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.

Etiological theories and treatments for chronic back pain. I. Somatic models and interventions.

This is the first part of an extended review of the etiology and treatment of chronic back pain (CBP). This paper will address the pathophysiology of CBP, the somatic conceptualizations that have been developed, and the treatment modalities that have been employed to alleviate the symptoms. The adequacy of the different models and treatments will be critically examined. The second paper in this set will examine psychological models and interventions. Common problems to both somatic and psychological approaches will be discussed at the close of the second paper.

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.

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.

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.

Peripheral nerve injury by chymopapain injection.

Chymopapain injected into the intervertebral disc space (chemonucleolysis) has been used clinically in patients with disc disease with success. Neurosurgical complications secondary to the procedure have, however, been reported. In this study, the authors have investigated the possible neurotoxic effect of chymopapain on the peripheral nerve in rat and primate models. While the extrafascicular injection caused no nerve fiber damage, the intrafascicular injection caused dose-related nerve fiber damage in both species.

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.

Chemonucleolysis for herniated nucleus pulposus in adolescents.

Fifty-five adolescents between the ages of thirteen and nineteen years underwent chemonucleolysis for one or more herniated lumbar discs at St. Michael's Hospital, Toronto, Ontario. The surgery was done by the senior one of us (J.M.) between 1972 and 1982. The duration of symptoms ranged from two months to three years. Pain in the lower limb was the predominant symptom in forty-eight patients. Reduction of the amount of straight leg-raising by 50 per cent or more, with or without pain in the ipsilateral hip when the asymptomatic limb was lifted (cross-over pain) and with or without pain radiating up or down the lower limb when the tibial nerve was pressed in the popliteal fossa (bowstring discomfort), was considered evidence of tension on or irritation of the nerve root and was present in all patients. Chemonucleolysis was considered as an alternative to discectomy and was performed only after the patient failed to respond to conservative management. An anaphylactic reaction occurred in one patient and was treated successfully. The most common symptom after injection was increased back pain, and it was controlled with medication. One patient had transient weakness of the extensor hallucis longus after injection. The length of follow-up ranged from two to twelve years (average, four years and six months), excluding one patient who was killed in an accident six months after injection. Chemonucleolysis did not relieve the symptoms in eleven of the fifty-five patients. These eleven patients all subsequently had surgical excision of the disc, and in them the chemonucleolysis was considered to have failed.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaphylactic reactions following the intradiscal injection of chymopapain under local anesthesia.

During the twelve-year period from January 1, 1970, through December 31, 1981, 4,282 patients with the diagnosis of herniated nucleus pulposus were treated by intradiscal injection of chymopapain under local anesthesia. Fifteen (0.35 per cent) of these patients sustained an anaphylactic reaction as defined by us. Twelve patients had subjective early warning signs before their blood pressure decreased, including a total-body burning or tingling sensation (five patients), a general feeling of ill health (four patients), and diffuse pruritus (three patients). Profound hypotension without subjective warning symptoms was the first indication of anaphylaxis in three patients. In all patients, hypotension requiring vigorous treatment was the life-threatening clinical manifestation of anaphylaxis, but respiratory distress severe enough to require endotracheal intubation did not occur. There were no deaths or known sequelae. Ten of the fifteen patients were women. Review of the medical histories of the fifteen patients and follow-up telephone interviews did not identify any other pre-disposing factor for the anaphylaxis. Twelve of the fifteen patients obtained complete relief of the symptoms of disc herniation. The advantage of the use of local rather than general anesthesia for chymopapain injection is that the patient remains responsive and can give an early warning of the subjective symptoms of anaphylaxis if they appear. This potential for early diagnosis allows early and aggressive treatment with intravenous fluids, epinephrine, steroids, and antihistamines, which can be effective in preventing death or permanent sequelae. In our experience, general anesthesia and routine endotracheal intubation are not necessary for intradiscal injection of chymopapain.

Chymopapain, chemonucleolysis, and nucleus pulposus regeneration.

UNLABELLED: In the adult mongrel dog, in vivo injection of chymopapain into the intervertebral disc resulted in disc-space narrowing at two weeks, with a complete loss of proteoglycan (as indicated by safranin-O staining) from the nucleus pulposus, the cartilaginous end-plates, and the annulus fibrosus. As demonstrated by [35S]sulphate-labeling and proteoglycan isolation, the nucleus pulposus retained the ability to synthesize proteoglycans, but these were degraded by endogenous proteolytic activity. Three months after chymopapain treatment the intervertebral disc showed an increase in height. There was a return of intense safranin-O staining in the annulus and the cartilaginous end-plates, and very prominently in the nucleus. The proteoglycans that were present were recovered as aggregates, with the proteoglycan monomer being slightly larger than in the controls. Six months after chymopapain treatment the intervertebral disc had increased further in height, and normal histology had been restored. The chemical composition and physical properties of the proteoglycans that were isolated from the nucleus pulposus were essentially the same as those from the controls. These observations suggest that the nucleus can regenerate following the injection of chymopapain. CLINICAL RELEVANCE: Our observations demonstrate that chymopapain has a profound but reversible effect on the intervertebral disc. The radiographic narrowing of the intervertebral disc following chymopapain injection correlates with the loss of proteoglycan content and structure. The restoration of normal disc height following chymopapain injection is explained by reconstitution of the intervertebral disc with normal proteoglycans. In experimental animals, chemonucleolysis with chymopapain appears to be less likely than surgical excision to permanently alter the biochemistry of the nucleus pulposus.

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.

Repeat chymopapain injections. Results and complications.

In this review of 35 patients who received repeat chymopapain injections, 41% had an excellent result, 37% had some improvement, and 22% showed no improvement. Of the 21 patients followed who had the same disc injected twice, 43% had an excellent result and 24% had no improvement. Of the three patients followed who had a different disc injected on the second occasion, one had an excellent result, and none showed no improvement. There was no significant difference between the two groups. Six patients (17%) had an anaphylactic reaction to the second injection. Five had a major reaction. Repeat chymopapain injection may be a valid treatment for a protruded disc but should not be performed until a definitive test for sensitivity is developed.

A randomized, double-blind study to compare low-dose with standard-dose chymopapain in the treatment of herniated lumbar intervertebral discs.

Postoperative low-back pain and spasm are the main drawbacks of chymopapain chemonucleolysis. To investigate if low-dose chymopapain could reduce this adverse reaction, without modifying the efficacy, 118 patients with persistent low-back and radicular pain due to a lumbar disc herniation underwent chemonucleolysis. 60 patients were randomly selected to receive 2 mL of standard-dose chymopapain (4,000 units) and 58 to receive 2 mL of low dose (2,000 units). The clinical outcome was assessed on study days 1, 30, and 60, and after 1 year by physicians who were unaware of the treatment, and on the basis of the patients' self evaluation. At day 60, Chemonucleolysis was rated as successful in 81% of the cases by the investigator and in 80% by the patient's self assessment. The percentage of good results was remarkably similar in the two treatment groups and this finding was confirmed after 1 year. There was some evidence that the low-dose treatment resulted in less frequent postoperative back pain but the difference was not statistically significant. Moreover, a comparable incidence of acute low-back pain and spasm was observed in the two treatment groups. Low-dose chemonucleolysis appears to be as effective as the standard dose, but the use of 2,000 units does not significantly lower the postoperative back pain.

Dural puncture using the lateral approach for chemonucleolysis.

The lateral approach for chemonucleolysis was developed to avoid dural puncture, which occurs with midline and posterolateral approaches. It is important to check for dural punctures during the procedure. If the dura is penetrated, a potential pathway is created for chymopapain to enter the subarachnoid space. Large doses of intrathecal chymopapain are highly toxic and small doses show a variable response. Because of the potential disastrous complications associated with intrathecal chymopapain, the chymopapain injection is contraindicated in the presence of a dural leak.

Prospective comparative study of intradiscal high-dose and low-dose collagenase versus chymopapain.

The mixed results of two studies on intradiscal therapy with collagenase versus chymopapain are presented. The first study was performed from January 1983 to March 1984 and consisted of 71 patients treated with collagenase injection (600 ABC units) and 93 patients treated with chymopapain injection (4,000 units) into lower lumbar discs. The second study was started in May 1985 and ended December 1985. The results of 41 patients injected with chymopapain and 45 patients injected with collagenase (400 ABC units) are reported. The overall success rate after 3 months was 69%/63% for chymopapain/high-dose collagenase and 73%/71% for chymopapain/low-dose collagenase and 75%/72% after 6 months for chymopapain/high-dose collagenase. Eighteen percent of the chymopapain-treated patients and 21% of the collagenase-treated patients of the first study had to be operated on within 6 months and 12% of chymopapain patients and 29% of collagenase patients within 3 months in the second study. Six of the 134 patients who had chymopapain treatment had slight allergic reactions. Patients who had collagenase treatment had no allergic reactions under the same regimen of systemic prophylactic measures. Patients who had high-dose collagenase injections suffered significantly more from postinjectional pseudoradicular and low-back pain in the first 3 months. In the first study, no permanent neurologic complications occurred. Two patients in the low-dose collagenase group developed cauda equina syndromes in the 2 weeks after injection because of large extruded disc fragments.

Levels of keratan sulfate-bearing fragments rise predictably following chemonucleolysis of dog intervertebral discs with chymopapain.

Chymopapain (1 mg) was injected into each of four-lumbar intervertebral discs of adult mongrel dogs. As expected, at 2 weeks, all injected discs exhibited marked loss of height (mean: 50% of original height) indicative of severe proteoglycan depletion. The appearance of keratan sulfate-bearing fragments in plasma was monitored by an ELISA-inhibition assay which uses a monoclonal antibody (1/20/5-D-4) specific for an epitope present only in the longest keratan sulfate chains. Levels of plasma keratan sulfate rose within 30 minutes and reached a maximum between 24 and 72 hours later. Levels then declined progressively but were still elevated at 2 weeks postinjection. Keratan sulfate-bearing fragments in plasma were purified by ion exchange chromatography on DEAE-Sephacryl and fractionated by sieve chromatography on Sepharose CL-6B. These plasma keratan sulfate-bearing fragments were found to be similar in size to keratan sulfate-bearing fragments generated by chymopapain digestion of dog nucleus pulposus proteoglycans, but slightly larger than single keratan sulfate chains obtained by alkaline borohydride treatment of dog nucleus pulposus proteoglycans. The results of this study show that measurements of blood levels of keratan sulfate could prove useful in monitoring effective degradation of disc proteoglycans in chemonucleolysis in man and help discriminate between ineffective enzyme placement, and alternative mechanisms of treatment failure.

Low-dose, low-volume chemonucleolysis. A biochemical study.

Thirty patients with persistent sciatica due to a single disc protrusion were injected with 0.5 ml (2.0 mg) or 2.0 ml (8.0 mg) of chymopapain. Serial 24-hour urine samples were collected 1 day preinjection and for 5 days postinjection for glycosaminoglycan analysis. There was a significant increase in urinary glycosaminoglycan in both groups following chemonucleolysis, but no significant difference was found between the two groups in the total excretion of glycosaminoglycan during the 5-day period. Low-dose, low-volume chemonucleolysis may be as effective as standard doses in releasing glycosaminoglycan from intervertebral discs.

The dose-related effect of intradiscal chymopapain on rabbit intervertebral discs.

STUDY DESIGN: This study analyzed the histological and biochemical responses of intervertebral disc tissue to intradiscal injection of varying amounts of chymopapain. OBJECTIVE: To determine the appropriate amount of chymopapain needed to accomplish effective degradation of proteoglycans (PG) in the nucleus pulposus of intervertebral discs. SUMMARY OF BACKGROUND DATA: Chymopapain is an accepted treatment alternative for patients with disc herniations. The recommended clinical dose of 2,000-4,000 pKats per injection is derived from early animal studies and empirical results in man. A lower effective dose could reduce the complication rate while providing similar clinical results. METHODS: Twenty to 4,000 pKat of chymopapain was injected into rabbit discs, and the level of keratan sulfate (KS) epitope in serum was measured at different times after the injection. The animals were killed after 6 days and the injected and two neighboring discs were examined histologically. RESULTS: The serum KS level did not change appreciably after injection of 20 pKat, rose moderately at 100 and 200 pKat, and rose strongly at 500 pKat. Doses greater than 500 pKat did not result in further increase in the KS level. CONCLUSION: Degradation of the disc proteoglycans is dose dependent and reaches a maximum at 500 pKat. Higher doses appear not to cause further loss of aggrecan molecules, and injection of more than 1,000 pKat produces significant annular destruction.

Biomechanical analysis of canine intervertebral discs after chymopapain injection. A preliminary report.

With the renewed interest in using chymopapain (CP) as a chemonucleolytic agent for treatment of sciatica and low-back pain, the present study was undertaken to investigate the biomechanical property changes in canine lumbar discs after CP injections. The short-term (30- to 120-minute) in vitro effects of such an enzymatic agent appear to be the same as those of saline solution, causing increased disc heights, stiffness values, and creep rates. In the in vivo study, after three weeks, CP-injected discs had significant reductions in disc height and compressive stiffness, but the creep rate was increased substantially. However, at three months after injection, these biomechanical properties began to reverse and approached those of the uninjected controls. Buffer solution (cysteine and EDTA) was tried, but the sample size was too small to provide conclusive information. The results suggest that CP causes a disc to change its material property, but such effects appear to be time-related.

Chymodiactin postmarketing surveillance. Demographic and adverse experience data in 29,075 patients.

Postmarketing surveillance data on 29,075 patients who received Chymodiactin (Smith Laboratories' formulation of chymopapain) intradiscal injections for a herniated lumbar intervertebral disc are summarized and tabulated. The serious adverse reactions reported include death, anaphylaxis, paraplegia, and discitis. Similar problems also have been reported for Discase (Baxter-Travenol's formulation of chymopapain). Of 11 deaths reported following Chymodiactin administration, only 3 appear to be related to the drug or procedure. Two of these three were due to anaphylaxis and the third to bacterial discitis with resultant meningitis. Paraplegia appeared to be primarily due to needle trauma or injection of contrast agent and enzyme into the subarachnoid space. Careful patient selection and needle placement are essential for avoiding serious problems.