Chemonucleolysis: Experience with 2000 Cases JOHN A. MCCULLOCH, M.D.*

binding capacity of the non-collagen ground substance of the nucleus pulposus, leading to rapid hydrolysis. In digesting the protein component of chondromucoprotein, polysaccharide, water and some polypeptide remnants of protein are released. The role of these polypeptide remnants in anaphylaxis is a subject of continuing study. The exact mechanism by which enzymatic dissolution of the nucleus pulposus relieves the pain associated with disk herniation is not known. Smith hypothesized that protrusion of the annulus fibrosus, interfering with nerve-root function, was caused by hydraulic pressure emanating from the nucleus pulposus. Decompressing the nerve root by enzymatic dissolution of the nucleus seemed a reasonable approach. This theory in turn raised 2 questions. First, it is known that despite successful relief of symptoms after chemonucleolysis, myelographic defects persisted for up to 6 weeks post-inject i ~ nRelief . ~ was thought to be attributable to some chemical effect of chymopapain on inflammation around the disk, rather than immediate physical decompression. Secondly, if a disk herniation is sequestered, injecting the remaining intradiskal portion with chymopapain should offer no relief of symptoms. This is an obvious statement which requires only a clear clinical definition of what constitutes a sequestered disk.

In 1964 SmithlS first published his results

of chemonucleolysis, unfolding the incredible story of chymopapain. In 1975 the drug ceased to be available in the United States, after results of a double-blind study were made available to the manufacturers of Discase. In 1979 the medical world is no closer to an answer about the efficacy of chemonucleolysis in the treatment of ruptured disks than it was 15 years ago. The purpose of this article is to describe the author's experience with chymopapain over the past 10 years, analyzing present trends and touching on unsolved problems. Based on the experience of 2000 cases, the author is convinced that chemonucleolysis is a valuable clinical procedure. Many surgeons, however, hold a diametrically opposite view. These divergent opinions either reflect adversely on the accuracy of the author's observation, or suggest that criticism results from inability to make an accurate diagnosis. All those who involve themselves in the controversy about the use of chymopapain must appreciate the concern directed by our patients who are desirous of avoiding back surgery. PHARMACOLOGY The action of chymopapain has been described in many p a p e ~ s Briefly, .~ this proteolytic enzyme is thought to upset the waterFrom the Commerce Court Medical Centre, Box 37, Commerce Court East, Toronto, Ontario, MSL 1A1, Canada. * St. Michael's Hospital, 30 Bond Street, Toronto, Ontario, MSB 1W8, Canada. Received: May 17, 1979.

TOXlCOLOGY There is a wide margin of safety between the effective therapeutic and toxic dose of chymopapain."." Tissues adjacent to the

0009-921X/80/0100/128 $00.90 0 J . B . Lippincott Co.

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nucleus that could be injected inadvertently or be bathed by leaking chymopapain are not altered pathologically by doses of chymopapain 100 times greater than the effective therapeutic dose. Chymopapain intrathecally will affect the basement membranes of the thin-walled vessels of the pia-arachnoid, causing fatal hemorrhage in rabbits and dogs. In order to avoid penetration of the dura and obviate the chance of chymopapain leaking along the outside of the needle into the subarachnoid space, a posterolateral approach to needle placement in the disk is employed. For a similar reason, chemonucleolysis should not be performed for 24 hours after myelography, thereby allowing any dural leak to seal. Some investigators have described toxic effects producing arachnoiditis and direct neural damage.IX Independent laboratory investigations by Stern,5Ford4and Macnabg have not demonstrated that arachnoiditis ever occurs as a sequela of experimental intrathecal or epidural injection of chymopapain. The author has one known case of arachnoiditis developing after chemonucleolysis. However, 2 independent observers both concluded that the arachnoiditis was due to the oil-soluble medium used in myelography. The risk of arachnoiditis following oil-soluble myelography was documented many years ago." The author has not observed increasing root neurologic deficit after chemonucleolysis. There are 2 reasons for this. A conscious patient will not permit penetration of a nerve root, and chymopapain in therapeutic dosage has no toxic effect on nerve tissue. No morphologic or functional changes were seen in frog or rabbit sciatic nerve preparations bathed in or injected with chymopapain.5 Moreover, experimental investigation using guinea pigs did not interfere with sensory conduction in the nerve root:; TERMINOLOGY Aside from the placebo effect of any procedure, chemonucleolysis can only resolve

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TABLE 1. Criteria for Diagnosis of Sciatica Due to a Herniated Intervertebral Disk 1 . Leg pain is the dominant symptom when com-

2.

3.

4.

5.

pared with back pain. It affects one leg only and follows a typical sciatic (or femoral) nerve distribution. Paresthesiae are localized to a dermatomal distribution. Straight-leg raising is reduced by 50%' of normal, and/or pain crosses over to the symptomatic leg when the unaffected leg is elevated, and/or pain radiates proximally or distally with digital pressure on the tibia1 nerve in the popliteal fossa. T w o of 4 neurologic signs are present (wasting, motor weakness, diminished sensory appreciation or diminution of reflex activity). A contrast study is positive and corresponds to the clinical level.

nerve-root symptoms that are produced by a herniated intervertebral disk. There is confusion in the literature as to the classic clinical syndrome produced by a disk rupture. For the purpose of this article, a herniated intervertebral disk is associated with specific symptoms and signs (Table 1). A patient with 3 , 4 or 5 of these clinical criteria probably has a herniated intervertebral disk as the source of symptoms. The criteria are composed of 2 symptoms, 2 signs and one investigative procedure. The 2 symptoms are quite specific and, along with the signs and investigation, exclude most other causes of radiating leg pain. In making the diagnosis of sciatica which is due to a disk herniation, 3 other causes of back and leg pain must be dealt with. Chemonucleolysis will not affect the radicular component of lateral recess or spinal canal stenosis, nor will it affect local mechanical problems such as degenerative disk disease. Second, chymopapain will not resolve nonorganic psychogenic regional pain problems that have as a component bizarre leg symptoms and signs. Third, non-mechanical skeletal problems ( c . g . ,tumors, infections) and neurologic problems (neuropathy) are contraindications to chemonucleolysis.

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PATIENT SELECTlON AND INVESTIGATION As the last step in conservative treatment, chemonucleolysis should be reserved for those patients in whom the surgeon could confidently expect a good result from laminectomy and diskectomy. There is a regrettable tendency for other surgeons to refer cases that they would not select for surgery for various reasons. This group of patients does not do well with chemonucleolysis. Patients must have undergone a reasonable trial of other forms of conservative treatment before chemonucleolysis is considered. This treatment should include either 2 weeks of complete bed rest, without improvement in sciatic pain, or passive straight-leg raising; or 3 months of acceptable ambulatory care in the form of brace support, anti-inflammatory and muscle-relaxant medication and well-supervised physiotherapy. Chemonucleolysis is reserved for those patients with sciatic pain which is due to a disk herniation as defined. On occasion patients present with a significant nerve-root deficit that was preceded by a brief episode of sciatica which subsided spontaneously. There is no evidence that any disk manipulation, including chemonucleolysis, will improve the rate of neurologic recovery in this patient. In selecting patients, care must be exercised in evaluating patients involved in motor-vehicle accident or compensation claims, or psychogenic pain syndromes. A patient in these settings may very well have a disk herniation, but the criteria need to be scrupulously applied. Routine investigation is carried out, including standard radiographs and blood work. If there is any doubt about unusual problems, a simple screen of erythrocyte sedimentation rate, alkaline phosphatase and serum calcium is done. Bone scanning and electromyographic assessment are not routine.

Clinical Orthopaedlcs and Related Research

All patients have some form of contrast study to verify the clinical impression. Young patients who have not had previous surgery are now undergoing epidural venography on an outpatient basis. Other patients undergo oil-soluble myelography , but a recent interest is developing in water-soluble myelography . Diskography is carried out as part of the operative procedure of chemonucleolysis. TECHNIQUE OF LATERAL DISKOGRAPHY AND CHEMONUCLEOLYSIS The technique of lateral diskography has been previously reported.12 The important technical points to be emphasized are as follows: 1. The procedure should be done under local anesthetic, so that the patient’s response to nerve-root impalement and the sensation experienced on diskography is available to the surgeon. Further, the complication of anaphylaxis is best treated pharmacologically without the medication of general anesthesia. 2 . Needle placement must be between the medial borders of the pedicles and in the center of the disk on lateral x-ray. 3. Water-based contrast material in the disk must be kept to a minimum. The author uses only a few drops of contrast material to verify the position of the needle tip and then carries out the diskogram with the same material used to mix the chymopapain, i . e . , distilled water. 4.The enzyme must be refrigerated up to the time of m e and mixed with 5 cc of distilled water that has been at room temperature. The mixed solution should be used immediately and cannot be stored. 5 . An adequate dose is considered to be 2 cc or 4000 U per disk, injected slowly over the space of 3 minutes. 6. The effect of the enzyme can often be seen immediately as a milky return back into the syringe or on the end of the needle when it is removed.

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POSTOPERATIVE COURSE Most patients notice immediate relief of the painful buttock and thigh component of sciatica. They are usually left with a deep calf ache (myotomal discomfort) and if paresthesiae were prominent before injection they persist, along with the myotomal discomfort, for weeks after the injection. On occasion the patient will notice relief of sciatica for a part of a day or a few days, only to have recurrence of symptoms. The author feels that this recurrence is due to a local inflammatory reaction within the dissolved disk and settles with time (one to 4 weeks) and the use of anti-inflammatory medication. Less commonly patients will report opposite sciatic-like pain which may be due to settling of the disk and pedicular descent on the nerve root. This complaint always settles and has not been a cause of failure. Neurologic recovery occurs in about 24% of patients and the pattern of return is quite variable. Loss of muscle bulk is very slow in recovering. Most patients have severe back pain immediately after the injection, which requires intramuscular narcotic medication. The pain usually subsides and can be readily controlled on the day of injection by corset support, ambulation and oral analgesia. The author is impressed that the more mobile a patient is immediately after this procedure, the less bothersome is the back pain. Rarely, the patients notice severe back spasms requiring a number of days of bed rest. The patients are usually discharged the day after the procedure and some patients have the chemonucleolysis on an outpatient basis.13 Chemonucleolysis is considered a failure if at 6 weeks the patient has significant sciatica, or if at 3 months the patient has disabling back pain. The patients are seen at one month to assess relief of leg pain, straightleg raising, neurologic improvement and the extent of disk-space narrowing on radiog-

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raphy. A patient who has been relieved of sciatica and manifests normal straight-leg raising and disk-space narrowing is considered an excellent result and no further problems are anticipated. At one month the patient is weaned from the corset support. On occasion one sees relief of sciatica and disk-space narrowing, with persistent limitation of straight-leg raising. This is thought to be due to a retained free fragment of disk, or lateral recess stenosis with nerve-root tension, but no nerve-root irritation. A few of these patients have had recurrent symptoms develop months or years later, requiring surgical intervention for decompression of the recess stenosis or excision of a sequestered disk.

RESULTS The author's experience includes about 2000 cases over the past 10 years. The first results were published in 19711 and 1977," each series demonstrating the usefulness of chemonucleolysis in the treatment of sciatica caused by root compression produced by a herniated intervertebral disk (Table 2). Patients who had had previous surgery, spinal stenosis or a significant psychogenic component to their pain did poorly. A recent mail survey, covering a period from February 1969 to June 1978, was conducted on 1576 patients in North America and Europe; 85% of the patients responded to the questionaire. Of those patients responding to the mail survey 67.6% obtained a successful result. Almost 80% of the patien% felt that the procedure was worthwhile and would opt for the injection in a circumstance similar to that which led them to seek medical attention initially. A detailed follow-up of 79 patients who had chemonucleolysis on an outpatient basis was completed in 1979. Age and sex distribution were similar to that in the 1977 study. Sixty-five of the 79 patients had 3 or more of the 5 criteria for the diagnosis of

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Results in Uncomplicated Spinal Pain

TABLE 2.

Failure

Success

Disk herniation Disk degeneration and other clinical conditions

N o . of Patients

Per Cent

N o . of Patients

Per Cent

158

70

67

30

28

27

74

73

a disk herniation and 89% achieved a good result. Forty patients had single-space injections and 38 obtained a good result. Of the 25 patients who had 2-space injections, only 18 obtained a good result. Statistics for neurologic recovery and disk-space narrowing matched previously published data." COMPLICATIONS NORTHAMERICAN EXPERIENCE In 16,985 reported cases of chemonucleolysis there have been 545 reactions or complications, an incidence of 3.2%.lS Sensitivity reactions form the bulk of these complications (1.5% overall), severe anaphylaxis being the most serious problem. Less than 0.5% of the author's patients suffered an anaphylactic reaction. All manifested profound cardiovascular collapse, but none of the 12 reactions had any respiratory distress requiring intubation. All patients responded to intravenous adrenaline, cortisone, and an adequate volume of intravenous fluid. Other sensitivity reactions, such as an immediate angioneurotic edema and delayed skin rashes, are infrequent and readily handled by intramuscular and oral antihistamines, respectively. In the 16,985 reported cases there were a number of procedure-related complications such as diskitis (lo), causalgia (3), arachnoiditis (4), subacute bacterial endocarditis (one), hepatitis (one), epidural abscess (one) and meningiomas (one) [0.7% of 16,985 cases]. One death occurred 5 months post-injection in the patient with subacute bacterial endocarditis.

Forty-nine (0.3%) patients had adverse reactions which could occur after any spinal procedure.'S The most serious of these was pulmonary embolism, which affected 16 patients, one of whom died after undergoing a pulmonary embolectomy. All the others recovered. One hundred and thirteen (0.8%) patients had complications develop after chemonucleolysis that were not normally associated with treatment of disk disease.lSIncluded were 2 cardiac arrests, one myocardial infarct and one cardiovascular collapse. Ten deaths occurred within one month of the injection of chymopapain. Of these, 5 may be directly related to the use of the drug and include 2 myocardial infarcts immediately post-injection, 2 severe anaphylactic reactions and one bacterial endocarditis. The author has had no patients with serious complications, aside from the 12 anaphylactic reactions, from which all the patients involved recovered without incident. One patient has a food allergy which may be related to chymopapain. Three diskitis reactions occurred and all recovered. CONTRAINDICATIONS AUTHOR' s EXPERIENCE Chemonucleolysis is contraindicated in patients who are allergic to papaya or those who have previously been injected with chymopapain. Chemonucleolysis is not indicated for severe cauda equina lesions or diffuse neurologic disorders, such as multiple sclerosis. Children under 14 years of age and

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pregnant women should not undergo chemonucleolysis. The author does not consider a suspected sequestered disk, leakage of dye at the time of diskography or significant radicular involvement to be contraindications to the procedure. Decompression of an already severely compromised nerve root, without surgical manipulation, should offer a better chance for neurologic recovery. DISCUSSION The removal of a herniated intervertebral disk, causing sciatica, by percutaneous surgery is an attractive concept. Disk surgery is not without risks or complications and requires hospitalization for 5 to 10 days. In contrast, because of the low incidence of complications following chemonucleolysis, and the brief hospital stay of up to 3 days, it becomes a valuable clinical tool. It is stressed that chemonucleolysis represents the last step in conservative treatment before surgery for the patient with sciatica caused by a herniated intervertebral disk, who has not responded to standard conservative treatment measures. This can be either a trial of 3 months’ ambulatory care in a brace and on medication support; or a trial of 2 weeks’ complete bed rest. Chemonucleolysis should be used only in those patients who would otherwise undergo a laminotomy and diskectomy. Too often, chemonucleolysis is viewed as a simple, innocuous procedure that can be carried out on patients who have been rejected for surgery for a variety of reasons. Consequently, when chemonucleolysis is first introduced in a community, one’s colleagues will refer a number of these patients. They should not be accepted for this mode of treatment. Any clinical treatment must be applied to the right patient, if the desired effect is to be achieved. Chemonucleolysis is no exception. If one confines oneself to patients who fulfil 3 or more of the five criteria for the

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diagnosis of a herniated intervertebral disk, a high percentage of good results can be anticipated. Extending the procedure to patients with significant psychogenic disability, spinal stenosis and to those who have failed to respond to previous surgical intervention reduces the percentage of good results. It is felt by a number of users that patients with a shorter duration of symptoms fare better than those with a prolonged duration of symptoms. It is the author’s experience that patients who have active sciatica and fulfil 3 or more of the 5 criteria do well, regardless of duration of symptoms. Technically, placement of the needle in the 5-1 disk space is difficult when first attempted, as are one’s first 100 meniscectomies. Once the technique is mastered, it is far simpler than laminectomy and diskectomy. Image-intensifier control and check X-rays should be used to verify needle position in the center of the disk space on both anteroposterior and lateral views. It is most important that no foreign material (such as contrast) be present in the space at the time of chymopapain injection. This is accomplished by using minute volumes of contrast material to verify needle tip position. If diluent (sterile water) is used for diskography, the disk space is left “clear” for the injection of chymopapain. The final technical point of importance is the use of adequate amounts of chymopapain. It is recommended that 2 cc (4000 U) be injected into each disk, in order to accomplish adequate enzymatic dissolution of the nucleus. There is much controversy over single versus multiple disk-space injections. If this procedure is confined to patients who have sciatica caused by a herniated intervertebral disk, single spaces should be injected. To date, the author is not aware of any study that conclusively demonstrates that multiplespace injections are better than singlespace injections. The question of when chemonucleolysis fails can be answered as follows. If at 4 to 6

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weeks the patient has the same leg pain as before the procedure, chemonucleolysis has been a failure and surgery is recommended. On 2 occasions the author has caused a marked increase in sciatica with the procedure, necessitating surgical intervention within a few days of the injection. Each patient had a massive sequestered disk which was obviously made worse by the expulsion of mass from the disk space with the injection of chymopapain. If at 3 months the patient has disabling back pain, the procedure is considered a failure and other treatment methods are indicated. Surgery following chemonucleolysis has not been more difficult than usual. For the sequestered disk, all that is necessary is to remove the free fragment. Nothing will be found in the disk space; thus opening the annulus to look into the space is unnecessary. At surgery, the author has not seen any dural or root changes, except for the one previously reported case of arachnoiditis." Nothing in the author's experience supports the suggestion that scarring occurs after chemonucleolysis. No discussion would be complete without mention of the double-blind study."'*"' Although the study can be criticized because of the short duration of symptoms, the poor choice of placebo and the early breaking of the code, it still remains the best study available on chemonucleolysis. If "thou shalt have but one criterion of clinical efficacy: the randomized, controlled doubleblind study,"" then another double-blind study will be required. Such a study is under way in Australia at the time of writing and attempts are being made in the United States to start a triple-blind study, comparing chymopapain, C.E.I. (cysteine hydrochloride, EDTA, disodium iothalamate) and true placebo (normal saline). Bringing a patient with sciatic pain to the operating room, violating the disk space

with a needle and possibly injecting placebo raises ethical questions that concern some surgeons who have rejected the doubleblind clinical trial. Perhaps the standard of clinical efficacy for a procedure such as chemonucleolysis should be reproduction of similar results by independent users, a state of the art we have repeated many times in C a n a d a . ~ , 7 ~ ~ . l l . l . ' , l ~

In all the controversy surrounding the use of chymopapain, one significant point has been missed. I n many patients the procedure can be used on an outpatient If half of the patients undergoing simple laminectomies in the United States had chemonucleolysis on an outpatient basis, the savings would approach a quarter of a billion dollars per year. In today's world, this represents a concept that requires serious consideration devoid of vested interests. SUMMARY Chemonucleolysis is a safe, relatively minor procedure which can be done with the patient under local anesthesia. If the procedure is confined to patients with sciatica resulting from a herniated intervertebral disk, and patients with non-organic spinal pain, spinal stenosis and poor response to previous surgery are excluded, good results can be anticipated. It is important that the technique include proper placement of the needle and injection of adequate amounts of chymopapain into a disk space which is free of other materials. Chemonucleolysis is a good procedure to bridge the wide gulf between standard conservative treatment and surgery. REFERENCES 1. DiMaio, V . J. M.: Two anaphylactic deaths

after chemonucleolysis, J . Forensic Sci. 188:187, 1969. 2. Dubuc. F., and Rouleau, C.: Lumbo-sciatica and chemonucleolysis, Union Med. Can. 106 (1):65, 1977 (French).

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3 . Chymopapain: a case study in federal drug regulation (Medical News), JAMA 240 (No. 3): 195, 1978. 4. Ford, L. T.: Experimental study of chymopapain in cats, Clin. Orthop. 67:68, 1969. 5. Garvin, P. J., Jennings, R. B., and Stern, I. J.: Enzymatic digestion of the nucleus pulposus: A review of experimental studies with chymopapain, Orthop. Clin. North Am. 8:27, 1977. 6. Hurteau, E. F., Baird, W. C., and Sinclear, E.: Arachnoiditis following the use of iodized oil, J. Bone Joint Surg. 36:393, 1954. 7. Kokan, P.: Chemonucleolysis: Symposium on application of proteolytic enzymes of carica papaya in broad clinical medicine, Moscow, 1978. 8. Kunkel, M.: Chemonucleolysis, Can. Orthop. Assoc. Ann. Meeting, 1974. 9. Macnab, I., McCulloch, J. A,, Weiner, D. S. , Hugo, E. P., Galway, R. D., and Dall, D.: Chemonucleolysis, Can. J. Surg. 14:280, 1971. 10. Martins, A . N., Ramirez, A,, Johnston, J., and Schwetschenau, P. R.: Double-blind evaluation of chemonucleolysis for herniated lumbar discs, late results, J . Neurosurg. 49:816, 1978.

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11. McCulloch, J. A.: Chemonucleolysis. J. Bone

Joint Surg. 59B:45, 1977. 12. McCulloch, 3. A., and Waddell, G.: Lateral lumbar discography, Br. J. Radiol. 51:498, 1978. 13. McCulloch, J. A.: Out-patient chemonucleolysis. To be published. 14. Parkinson, D., and Shields, C.: Treatment of protruded lumbar intervertebral discs with chymopapain (Discase), J. Neurosurg. 39:203, 1973. 15. Product license application, Travenol, Thetford Norfolk, 1979. 16. Schwetschenau, P. R., Archimedes, R., Johnston, J., Barnes, G., Wiggs, C., and Martins, A.: Double-blind evaluation of intradiscal chymopapain for herniated lumbar discs, early results, J. Neurosurg. 45:622, 1976. 17. Schutz, H., Fleming, J. F. R., and Vanderlinden, R. G.: Results of chemonucleolysis in disc patients, Congress of Neurological Sciences, Vancouver, 1978. 18. Shealy, C. N.: Tissue reactions to chymopapain in cats, J. Neurosurg. 26:327, 1967. 19. Smith, L.: Enzyme dissolution of the nucleus pulposus in humans, JAMA 187:137, 1%4.