J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.5.508 on 1 May 1976. Downloaded from

Journal ofNeurology, Neurosurgery, andPsychiatry, 1976, 39, 508-513

Chymopapain in the treatment of ruptured lumbar discs1 Preliminary experience in 48 patients

J. C. MAROON, R. A. HOLST, AND C. P. OSGOOD From the Department ofNeurological Surgery, University ofPittsburgh School ofMedicine, Pittsburgh, Pennsylvania 15261, USA

SYNOPSIS The results of chemonucleolysis in 48 patients with lumbar disc disease revealed marked improvement in 58 %, slight improvement in 23 %, and no improvement in 19 %. Serious anaphylactic reactions occurred in two patients. These results and those of other neurosurgical and orthopaedic studies are summarized and compared with the 70 % improvement rate obtained with a placebo in a recent double blind controlled cooperative study. Only those few investigators participating in the Protected by copyright. double blind study are now permitted to use intradiscal chymopapain. It is concluded that the ultimate place ofchemonucleolysis, if any, in the treatment ofruptured lumbar discs remains to be determined.

Chemonucleolysis or percutaneous enzymatic however, have been diminished by additional intervertebral discolysis was first used clinically observations on the potential hazards of such in 1963 (Smith, 1964). Twelve years later, treatment (Shealy, 1967; Travenol, 1970; Scoville despite the fact that over 15 000 patients and Silver, 1975; Sussman, 1975; Watts et al., have since been treated for lumbar disc 1975b). disease with this technique by over 40 primary The nation-wide instructional courses in investigators, there is still no unanimity con- the basic and clinical aspects of chemo- cerning its clinical use. Enthusiastic pro- nucleolysis sponsored by the AAOS have gener- ponents have been counterbalanced by equally ated a significant degree of interest in both the

zealous critics. In several series, the results have neurological and the orthopaedic surgeons who http://jnnp.bmj.com/ appeared to be at least as good if not better than have attended. Despite the pressure for general conventional open surgical intervention (Brown, release of the drug, the caution exhibited by the 1969; Parkinson and Shields, 1973; Onofrio, manufacturer, the Surgical Drugs Advisory Com- 1975; Wiltse et al., 1975). In 1974, after reviewing mittee of the FDA, and also the American the results of 37 orthopaedic investigators, the Association of Neurological Surgeons appears Committee on Chymopapain (Discase) of the justified. A recent preliminary report of the only American Academy of Orthopedic Surgeons double blind cooperative study on the clinical (AAOS) (1974) stated that 'the of effects of chymopapain indicated that a placebo on October 2, 2021 by guest. chymopapain is an acceptable (safe within a was equally as effective as chymopapain in reasonable degree of medical probability) and producing pain relief in patients with ruptured effective method of treatment of pain resulting lumbar discs-70 % of those treated by each from an abnormal lumbar disc'. The potential drug (DeSaussure, 1975). widespread clinical effects of this conclusion, The purpose of this report is to document our preliminary results and complications in 48 I Supported in part by a grant from the Monsour Foundation, Jeannette, Pennsylvania, USA. patients and to compare them with other recently (Accepted 2 December 1975.) reported studies. 508 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.5.508 on 1 May 1976. Downloaded from

Chymopapain in the treatment ofruptured lumbar discs 509

METHODS The patient was then given a general anaesthetic in the supine position on a fluoroscopic table in the SELECTION OF PATIENTS Patients were selected as operating room and then placed into the lateral potential candidates for chemonucleolysis only if position and flexed by means of an inflatable pillow they had symptoms of lumbar disc disease with low beneath the iliac crest. Using image intensification back and/or radicular pain into one or both ex- fluoroscopy, a number 18 gauge thin walled 15 cm tremities and were not relieved after a strict con- spinal needle was placed into the midportion of the servative regimen of bed rest, physical therapy, heat, affected disc from a posterolateral approach begin- and analgesics. All patients were required to be ning 8 cm to 10 cm from the midline. Discography between the ages of 21 and 65 years and otherwise in was performed using 0.75 to 1.5 ml meglumine good health. Positive physical findings consisted of iothalamate (Conray) injected into those discs one or more of the following: (1) positive straight leg suspected from physical and radiological examina- raising on the symptomatic side and/or crossed tions to be abnormal. The discograms were then straight leg raising with pain referred to the sympto- evaluated for correct needle placement as well as for matic side; (2) mild weakness of the dorsi- or plantar extravasation of contrast agent into the epidural flexors of the foot of an apparently non-progressive space. No was injected into any patient in and long standing nature; (3) an appropriate sensory whom there was extravasation of the contrast agent. loss; and (4) evidence of depressed or absent reflexes Having confirmed the appropriate placement of consistent with the clinical syndrome. Diagnostic the needle, 1.0 ml or 2000 units of chymopapain studies in all patients included the routine haema- (Discase) was then injected through a sterile filter. tological studies, radiographs of the chest and The needle was left in place for five minutes to prevent lumbosacral spine, and electrocardiogram, and a

leakage out of the disc space and then withdrawn. Protected by copyright. myleogram using iophendylate (Pantopaque) which During this interval, vital signs including heart rate, demonstrated an extradural defect consistent with a ECG, and blood pressure were monitored continu- herniated lumbar disc. All women underwent pelvic ously. Adrenaline and vasopressors were immediately examinations. Electromyograms were obtained when available if needed. If at the end of five minutes the indicated. vital signs were stable, the needle was removed and Patients were excluded from consideration if they the patient wakened. Postoperative management exhibited any one or more of the following criteria: consisted of analgesics, muscle relaxants, and bed rest (1)apending evaluation of or claim for compensation; for at least 12 hours before bathroom privileges were (2) profound or progressive weakness of muscle granted. Walking was encouraged the following day, groups of the lower extremities; (3) any degree of and additional in-hospital instructions in back care urinary or anorectal dysfunction; (4) known or and exercises were given before discharge. Patients suspected pregnancy; (5) previous injection with who performed sedentary or office work were urged chymopapain; and (6) evidence of a narrow spinal to be away from theirjobs for from three to five weeks. canal syndrome or other pathology as suggested by Those with more demanding physical requirements physical findings or myelography. were offfor variably longer periods oftime, depending were then All patients meeting the above criteria on the follow-up results. offered the possibility of participating in the clinical http://jnnp.bmj.com/ study with chymopapain after being fully informed of the reported complications and experimental nature RESULTS of the project. A five page instruction sheet in lay language was given to all patients. This explained the The duration of symptoms was from one month history, presumed mechanism, complications, and to 10 years with a median period of 18 months. technical aspects of the procedure. After 24 hours, The period of follow-up ranged from four to 14 the patient was again approached to answer any months. Those few patients who were not physi- questions regarding the procedure. If he chose examined one or more times after injection on October 2, 2021 by guest. enzymatic treatment in place of surgery, a special cally consent form, approved by our Human Experimental were contacted by telephone and asked specific Committee for this purpose, was signed and questions regarding their pain, working habits, witnessed. and post-injection status. The results are graded according to the follow- TREATMENT PROCEDURE On the day of injection, all ing criteria: 'marked improvement' denotes patients received 1 g cortisone or its equivalent progressive and sustained relief from radicular intravenously not less than 90 nor more than 180 pain and/or back ache and diminution of clinical minutes before the enzyme injection was to be given. signs, similar in pattern to the relief and improve- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.5.508 on 1 May 1976. Downloaded from

510 J. C. Maroon, R. A. Holst, and C. P. Osgood ment which follows successful surgical interven- 25 year old nurse who had a significant aggra- tion. This category includes other ratings of vation of radicular pain and increased urinary 'good', 'excellent', and 'symptom-free'. 'Slight frequency after chemonucleolysis. Surgical improvement' signifies incomplete relief of exploration seven days after chymopapain radicular pain and/or back ache with residuals of injection at the L4-5 and the injected L5-S1 one or the other or both, but no incapacitating interspace revealed only a slight bulge of the pain and with some improvement in the physical L5-S1 disc. This disc was excised, and the nucleus signs. 'Unimproved' indicates no improvement. pulposus had a homogeneously white milky This includes categories of 'no relief', 'poor', and appearance and did not have the particulate 'no change' as well as those patients who had characteristics usually encountered in the removal slight improvement but whose signs and symp- of a lumbar disc. Microscopically, however, our toms were not sufficiently mitigated to avoid pathologist could not differentiate this disc surgical intervention. material from that routinely removed from other Marked improvement occurred in 28 patients surgical cases. This patient improved dramatically (58 %). Although single intervertebral discs (L4-5 after surgical exploration and returned to her or L5-S1) were injected in most cases, two patients nursing activities. Six months later, however, she had two discs injected (L4-5 and L5-S1) and one again developed severe recurrent radicular pain patient had three discs injected (L3-4, L4-5, and into both lower extremities which required a L5-S1) based on the results of physical findings prolonged hospitalization of three and a half and/or myelography. Eleven patients obtained weeks. Repeat myelogram was interpreted as marked improvement within the period of normal, and, with conservative and psychiatric Protected by copyright. hospitalization after injection, which was usually therapy, she improved again to return to her three to six days. Ten patients improved between former nursing activities. The ninth patient the time of discharge and the first follow-up refused surgery. examination in approximately four to five weeks. In two patients, free fragments of herniated Seven patients obtained their maximum improve- discs were found laterally and in two others, ment between one and three months after spondylotic ridges were thought to be aetio- injection. All patients returned to their former logically responsible for the radicular pain. In work. one additional patient, a protruding disc was Slight improvement occurred in 11 patients excised. In all five ofthese patients, good sympto- (23 %). Two had injections into both the L4-5 matic relief of their radicular and/or their low and L5-S1 interspaces, and one patient had an back pain occurred. In three additional patients, injection into the L3-4 and L4-5 interspaces. The surgical exploration was carried out with no remainder had single injections, into either the significant improvement in the radicular or low had with L4-5 or L5-S1 interspace. Six of the 11 patients back complaints. Two radicular pain http://jnnp.bmj.com/ experienced good to excellent relief of pain in the signs of weakness of the extensor muscles of the immediate post-injection period, but from three foot and a positive straight leg raising sign, but weeks to three months after injection either low no significant pathology was found at surgical back and/or radicular pain returned and only exploration. In a third patient, a bulging L4-5 'slight improvement' could be documented. In disc was excised, but again with no significant five patients there was a slight diminution in pain, improvement in the radicular complaints. usually in the radicular leg component but with a persistence of low back discomfort. The six COMPLICATIONS An increase in low back pain on October 2, 2021 by guest. patients who worked before injection returned to occurred in most patients and lasted from two to their occupation. Five patients who were offwork 14 days. This was usually mild to moderate and before injection did not return to their employ- was controlled with the usual analgesics and ment after injection. muscle relaxants. Severe muscle spasms, however, Nine patients (19%) were rated as 'un- developed in two patients and required extensive improved'. Seven of the nine had surgical hospitalization for three and a halfand four weeks exploration between one and five months after respectively after injection. Morphine gave only chymopapain injection. The eighth patient was a temporary relief, ambulation was impossible, and J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.5.508 on 1 May 1976. Downloaded from

Chymopapain in the treatment ofruptured lumbar discs 511 the pain involved the paravertebral muscles in the macular rash over the upper trunk and extremities lumbosacral area bilaterally, the buttocks, and and had a drop in systolic blood pressure from both legs. Steroids in high doses were adminis- 130 to 80 mmHg. This again responded to tered to both patients with questionable relief. In appropriate intravenous therapy, and no one, the sedimentation rate was slightly elevated, permanent sequelae were noted. but tomograms of the lumbosacral area several weeks after treatment showed no evidence ofbone DISCUSSION erosion. In both patients, complete relief of their previous radicular pain subsequently occurred, In scrutinizing the reported results of chemo- and both were eventually classified as being nucleolysis, one is confronted with the variable markedly improved. criteria used in the selection of patients and in Four patients developed severe pain into the evaluation and also the inherent danger of sum- opposite leg with concurrent diminution of the mating rather small individual series dealing with radicular pain for which the injection was carried such a complex problem as 'sciatica'. Enough out. In one of these four, hyperpathia in the data are available, however, to at least make opposite leg lasted approximately six weeks, after comparisons and useful observations. which it subsided completely. One patient devel- In the Table we have summarized the results of oped nuchal rigidity, an elevated temperature, four neurosurgical groups and also the combined and a diffuse macular rash two days after statistics of 37 orthopaedic investigators who A lumbar puncture revealed presented their results in private patients who had injection. subsequent Protected by copyright. a spinal fluid protein of 0.9 g/l with two lympho- had no prior surgery to the Committee on Chymo- cytes/mm3. Within seven days with symptomatic of the American Association of Ortho- therapy, the syndrome cleared, and the patient pedic Surgeons in September, 1973 (Parkinson was discharged completely relieved of her radicu- and Shields, 1973; AAOS, 1974; Onofrio, 1975; lar pain, which had persisted for six months and Watts et al., 1975a). The failure rate for both was refractory to all conservative therapy. groups was an identical 14%. The primary area of The most serious complications were ana- difference was in the higher percentage of 'slight' phylactic reactions that occurred in two patients. or 'some improvement' and a comparative In one, immediately after injection, there was a decrease in the 'marked improvement' in the precipitous drop in the systolic blood pressure neurosurgical series. Onofrio's (1975) results from 120 to 60 mmHg with a corresponding sinus stand out as a striking exception, especially in tachycardia. Immediate intravenous adrenaline view ofhis treatment of an additional 170 patients was given with a prompt response of the blood not included in his initial report but in whom the pressure and no permanent sequela. In the second same success rate was obtained.

patient, approximately six minutes after the Although the follow-up has been relatively http://jnnp.bmj.com/ injection, as he was being turned from the brief, our findings have been consistent with operating room table to the bed and while still others in that maximum benefits appear to occur intubated, there was a profound drop in the within one to two months after injection. Allow- systolic blood pressure to an unobtainable level ing for a few late failures and possible successes, and the onset of ventricular tachycardia. Im- our results remain virtually identical to those of mediate resuscitative measures included intra- Watts et al. (1975b), with the exception of a venous administration of adrenaline, external significantly higher complication rate. cardiac massage, and intravenous lidocaine As has been emphasized by others, this is by no on October 2, 2021 by guest. infusion. This patient also made a complete means a 'benign' procedure. A 1% anaphylactic recovery from the anaphylactic reaction, but reaction is a frequently quoted figure (Brown, required subsequent laminectomy because of 1969; Travenol, 1970; Watts et al., 1975a; Wiltse failure to improve from the chemonucleolysis. A et al., 1975), but, in two patients out of our total herniated L4-5 disc was removed. One additional of 48, life threatening cardiovascular reactions allergic reaction occurred secondary to meg- developed, and catastrophe was averted only by lumine iothalamate which was injected for immediate and appropriate cardiorespiratory discography. The patient developed an immediate therapy. Both patients received the recommended J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.5.508 on 1 May 1976. Downloaded from

512 J. C. Maroon, R. A. Holst, and C. P. Osgood

TABLE RESULTS WITH CHYMOPAPAIN IN LUMBAR DISC DISEASE

Improvement Marked Slight Minimal or none Total (no.) (%) (no.) (%) (no.) (%) (no.) Neurosurgical results University of Pittsburgh 28 58 11 23 9 19 48 Mayo Clinic (Onofrio, 1975) 60 83 5 7 7 10 72 University ofTexas-Dallas (Watts et al., 1975b) 59 59 22 22 19 19 100 University of Manitoba*t 29 40 39 54 4 6 72 Total (no.) 176 77 39 292 Percentage 60 26 14 Committee on Chymopapain of the American Academy of Orthopedic Surgeons Total (no.) 4 893 919 914 6 726 Percentage 72 14 14

*Determined by degree of back pain. tParkinson (1975)-personal communication. dose of steroids before chemonucleolysis and MacNab (1973) reported no significant change in neither had a history of allergy to or its the myelographic defect in a small series of derivative products. Also, no technical difficulties patients. Watts et al. (1975b) have suggested thatProtected by copyright. with needle insertion or injection were en- chymopapain may be flushed into a torn annulus countered in either patient. and affect the function ofpain fibres in this region, Although mild to moderate low back dis- thus producing its therapeutic effect. Sussman comfort is a well recognized sequela of chemo- (1975) suspects that the clinical improvement nucleolysis, the severity and persistence of the associated with chymopapain injection derives lumbosacral muscle spasm in two patients was from such non-specific factors as placebo effect, truly alarming. Both reported that they had never improper case selection, alkaline wash, or experienced pain of such intensity, and narcotics neuronal injury. in both patients gave only mild relief. In view of the significant number of patients These severe complications as well as the who have been promptly and apparently perman- additional problems noted above and also those ently relieved of pain by chemonucleolysis, the reported by Watts et al. (1975b) stand in contrast report of the cooperative study using a double to the results of others (Parkinson and Shields, blind protocol is particularly intriguing. The 1973; Onofrio, 1975; Wiltse et al., 1975). In observation that 70% of patients given a general Onofrio's (1975) series of 242 patients, no ana- anaesthetic and injected with a placebo have http://jnnp.bmj.com/ phylactic reactions occurred, and the only obtained relief of pain due to herniated lumbar complications were limited to three cases of discs underscores our glaring lack of under- aspiration, presumably secondary to intubation standing ofthe pathophysiology and psychosocial in the lateral position. Parkinson and Shields aspects of the pain associated with lumbar disc (1973) have also reported no serious complica- disease. tions. The reasons for this are unexplained and, White (1968) has warned that when personality although unlikely, perhaps are due to chance factors are unfavourable a poor result is almost on October 2, 2021 by guest. alone since the technical aspects of the procedure certain in the operative treatment of lumbar are virtually the same in the hands of all disc disease, no matter how accurate the ana- investigators. tomical diagnosis or how skilful the surgeon. Despite intensive investigation into the bio- Recently, Wiltse and Rocchio (1975) evaluated chemistry, toxicology, and pharmacology of preoperative psychological tests as predictors of chymopapain, the precise mechanism by which success of chemonucleolysis in the treatment of pain is relieved remains unclear (Watts et al., rather rigidly selected patients with the low back 1975a). Inpatientshavingfollow-up myelography, syndrome. They found that the hypochondriasis J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.5.508 on 1 May 1976. Downloaded from

Chymopapain in the treatment ofruptured lumbar discs 513 and hysteria scores of the Minnesota Multiphasic MacNab, 1. (1973). Chemonucleolysis. Clinical Neuro- Personality Inventory were reliable predictors of surgery, 20, 183-192. which patients would have excellent and which Onofrio, B. M. (1975). Injection of chymopapain into intervertebral discs: preliminary report on 72 patients would have poor symptomatic results. Patients with symptoms of disc disease. Journal ofNeurosurgery, with very low scores (54 and below) were 90% 42, 384-388. certain ofhaving a good or excellent symptomatic Parkinson, D., and Shields, C. (1973). Treatment of pro- improvement, while only 10% of patients who truded lumbar intervertebral discs with chymopapain were extremely high (85 and above), regardless of (Discase). Journal ofNeurosurgery, 39, 203-208. positive physical findings, showed this degree of Scoville, W. B., and Silver, D. (1975). Results of Scoville improvement. Preoperative ratings by the sur- and Silver's questionnaire on chymopapain. Journal of geons of the degree to which the patient's Neurosurgery, 42, 487. symptoms were psychogenic in origin were also Shealy, C. N. (1967). Tissue reactions to chymopapain in of considerable predictive value. cats. Journal ofNeurosurgery, 26, 327-330. For the present, the role of chemonucleolysis Smith, L. (1964). Enzyme dissolution of the nucleus remains in limbo with clinical application con- pulposus in humans. Journal of the American Medical fined only to those investigators participating in Association, 187, 137-140. the double blind protocol. Its future place, if any, Sussman, B. J. (1975). Inadequacies and hazards of in the clinical treatment of lumbar disc disease chymopapain injections as treatment for intervertebral must await the further critical, objective, and disc disease. Journal ofNeurosurgery, 42, 389-396. prolonged evaluation of this multicentre Travenol Research Summary (1970). Discase, 2S120, 16. cooperative study. Watts, C., Hutchinson, G., Stern, J., and Clark, K. Protected by copyright. (1975a). Comparison of disease treatment by chymopapain injection and open surgery. We are indebted to Mrs. Ellen Narvin for her editorial Journal ofNeurosurgery, 42, 397-440. assistance. Watts, C., Knighton, R., and Roulac, G. (1975b). Chymo- papain treatment of invertebral disc disease. Journal of Neurosurgery, 42, 374-383. REFERENCES White, A. W. M. (1968). The compensation back. Applied American Academy of Orthopedic Surgeons (1974). Therapeutics, 8, 971-974. Report of the Committee on Chymopapain (Discase). Wiltse, L. L., and Rocchio, P. D. (1975). Pre-operative American Academy of Orthopedic Surgeons: Chicago, psychological tests as predictors of success of chemo- Ill. nucleolysis in the treatment of the low back syndrome. Brown, J. E. (1969). Clinical studies on chemonucleolysis. Journal ofBone andJoint Surgery, 57-A, 478-483. Clinical Orthopedics, 67, 94-99. Wiltse, L. L., Widell, E. H., and Yuan, H. A. (1975). DeSaussure, R. L. (1975). Special communication to Chymopapain chemonucleolysis in lumbar disc disease. members of the American Association of Neurological Journal of the American Medical Association, 231.

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