GlcN treatment might be useful in a situation where GlcN is limiting, such as where there is a rapid replacement of cartilage PG.

[Late myelopathy after chemonucleolysis. Case report and review of the literature]. / Spätmyelopathie nach Chemonukleolyse. Fallbericht und Ubersicht über die Literatur.

Chemonucleolysis is a debated therapeutic method for herniated lumbar disc. We report a patient who suffered a sequence of characteristic sequels cumulating in late-onset myelopathy with persistent spastic paraplegia, sensory loss below T8 and bladder incontinence. Complications of chemonucleolysis are less frequent as compared to herniated disc surgery, but may cause severe impediment. Serious complications are anaphylactic shock, intracranial or spinal hemorrhage and transverse myelitis. This has to be taken into account for indication and patient information.

[Lumbar disk prolapses and radiological spinal intervention. What do the randomized controlled trials say?]. / Lumbale skiveprolapser og radiologisk ryggintervensjon. Hva sier randomiserte kontrollerte studier?

We searched the Medline database and examined 11 randomized controlled trials to evaluate the efficacy of treating lumbar herniated discs by injection with chymopapain or by automated percutaneous discectomy. Our findings show that chemonucleolysis with chymopapain is a documented treatment which is better than placebo, but consistently inferior to surgical discectomy. The two randomized controlled trials to evaluate automated percutaneous discectomy fail to show efficacy that is any better than would be expected from a placebo response. We conclude that surgical discectomy is the best treatment option for a herniated disc when conservative efforts have failed.

Comparative study of surface displacement in discs following chemonucleolysis and lasernucleotomy.

BACKGROUND AND OBJECTIVE: Dynamic changes of the dorsolateral protrusion site have been postulated to play an important role in the therapeutic effect of lasernucleotomy and chemonucleolysis. Basic biomechanical effects of the anulus after lasernucleotomy and chemonucleolysis are investigated. STUDY DESIGN/MATERIALS AND METHODS: This study evaluates the in vitro bulging of lumbar discs comparing lasernucleotomy and chemonucleolysis. The horizontal displacement at the ventral and dorsolateral surface of 20 cadaver discs were tested by application of a continuously increasing axial deformation before and after therapy. The increase in horizontal displacement due to this longitudinal deformation was measured. RESULTS: Bulging was significantly lower at the puncture site of the chemonucleolysis needle as well as at that of the laser trocar. Significantly reduced bulging of the anulus was observed after chemonucleolysis. Slightly increased bulging was observed after lasernucleotomy in the total posterior region. There was a tendency to decreased stiffness after chemonucleolysis and a significantly decreased stiffness after lasernucleotomy. CONCLUSIONS: The in vitro effect of lasernucleotomy seems to be based on reduction of the stiffness by distributing the load all over the anulus, whereas chemonucleolysis reduces bulging.

Intervertebral disc reconstitution after chemonucleolysis with chymopapain is dependent on dosage.

STUDY DESIGN: The current report describes a study in beagles in which the effects of intradiscal injection of three doses of chymopapain were evaluated with respect to the reduction of disc width and reconstitution of the nucleus pulposus. OBJECTIVES: To establish an intradiscal dose of chymopapain that would achieve optimal reduction in disc height followed by maximum reconstitution of the nucleus pulposus. SUMMARY OF BACKGROUND DATA: Earlier reports of the efficacy of high and low doses of chymopapain for chemonucleolysis have provided conflicting data, and a scientific basis for an appropriate dose is lacking. METHODS: Four mature, female beagles were subjected to chemonucleolysis using three doses of chymopapain as Chymodiactin (31, 63 and 125 picokatals/disc) injected into the L2-L3, L1-L2, and L3-L4 discs. Disc widths were monitored radiographically over 32 weeks. Proteoglycans were radiolabeled by intravenous injection with Na2 35SO4 (1 mCi/kg) 24 hours before sacrifice, and their specific activities (disintegrations per minute/mg proteoglycan), hydrodynamic size, and ability to aggregate determined. RESULTS: Sixty-three picokatals of Chymodiactin produced optimal disc reconstitution after chemonucleolysis. A reduction in disc height of approximately 35% was evident within 1 month and this slowly returned to approximately 90% of the preinjection value after 32 weeks. The nucleus pulposus contained approximately 75% of the proteoglycan content of control tissues, and most of these formed aggregates with hyaluronan. Disc collagen levels remained relatively unaffected by treatment. CONCLUSIONS: This study demonstrates that an effective reduction in disc width compatible with later reconstitution of the nucleus pulposus can be achieved experimentally with an appropriate dose of chymopapain. These data clearly indicate that an optimal dose of chymopapain for chemonucleolysis in humans needs to be established.

Incidence and risk factors for latent sensitization to chymopapain: predictive skin-prick tests in 700 candidates for chemonucleolysis.

Seven hundred patients were investigated prospectively before undergoing chemonucleolysis. A past history of allergy and/or previous exposure to papain, either in food, beverages or drugs, was sought, and a skin-prick test with chymopapain was performed. Based on the results obtained, the subjects were classified into four groups: Group I--225 non-atopic non-papain-exposed subjects; Group II--285 non-atopic papain-exposed subjects; Group III--69 atopic non-papain-exposed subjects; and Group IV--121 atopic papain-exposed subjects. Latent sensitization to papain was observed in 0.4% of subjects in Group I, 3.16% in Group II, 5.8% in Group III and 7.4% in Group IV. The odds ratios were 13.8 for atopy and 7.3 for exposure to papain. Interaction between atopy and papain exposure did not result in a significantly greater risk. Neither sex nor age nor a history of a previous drug reaction were risk factors. Only one patient out of the 23 who were sensitive to papain had no risk factor. The 677 skin-test negative patients then underwent chemonucleolysis and none of them had an anaphylactic reaction. This was significantly less frequent: (P = 0.04) than the incidence in a random population (0.45%). Prick tests performed 6 weeks and 6 months after chemonucleolysis revealed newly acquired sensitization in 36% of the patients. Atopy was not a risk factor for this event.(ABSTRACT TRUNCATED AT 250 WORDS)