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Short and long-term effects of chymopapain on nervous transmission were studied in rats. The drug was injected into the lumbar spinal canal. Action potentials evoked by electrical stimulation of the sciatic nerve were recorded at the dorsal root entry zone of the lumbar cord. One group of rats was pre-treated with dexamethasone. Chymopapain prolongs impulse latency compared to that of control rats treated with isotonic saline. The effect is dose dependent and can last for several weeks. Rats pre-treated with dexamethasone showed milder impairment of nervous transmission after chymopapain injection compared to the rats treated only with papain.

Myeloscopic normal findings are demonstrated in the rhesus monkey (macaca fascicularis, crab-eating monkey). It can also be shown that six weeks after intrathecal administration of the proteolytic enzyme chymopapain, obvious pathological changes can be seen endoscopically in the nerve roots. It can, therefore, be said that the intrathecal administration of chymopapain is strictly contraindicated due to the proven unfavourable neurotoxic side effects.

Chymopapain is a proteolytic enzyme injected intradiscally for the treatment of herniated lumbar discs. The average success rate is 73 percent for elimination of backache and sciatica. Side effects occur in three percent of patients, the most serious being anaphylaxis in about one percent. A majority of patients experience severe back pain or spasms during the first 24-48 hours after treatment. This treatment modality consumes fewer hospital days and produces a quicker return to work than does surgery. It does not affect subsequent surgical procedures adversely. Chymopapain chemonucleolysis is safe and effective when administered by experienced physicians and when adequate precautions are taken. It can be considered the last step before surgery in the conservative management of herniated lumbar discs.

Chemonucleolysis is an effective treatment of sciatica due to herniated lumbar disc after conservative treatments have failed. Provided the proper technique is applied and the patients are well selected (complete herniation or herniation within a narrow spinal canal being excluded), surgery can be avoided in the majority of cases. Chemonucleolysis does not in any way complicate subsequent surgery if required and post-nucleolysis surgery gives the same results as first intention surgery. The method, therefore, should not be regarded as an alternative to surgery but as the last stage of conservative treatment. Allergic reactions are the only true side-effects and require special precautions.

Chymopapain chemonucleolysis was performed on 100 patients with primary lumbar intervertebral disc disease. The results were compared with those of 174 patients who underwent laminotomy, foraminotomy, and discectomy. Primary lumbar intervertebral disc disease was arbitrarily divided into degenerative, complex, previous surgical, and simple disc syndromes. No difference was seen between chemonucleolysis and surgery in the first three divisions; between 55 percent and 60 per cent of patients responded successfully to treatment. In the simple disc division 89 per cent of the surgical and 60 per cent of the chemonucleolysis patients had successful results.

Electrically evoked compound action potentials were used to quantify the neurophysiologic abnormalities caused by application of chymopapain into the lumbar spinal canal in rats. A branch of the sciatic nerve was stimulated with voltage impulses of constant amplitude (40 V) and duration (0.1 msec) at the right external malleolus. The responses were recorded at the dorsal root entry zone L1. The authors used different doses of chymopapain (low dose = 100 IU, middle dose = 250 IU, and high dose = 500 IU). The control rats were subjected to exactly the same stimulus and recording procedures, but the test solution was a corresponding volume of isotonic saline. The prolongation of the latency of the electrically evoked potential due to chymopapain is very clear at the doses of 250 IU and 500 IU, being about 10 to 15% relative to the mean latency before application of the drug. This study indicates that locally applied chymopapain has a dose-dependent effect on nerve conduction properties.

The median lethal dose (LD50) of chymopapain B in mice was 82 mg/kg (22,000 units/kg) with 95% confidence limits of 75-90 mg/kg (20, 122-24, 146 units/kg) and in rats 92 (24,683 units/kg) with 95% confidence limits of 83-102 mg/kg (22,268-27, 366 units/kg). The mechanism of toxicity was hemorrhage due to destruction of the cement substance of the blood vessels. Intervertebral disc injection of chymopapain B in the rabbit at a dose level of 186 micrograms (50 units) caused chemonucleolysis in 67% of the rabbits as evidenced by partial dissolution of the nucleus pulposus. Chemonucleolysis was also noted at higher doses. No adverse affects were noted with a 20 fold increase to 3.7 mg (1000 units). A dose of 18.6 mg (5000 units)/disc caused paralysis of the hindlegs. A dose as high as 26.6 mg (7143 units) /disc caused nearly complete dissolution of the nucleus pulposus and can cause disruption of the annulus fibrosus and death. Guinea pigs receiving a sensitizing dose of 0.003 mg/kg (0.8 units/kg) chymopapain B intraperitoneally six times over two weeks were challenged with an intravenous dose of 0.03 mg (8 units)/kg. All animals exhibited marked anaphylactic signs with a resulting 50% fatality rate.

Using magnetic resonance imaging, conventional histology, and spinal evoked potentials, the authors studied the short-term effects of chymopapain on nerve tissue in the lumbar vertebral canal region in rats. Chymopapain in different concentrations was injected into the subarachnoid space in 31 rats. As early as 20 minutes later latency changes in the evoked potentials were observed; the histologic examinations after two hours showed bleeding, swelling of the myelin, and vascular changes. Magnetic resonance imaging of the lumbar spine, performed after six hours, showed a markedly stronger signal, indicative of an intraspinal edema, as compared to the control group. The authors' studies are clear proof that changes in nerve tissue following contact with chymopapain occur considerably faster than hitherto assumed in the literature.

In the first of a two-part study, the authors review the known biochemical, pharmacological, toxicological, and experimental data concerning chymopapain and the intervertebral disc. They describe the action of this proteolytic enzyme, which apparently disrupts the protein mucopolysaccharide component of disc material, most marked in the nucleus pulposus. A rapid conversion to collagen causes a loss of disc space height; toxicity appears to result from alteration of bonding between capillary endothelial cells that in turn produces hemorrhage. Part 2 reviews significant reported results and complications of clinical chemonucleolysis.

The effect of chymopapain and contrast media in the epidural space on meninges has not been studied conclusively. The authors injected chymopapain into the epidural space of monkeys and measured the degree of arachnoid fibrosis that resulted. Animals were given injections of 1.2 mL of diatrizoate (280 mg iodine per milliliter), chymopapain (100 IU/mL), kaolin (100 mg/mL) (as a positive control), or saline (0.9%) (as a negative control). Three months later the animals were killed; the dural sac was removed intact and was fixed, sectioned, stained, and examined with light microscopy. Kaolin-treated animals developed mild to marked fibrosis of the dura. The saline- and diatrizoate-treated animals developed little or no evidence of fibrosis. One of four chymopapain-treated animals developed degenerative changes in dorsal nerve roots and fibrosis in the adjacent arachnoid. The other chymopapain-treated animals had little or no evidence of fibrosis. The studies suggest that neither diatrizoate nor chymopapain causes arachnoid fibrosis.

The effect of diatrizoate on the chronic toxicity of chymopapain in the epidural space was studied. Chymopapain was injected epidurally into four monkeys; chymopapain plus diatrizoate meglumine, into four. In 3 months, neither group developed significantly more arachnoiditis than a control group of animals that had received epidural injections of physiologic saline. No synergistic effect of chymopapain and diatrizoate on the meninges was detected.