Comparison of the effectiveness of four major drugs prescribed for chronic low back pain in Japan ーNationwide multicenter study

Gen Inoue, Takashi Kaito, Yukihiro Matsuyama, Toshihiko Yamashita Mamoru Kawakami, Kazuhisa Takahashi, Munehito Yoshida Shiro Imagama, Seiji Ohtori, Toshihiko Taguchi, Hirotaka Haro Hiroshi Taneichi, Masashi Yamazaki, Kotaro Nishida, Hiroshi Yamada Daijiro Kabata, Ayumi Shintani, Motoki Iwasaki, Manabu Ito Naohisa Miyakoshi, Hideki Murakami, Kazuo Yonenobu Tomoyuki Takura, Joji Mochida

The Project Committee of the Japanese Society for Spine Surgery and Related Research (JSSR) Disclosures

The authors have nothing to disclose. Purpose To compare the effectiveness of acetaminophen, celecoxib, loxoprofen, and the tramadol / acetaminophen combination drug (T+A CD) using several outcome measures, and to establish evidence of the optimal pharmacological treatment option for cLBP.

Project research of JSSR • Started in 2014 as Japanese nationwide multicenter study to examine the cost-effectiveness of drug therapy for cLBP

• Subjects are patients with cLBP treated with four major drugs, loxoprofen, celecoxib, acetaminophen, and T+A CD used for cLBP in Japan

• Total 602 patients were included from January 2014 to June 2016, and prospectively analyzed for 6 months. Materials and Methods Patients who were treated with one of the major drugs for cLBP in Japan, Acetaminophen, Celecoxib, Loxoprofen, or tramadol / acetaminophen combination drug (T+A CD). Inclusion cliteria n=471 (male: 269, female: 202) Ø LBP lasting for ≥ 3 months Ø Age: 20 -85 years old mean 73.0 years old Ø BS-POP <10 on the physician version mean BMI: 23.4 and <15 on the patient version duration of LBP: 24.3 months Exclusion cliteria Occupation +: 74.1%, -: 25.9% Ø prescription of two or more drugs from among 4 drugs Diagnosis Ø coexistence of a gastrointestinal disorder with lumbar spinal stenosis: 28.4% hemorrhage Ø severe cardiac, hepatic, or renal disease lumbar spondylosis: 21.1% Ø hematologic disease, as with bleeding diathesis Ø dementia or another psychiatric disorder chronic low back pain: 15.6% Ø coexistent or previous history of alcohol or drug lumbar spondylolisthesis: 5.6% dependence Ø history of a malignant neoplasm within five years Evaluations Visual analogue scale (VAS) for LBP, EQ-5D, JOA score,Rolland- Morris Disability Questionnaire (RDQ), JOABPEQ, SF-8 These treatment measures were evaluated every months until 6 months after allocation Statistics ØVariables were compared among treatment groups using baseline data and Kruskal–Wallis and chi-square tests for continuous and categorical variables, respectively. ØMultivariable linear regression analyses was conducted to compare these treatments’ effects on the change in each outcome measure at one and 6 months after allocation. ØThe analysis included the change from baseline for each outcome at each time point as a dependent variable. ØIndependent variables indicated that the medicine was prescribed continuously from baseline, observation, and cross-product terms. Baseline and mean dose of 4 groups

Acetaminophen Celecoxib Loxoprofen T+A CD VAS for LBP 50mm 55mm 53mm 50mm EQ-5D 0.65 0.65 0.65 0.65 JOA score 19.0 20.0 20.0 18.0 * RDQ 9.0 10.0 10.0 10.0 LBP 43.0 43.0 43.0 43.0 Lumbar function 33.0 33.0 33.3 33.0 JOABPEQ Walking ability 43.0 43.0 50.0 43.0 Social life function 51.0 51.0 51.0 50.5 Mental health 51.0 50.0 53.0 50.0 PCS 37.3 38.0 37.6 35.6 SF8 MCS 48.5 49.8 49.0 49.1 Mean Dose 1,137±31.7mg 209±1.5mg 2.4±0.1T 2.9±0.1T

*JOA score showed statistical difference at baseline. VAS for LBP JOA score

N.S. *

Acetaminophen Celecoxib Loxoprofen T+A CD N.S. N.S.

SF8 Physical component summary Mental component summary

N.S. N.S.

N.S. N.S. LBP Lumbar function JOABPEQ

Acetaminophen Celecoxib Loxoprofen T+A CD NS NS NS NS

Walking ability Social life function Mental health

*

NS NS NS NS NS Discussion

JOA score JOABPEQ_mental health

Acetaminophen Celecoxib Loxoprofen T+A CD

Significant difference

Acetaminophen：Activation of the descending pain modulatory system via receptors in the midbrain and medulla oblongata Inhibits cyclooxygenase (COX) but few anti-inflammatory effect

Influence of inflammatory pain component may be limited in cLBP status. JOABPEQ_mental health SF8- MCS

Acetaminophen Celecoxib Loxoprofen T+A CD

As effectiveness on mental aspect, almost no difference was observed among 4 drugs. Mental component summary of SF8 continued worsening during 6months

Pharmacological treatment for cLBP is difficult to improve patients’ symptom, especially in mental component. Conclusions Ø The treatment effect of the four major drugs on cLBP was compared during 6 months. Ø Statistical comparisons were performed at 1 and 6 months, and the mental health component of JOABPEQ at 1 month and the JOA score at 6 months showed significant differences among the four drugs, and acetaminophen showed the greatest effect. Ø The effects on pain were not significantly different between the four drugs, and no improvement in mental aspect was obtained throughout the 6 months. Ø To identify the small difference of the treatment effect on cLBP, multiple, comprehensive evaluations using several treatment measures should be desirable, but still hard to detect the difference.