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Purpose: To analyze leg pain severity data from a randomized controlled trial (RCT) of lumbar disc surgery using integrated approaches that adjust pain scores collected at scheduled follow-up visits for confounding clinical events occurring between visits. Methods. Data were derived from an RCT of a bone-anchored annular closure device (ACD) following lumbar discectomy versus lumbar discectomy alone (Control) in patients with large postsurgical annular defects. Leg pain was recorded on a 0 to 100 scale at 6 weeks, 3 months, 6 months, 1 year, and 2 years of follow-up. Patients with pain reduction ≥20 points relative to baseline were considered responders. Unadjusted analyses utilized pain scores reported at follow-up visits. Since symptomatic reherniation signifies clinical failure of lumbar discectomy, integrated analyses adjusted pain scores following a symptomatic reherniation by baseline observation carried forward for continuous data or classification as nonresponders for categorical data.
Results: Among 550 patients (272 ACD, 278 Control), symptomatic reherniation occurred in 10.3% of ACD patients and in 21.9% of controls (p < 0.001) through 2 years. There was no difference in leg pain scores at the 2-year visit between ACD and controls (12 versus 14; p = 0.33) in unadjusted analyses, but statistically significant differences favoring ACD (19 versus 29; p < 0.001) in integrated analyses. Unadjusted nonresponder rates were 6.0% with ACD and 6.7% with controls (p = 0.89), but 15.7% and 27.8% (p = 0.001) in integrated analyses. The probability of nonresponse was 16.4% with ACD and 18.3% with controls (p = 0.51) in unadjusted analysis, and 23.7% and 31.2% (p = 0.04) in integrated analyses.
Conclusion: In an RCT of lumbar disc surgery, an integrated analysis of pain severity that adjusted for the confounding effects of clinical failures occurring between follow-up visits resulted in different conclusions compared to an unadjusted analysis of pain scores reported at follow-up visits only.
Healthy and degenerating intervertebral discs (IVDs) are innervated by sympathetic nerves, however, adrenoceptor (AR) expression and functionality have never been investigated systematically. Therefore, AR gene expression was analyzed in both tissue and isolated cells from degenerated human IVDs. Furthermore, human IVD samples and spine sections of wildtype mice (WT) and of a mouse line that develops spontaneous IVD degeneration (IVDD, in SM/J mice) were stained for ARs and extracellular matrix (ECM) components. In IVD homogenates and cells α1a-, α1b-, α2a-, α2b-, α2c-, β1-, and β2-AR genes were expressed. In human sections, β2-AR was detectable, and its localization parallels with ECM alterations. Similarly, in IVDs of WT mice, only β2-AR was expressed, and in IVDs of SM/J mice, β2AR expression was stronger accompanied by increased collagen II, collagen XII, decorin as well as decreased cartilage oligomeric matrix protein expression. In addition, norepinephrine stimulation of isolated human IVD cells induced intracellular signaling via ERK1/2 and PKA. For the first time, the existence and functionality of ARs were demonstrated in IVD tissue samples, suggesting that the sympathicus might play a role in IVDD. Further studies will address relevant cellular mechanisms and thereby help to develop novel therapeutic options for IVDD.