CLINICS 2007;62(2):175-80

CLINICAL SCIENCES

CHEMONUCLEOLYSIS IN LUMBAR DISC

HERNIATION: A META-ANALYSIS

José Mauro Cardoso Couto, Euclides Ayres de Castilho, Paulo Rossi Menezes

Couto JMC, Castilho EA de, Menezes PR. Chemonucleolysis in lumbar disc herniation: a meta-analysis. Clinics.
2007;62(2):175-80.

PURPOSE: To carry out a systematic review and meta-analysis of the efficacy of chemonucleolysis in the treatment of lumbar
disc herniation.
METHODS: Clinical trials were selected from 3 electronic databases (The Cochrane Controlled Trials Register, MEDLINE, and
EMBASE). Data were analyzed with the software STATA, using the meta command.
RESULTS: Twenty-two clinical trials were eligible. For chemonucleolysis versus placebo, the summary risk ratio estimate for
pain relief as outcome was 1.51 (95% CI: 1.27-1.80). The summary estimate was 1.07 (95% CI: 0.95-1.20) for the comparison
between chymopapain and collagenase. Regarding chemonucleolysis with chymopapain versus surgery, the fixed-effect summary
estimate of effect for pain relief was 0.93 (95% CI: 0.88-0.98) with surgery as the reference group. In this case, heterogeneity was
statistically significant.
CONCLUSIONS: Chemonucleolysis with chymopapain was superior to placebo and was as effective as collagenase in the
treatment of lumbar disc prolapse. Results for studies comparing chemonucleolysis with surgery were heterogeneous, making it
difficult to interpret the summary measure of effect.

KEYWORDS: Chemonucleolysis. Chymopapain. Systematic review. Meta-analysis. Lumbar disc herniation.

INTRODUCTION technique for lumbar disc herniation, presenting lower rates

of complications in comparison with discectomy.6 Accord-
Surgery to treat lumbar disc prolapse was introduced in ing to some authors, fewer days in the hospital was found
1934,1 and ever since it has been considered as the main for patients treated with chemonucleolysis, when compared
treatment modality when conservative treatment has failed.2 to traditional surgery,7,8 which augmented the considerable
However, the therapeutic efficacy of surgical intervention has cost savings.9–12 In a prospective study with a follow-up of
been a concern, considering that 20% of the patients are still at least 5 years, among 112 patients treated by
in pain after surgery,3 and that 7% to 15% of the patients chemonucleolysis, 83% had excellent/good results, 10%
undergoing discectomy develop the syndrome of failure of were unchanged, and 8% were worse after
the lumbar surgery.4 Alternative techniques have been de- chemonucleolysis.13 Nevertheless, an increased global cost
veloped and tested, and chemonucleolysis, which refers to was observed if a conventional surgery was needed follow-
the use of chymopapain for enzymatic lysis of the nucleus ing failure to improve after an initial chemonucleolysis.14
disc, has been among the most relevant. This technique was Some studies have shown superior efficacy of
first described by Smith in 19645 and is the least invasive chemonucleolysis with chymopapain, as compared with pla-
cebo,15–17 but there are conflicting results.18 In a systematic
Department of Preventive Medicine, São Paulo University Medical School – review of surgical procedures for lumbar disc prolapse that
São Paulo/SP, Brazil.
Email: castil@[Link] included studies published until 1999, discectomy presented
Received for publication on October 24, 2006. better efficacy than chemonucleolysis with chymopapain,
Accepted for publication on December 05, 2006.
which produced better outcomes than placebo.17 However,

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Couto JMC et al.

there was evidence of heterogeneity of results between stud- ity given by Jadad’s scores21 and by the classification of
ies, which makes the summary effect measure of the meta- The Cochrane Collaborative Group.22 The evaluation of the
analysis questionable. Chymopapain has been substituted for methodological quality of the studies that involved surgery
collagenase by some physicians due to side effects of colla- was accomplished exclusively with the Cochrane scale,
genase, mainly allergic reactions.19,20 The aim of the present which does not included blindness, a condition that can-
study was to carry out a systematic review and meta-analy- not be fulfilled in the cases of surgery. Assessment of study
sis of the efficacy of chemonucleolysis in the treatment of quality included whether there was randomization, blind-
lumbar disc herniation. ing, assessment of time from intervention to outcome, re-
port of losses to follow-up, and use of standardized assess-
METHODS ment of outcome. Study quality was assessed by 2 inde-
pendent raters (JMCC and EAC), and discrepancies in rat-
This project was approved by the local Internal Review ings were resolved by consensus between the raters. Data
Board. were also independently extracted from the studies by 2
of the authors (JMCC and EAC), and disagreements were
Selection of studies and search strategy resolved by consensus between them.

Studies eligible for inclusion in this systematic review Statistical analysis

had the following characteristics: they were randomized and
nonrandomized clinical trials of interventions using Data were analyzed with the software STATA version
chemonucleolysis with chymopapain or collagenase versus 8.0, using the meta command (StataCorp, 200x). For each
placebo or surgery; involved patients of any age with clini- study, a risk ratio and its 95% confidence interval were cal-
cal symptoms compatible with lumbar disc herniation with culated. Pooled estimates were calculated with fixed effect
sciatic pain who underwent computerized tomography estimates, using inverse-variance weighting. When the het-
(CT), magnetic resonance imaging (MRI), or myelography; erogeneity test yielded a P value < 0.1, a new summary
reported relief of pain as determined by any method as the measure was then obtained using random-effects models
endpoint of interest; reported the number/proportion of for binary outcomes. Possibility of publication bias was
positive results; and published in any language. analyzed with the funnel plot graph.
Three electronic databases were searched, covering the
period from January 1966 through June 2003: the Cochrane RESULTS
Controlled Trials Register, MEDLINE, and EMBASE. Ref-
erence lists of studies found in the database search and ta- The database search identified 1023 articles (600 in
bles of contents of specialized journals were also checked. MEDLINE, 394 in EMBASE, and 29 in the Cochrane da-
The search terms in MEDLINE were: INTERVERTE- tabase), and search of the bibliographic references yielded
BRAL-DISK-CHEMOLYSIS, CHYMOPAPAIN, an additional 21 publications. Of these, 22 were clinical
DISCASE, CHYMODIACTIN, NUKLEOLYSIN, trials involving chemonucleosis as one of the modalities
CHEMONUCLEOLYSIS, INTERVERTEBRAL near DISK of treatment for lumbar disc herniation (Figure 1). One of
near CHEMOLYSIS, INTERVERTEBRAL-DISK-DIS- such trials was then excluded because it was not possible
PLACEMENT, SLIPPED near (DISC or DISCS or DISK to extract data for the meta-analysis, and 1 article included
or DISKS), DISPLACE* near (DISC or DISCS or DISK 2 studies.
or DISKS), PROLAP* near (DISC or DISCS or DISK or Chemonucleolysis versus placebo was compared in 5
DISKS), HERNIATED near NUCLEUS near PULPOSUS, studies published in 1978 through 1988 (Table 1). Sample
DISCECTOMY or DISKECTOMY, PERCUTANEOUS sizes ranged from 39 to 136. All studies had random allo-
near* NUCLEOLYSIS, ENZYME* it THERAPEUTIC- cation and blinding regarding patient grouping. The length
USES, ENZYME near INJECTION, (INTRADISC* or of follow-up varied from 3 months to 2 years. All studies
INTRADISK*) near (STEROID* or TRIAMCINOLONE), had good quality scores according to both Cochrane and
COLLAGENASE*, SCIATICA, BACK-PAIN, LOW- Jadad criteria. The summary risk ratio estimate for pain re-
BACK-PAIN, TAIL-EQUINE, TAIL near COMPRESS*. lief as the outcome was 1.51 (95% CI: 1.27-1.80), favoring
chemonucleolysis (Figure 2). The summary estimate did not
Quality assessment and data extraction vary when each of the 5 studies was excluded 1 at a time.
Chemolucleolysis with chemopapain versus collagenase
Studies were classified according to the criteria of qual- was compared in 4 studies published in 1987 through 2001

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CLINICS 2007;62(2):175-80 Chemonucleolysis in lumbar disc herniation: a meta-analysi
Couto JMC et al.

(Table 2). Sample sizes varied from 83 to 164 and there for all 4 studies were C and 3, respectively. Risk ratios for
was random allocation to groups in all 4 studies, but there pain relief, comparing use of chymopapain compared to
was no information on blinding. Cochrane and Jadad scores collagenase varied from 0.94 to 1.38, yielding a summary
estimate of 1.07 (95% CI: 0.95-1.20, Figure 2).
Chemonucleolysis versus surgery was compared in 12
studies published in 1973 through 1996 (Table 3). Sample
sizes varied from 29 to 358 participants. There was ran-
dom allocation to groups in 6 studies, systematic alloca-
tion was used in 2 studies, and participant’s choice was used
in 3 studies. One study did not give information on the al-
location method used. There was no blinding in all but one
study. Cochrane scores were C for all 12 studies, and
Jadad’s scores varied from 1 to 3. The fixed-effects sum-
mary estimate of effect for pain relief as the outcome and
surgery as the reference group was 0.93 (95% CI: 0.88-
0.98), Figure 2). However, the heterogeneity test had a P
value < 0.10, suggesting a higher-than-chance variability
of estimates between studies. A random-effects summary
estimate was then calculated as 0.9 (95% CI: 0.8-1.0).
Chemonucleolysis was found to be superior to surgery in
3 studies, but only in 1 study was the difference statisti-
cally significant, whereas in 5 out of the 9 studies favoring
surgery, the difference was statistically significant. For
those studies showing superiority of chemonucleolysis,
when the summary measure of effect was calculated with
the exclusion of 1 study at a time, a strong contribution of
the study by Nordby was observed, with a risk ratio of 1.57.
Figure 1 - Search results of clinical trials comparing chemonucleolysis with
The funnel plot analysis suggested the possibility of pub-
placebo, collagenase, or surgery in the treatment of lumbar disc herniation. lication bias (Figure 3).

Table 1 - Clinical trials of chemonucleolysis versus placebo

Trial Publication Study Number of Age (yr) Losses to Assestment Length of Jadad Cochrane Chymopapain
year country individuals range Allocation Blinding follow-up of outcome follow-up score score (IU)

Martins23 1978 USA 66 18-65 random yes ... questionnaire 6 months 9 C 4000
Javid16 1983 USA 108 18-60 random yes ... clinical 6 months 3 C 4000
examination
+ questionnaire
Fraser15 1984 Australia 60 19-69 random yes ... patient views 3 years 3 C 4000
Feldman24 1986 France 39 21-77 random yes ... questionnaire + 5 years 3 C 4000
analogic visual
scale
Dabezies7 1988 USA 136 18-70 random yes 10 questionnaire 6 months 5 A 3000

. . . = not mentioned

Table 2 - Clinical trials of chemonucleolysis versus collagenase

Trial Publication Study Number of Age (yr) Losses to Assestment Length of Jadad Cochrane Chymopapain
year country individuals range Allocation Blinding follow-up of outcome follow-up score score (IU)

*Hedtmann25 1987 Germany 164 20-60 random ... ... McNab criteria 6 months 3 C 4000
Hedtmann25 1987 Germany 86 20-60 random ... ... score+analogic 6 months 3 C 4000
visual scale
Hedtmann26 1992 Germany 100 ... random ... ... good/fair/poor 3 years 3 C 4000
criteria
Wittenberg27 2001 Germany 100 20-60 random ... 16 good/fair/poor 5 years 3 C 4000
criteria

*Includes 2 studies . . . = not mentioned

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Couto JMC et al.

Figure 2 - Forest plots with results of individual studies and summary effect estimates for chemonucleolysis versus placebo, collagenase, and surgery.

Table 3 - Clinical trials of chemonucleolysis versus surgery

Trial Publication Study Number of Age (yr) Losses to Assestment Length of Jadad Cochrane Chymopapain
year country individuals range Allocation follow-up of outcome follow-up score score (IU)

Nordby9 1973 USA 191 ... ... 9 McNab criteria ... 1 C 2000-4000
Watts28 1975 USA 274 ... consecutive cases ... clinical examination 3 months 2 C 4000
Ejeskär29 1983 Sweden 29 19-73 random ... questionnaire 1 year 3 C 4000
Crawshaw30 1984 England 52 ... random 2 clinical examination + 1 year 3 C 4000
questionnaire + analogic
visual scale
Ramirez11 1985 USA 80 16-76 patient‘s option ... ... ... 1 C ...
Lavignnolle31 1987 France 358 ... random ... McNab criteria ... 3 C 4000
Brown32 1989 USA 70 ... patient‘s option 11 pain scale 0 - 100 3 months 1 C ...
van Alphen33 1989 Netherlands 151 18-45 random ... patient views 1 year 3 C 4000
Stula34 1990 Switzerland 69 22-54 random ... ... ... 3 C ...
Muralikuttan35 1991 North Ireland 92 19-60 random ... pain scale 0 - 100 + score 1 year 3 C 4000
Javid16 1995 USA 200 17-72 patient‘s option + ... patient views 6 months 1 C 3000
surgery in no
contiguous herniation
Bradbury36 1996 England 60 13-19 consecutive cases 2 analogic visual scale + 1 year 2 C 2000-4000
questionnaire (St. Thomas)

. . . = not mentioned

DISCUSSION in their effectiveness.

The number of studies comparing chemonucleolysis
In the present systematic review with meta-analysis, against placebo and chemonucleolysis against collagenase
chemonucleolysis with chymopapain was shown to be su- were low, leading to a lack of statistical power in the tests
perior to placebo and was as effective as collagenase in the of heterogeneity of estimates. Nevertheless, by visual inspec-
treatment of lumbar disk herniation. Results for studies tion and by recalculating summary measures excluding 1
comparing chemonucleolysis with surgery were heteroge- study at a time, no sign of heterogeneity was found. The low
neous, making it difficult to interpret the summary meas- number of studies also made it difficult to assess any possi-
ure of effect, which showed both options to be equivalent bility of publication bias using the funnel plot strategy.

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CLINICS 2007;62(2):175-80 Chemonucleolysis in lumbar disc herniation: a meta-analysi
Couto JMC et al.

However, quality scores for selected studies comparing

chemonucleolysis against placebo were high, supporting the
conclusion that chemonucleolysis with chymopapain is ef-
fective in reducing the pain caused by lumbar disc hernia-
tion.

ACKNOWLEDGMENTS

We thank Dr. Evandro S. Freire Countinho of the

Oswaldo Cruz Foundation for his contribution to the study.
JMCC was supported by the National Council for Scien-
tific and Technological Development - CNPq.
Figure 3 - Funnel plot for clinical trials comparing chemonucleolysis vs.
surgery (negative log OR favors surgery)

RESUMO

Couto JMC, Castilho EA de, Menezes PR. Quimonu- de 1,07 (I 95% C: 0,95-1,20) para a comparação entre
cleólise em hernia de disco lombar: metanálise. Clinics. quimopapaína e colagenase. Em um modelo de efeitos fi-
2007;62(2):175-80. xos, a razão de risco, para melhora da dor, foi 0,93 (I 95%
C: 0,88-0,98), tendo a discectomia como grupo de referên-
OBJETIVO: Avaliar a eficácia da quimonucleólise no tra- cia. Nesse caso, um teste de heterogeneidade foi conside-
tamento da hérnia de disco lombar por meio de uma rado estatisticamente significante.
metanálise de ensaios clínicos. CONCLUSÕES: a eficácia da quimonucleólise foi supe-
MÉTODOS: Os ensaios clínicos foram selecionados de rior à do placebo e semelhante à da colagenase. Os
três bases de dados eletrônicas( Cochrane, MEDLINE, e resultados dos estudos referentes à comparação entre
EMBASE). Os dados foram analisados por intermédio do quimonucleólise e cirurgia foram heterogêneos, o que
aplicativo STATA, com o comando meta. implica interpretação não-trivial da medida de efeito.
RESULTADOS: trabalhamos com 22 ensaios clínicos. Para
a comparação entre quimonucleólise e placebo, a estima- UNITERMOS: Quimonucleólise. Quimopapaína. Revisão
tiva da razão de riscos, tendo melhora da dor como desfe- sistemática. Metanálise. Hérnia de disco lombar.
cho, foi de 1,51 (I 95% C: 1,27-1,80). Aquela medida foi

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