Surgical trauma produces complex local biochemical changes that contribute to inflammation and acute postoperative pain, and in some cases to chronic pain.1 Tissue injury induces an increase in the complex cascade of inflammatory cytokines that can induce peripheral and central nervous system sensitization, leading to hyperalgesia.2 In a set of articles in this issue of the journal, Hu et al.3,4 describe the role of one of these inflammatory cytokines, interleukin (IL)-1β, in postsurgical wound healing and acute postoperative pain. In a rodent model of incision pain, they demonstrated that the antiinflammatory cytokine, IL1ra, which antagonizes the binding of IL-1β to its receptor, decreases postoperative mechanical hypersensitivity when administered intraperitoneally. In addition, the concentration of other inflammatory cytokines, such as IL-6 and tumor necrosis factor (TNF)α, were reduced in wound skin tissue. This complements their human studies, which showed that IL-1β stimulated cytokine production, especially IL-8, in vitro in primary human keratinocytes, and that IL-1β and IL-8 levels were highly correlated in surgical wound exudates from both cesarean incisions and sunburn-induced blisters. The authors suggest that because a commercially available recombinant version of IL1ra, anakinra, is already in use in rheumatoid arthritis patients, a clinical trial to assess its value in improving wound healing and reducing pain when administered perioperatively can be considered.
What are the main issues to consider before using any type of cytokine modulator to reduce inflammation and pain during the perioperative period? First, how serious a problem is wound healing and acute postoperative pain for each type of surgery being considered? Second, are some of the inflammatory immune mediators necessary as part of the normal defense of the surgical wound to prevent infection? With small incisions of skin and underlying muscle with minimal retraction, postoperative outcomes are usually good and recovery is uneventful. Therefore, cytokine manipulation may not be needed. However, for major types of surgery, e.g., joint replacement surgery, spine, or thoracotomy, acute postoperative pain may be severe and can delay rehabilitation. In addition, with procedures such as knee replacement surgery and thoracotomy, the incidence of persistent postsurgical pain is relatively high5; therefore, there are even more incentives to consider reducing postsurgical inflammation.1
The relative importance of each cytokine may differ depending on the type of surgery. With hip replacement surgery, concentrations of IL-1β, IL-6, and IL-8 increase in hip drain exudates, whereas TNFα levels decrease.6 Similarly, as described in this issue of the journal, in cesarean delivery, local inflammatory mediators such as substance P, IL-1, IL-6, IL-8, and IL-10 are increased.7 However, it is not known whether controlling surgical site IL-1β release or binding would be more important than suppressing IL-6 or IL-8 in improving wound healing and reducing pain. In the earlier stages of wound healing (up to 24 hours), neutrophils are the dominant cell type in the local immune response,8 – 10 and after hip replacement surgery, there is upregulation of gene expression for such inflammatory modulators as macrophage migration inhibitory factor, IL1ra itself, the chemokine CCL20, and receptors for IL-8 and IL-18 in neutrophils extracted from the wound drainage.11 Recent basic12 and clinical studies13 all point to IL-1 as the main local tissue receptor type correlated with postoperative analgesia.
Choosing the correct dose of the IL-1 receptor blocker, anakinra, for a clinical trial affecting surgical outcomes may not be obvious, based on approved doses for rheumatoid arthritis. In the rodent incision model, the anakinra dose to reduce postoperative mechanical hypersensitivity was 100 mg/kg. However, the daily dose in rheumatoid arthritis patients is 100 mg,4,12 which is approximately 1 mg/kg. Whereas the antihyperalgesic doses in rodent pain models are often much larger than doses used clinically to reduce pain, it is possible that the maximum approved anakinra dose for patients may be inadequate to decrease postoperative pain. In a review of clinical trials using anakinra for chronic rheumatoid arthritis, the incidence of serious infections was 1.8% in the anakinra group versus 0.6% in the placebo group.14 Although for cutaneous wounds this may not be a real clinical issue, for major joint replacement surgery, an infected prosthesis could be detrimental. All of the above issues apply not just to anakinra, but to inflammatory cytokine modulators in general (e.g., TNFα inhibitors: etanercept, adalimumab, infliximab).
The 2 articles in this journal,3,4 along with previous animal studies,15,16 provide a rationale for IL1ra administration in the perioperative setting. Nevertheless, it is important that the choice of surgery for an initial clinical trial is chosen judiciously. A key consideration is that the surgery in question be one in which surgical outcomes have a relatively high incidence of acute pain, and possibly chronic pain, so that a successful treatment will be clinically and statistically significant. In addition, the type of surgery chosen for study should be one in which infection would be relatively easy to treat, should one occur.
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