Local anesthetic injections with or without steroid for chronic non-cancer pain: a protocol for a systematic review and meta-analysis of randomized controlled trials

Chronic non-cancer pain (CNCP), defined as pain persisting beyond the period of normal healing (typically ≥3 months), is commonly experienced by a large proportion of adult population. In the USA, according to 2008 estimates, approximately 100 million adults were affected by CNCP with associated treatment costs ranging from $560 to $635 billion (US). This is greater than annual treatment costs of heart disease, cancer, or diabetes [1]. In the UK, 53 % of seniors reported that CNCP was the most important factor impacting their quality of life [2]. Chronic low back pain (CLBP) has been noted to be the leading cause of years lived with disability, with neck pain as the fourth common cause [3]. CNCP accounts for a large number of physician encounters in the elderly and aging population. In the USA alone, the proportion of CLBP patients requesting care from a health provider increased from 73.1 to 84.0 %, between 1992 and 2006 [4]. Conditions characterized or defined by the presence of pain accounted for five of the leading ten conditions associated with the most years lived with disability [5]. Common peripheral (non-axial) CNCP conditions include pain in upper or lower limbs, knee and shoulder joints, headache, carpal tunnel syndrome, epicondylitis, fascitis and others.

A clear understanding of the underlying pathogenesis of CNCP is important to drive treatment decisions; however, despite decades of research, the mechanisms underlying most CNCP conditions are unclear [5]. CNCP conditions involve a complex interplay of active pain pathways leading to sensory signaling, along with peripheral and central sensitization as a result of nervous system changes induced by temporary and long-term neuroplasticity. Changes resulting from sensitization lead to modulation of pain signals, which vary from patient to patient. Most CNCP conditions do not have definitive treatment, and physicians have limited options for symptomatic management. Analgesic medications are not always effective and need to be given on a daily basis; they also involve a risk of drug interaction especially in the elderly adult population. Corticosteroid injections (CSI) are commonly used to manage many CNCP conditions, despite variability in their clinical presentation and underlying pathophysiology. For neuraxial pain, epidural steroid injections (ESI) are the most commonly performed interventions, and in the USA alone, the number of ESIs administered to Medicare recipients essentially doubled between 2000 and 2004 (from 740,845 to 1,437,962 procedures/year) [6]. CSIs are also widely used as injections to knee [7], shoulder [8], carpal tunnel [9], nerve blocks for occipital nerve [10], suprascapular nerve [11], tendinous injections for medial and lateral epicondyle [12], and even for simple trigger point injections [13].

The rationale for injecting local anesthetics (LA) is to block sensory signals from the region being injected. Although often used for diagnosis—because it should only lead to a temporary blockade—an injection of LA has the potential to decrease sensitization, which is a feature of chronic or persistent pain, thereby possibly prolonging the treatment effect of LA beyond its pharmacological duration of action [14]. Historically, many investigators have published on the successful use of epidural injections of saline and LA. Cathelin. F, Pasquier and Leri, and Sicard published reports as early as 1901 [15]. Later, Evans (1931) published a successful report using procaine and saline in 22 of 40 patients [16]. Cyriax published multiple manuscripts referring to safe use of epidural injections using only LA and steroids in more than 20,000 cases [17, 18]. In fact, up until the 1950s, the injectate used for epidural injections in sciatica consisted of LA and saline. The first recorded use of steroids in epidural space was by Lievre et al. in 1953 [19]. Discovered by Philip Hench in the 1940s [20], glucocorticoids are potent anti-inflammatory agents. Since then, steroids have been injected for nearly every chronic pain indication [21]. In clinical practice, steroids are typically combined with LA, with or without saline [15]. This practice stems from the hope that the addition of steroid can lengthen the treatment effect [22]. For most CNCP conditions (except for evidently inflammatory conditions such as rheumatoid arthritis), there is no evidence that CSI are disease-modifying agents [23]. Whether steroids have any direct effect on pain generation or transmission is not clear. There is some experimental evidence demonstrating suppression of ectopic discharge in neuromas [24]. Pre-clinical experiments suggest that steroids may reduce neuropathic pain; however, a paradoxical effect of increased pain in some patients has also been shown [25]. Surprisingly, there are few clinical studies that have attempted to elicit the mechanism behind steroid’s effect on chronic pain other than as an anti-inflammatory [26]. Thus, the use of steroid for interventions in CNCP lacks clear rationale.

Corticosteroids can have systemic and local adverse effects. Systemic side effects are largely dependent upon the patient’s physiology, injected dose, and systemic absorption. Theoretically, these systemic effects can occur when the dose of steroids injected exceeds the rate of endogenous steroid production of about 20 mg per day of hydrocortisone or its equivalent and potentially cause suppression of pituitary adrenal axis, hypercorticism, Cushing’s syndrome, osteoporosis, avascular necrosis of bone, steroid myopathy, weight gain, fluid retention, and hyperglycemia [21]. Although these risks are unlikely with a single injection, in clinical practice most patients receive multiple CSI injections at frequent intervals, and it is not uncommon for patients to suffer from multiple chronic pain conditions treated with steroid injections by different physicians, without necessarily accounting for the systemic effects of steroid injected elsewhere. Local adverse effects include soft tissue atrophy, depigmentation [27], and alopecia [28]. Beyond the above recognized adverse effects, the neuraxial steroid injections (epidural, facet joint) risk causing rare, but catastrophic neurologic injuries such as stroke and spinal cord injury [29].

Existing systematic reviews of injection therapy for CNCP conditions have not specifically compared LA vs. LA and steroid injections. Further, some reviews have considered LA injection to be a neutral agent, and combined this intervention with other biologically inactive control agents such as saline injections [12, 30]. More recently, within the last quarter of 2015, two additional reviews have been published. Manchikanti et al. reviewed all spinal injections targeted at epidural, facet joint/nerve, and disc pain conditions. Due to the existing heterogeneity, a meta-analysis was not considered feasible. All RCTs using an active control design were included. They observed that LA alone was as equally effective as LA with steroid, except in disc herniations [18]. The review by Chou et al. also focussed only on epidural injections for radiculopathy and spinal stenosis, without any restriction for the agent used and duration of chronic pain. They combined LA along with saline as placebo comparator. Their results showed a small effect favoring the use of steroids only in radiculopathy for short-term reduction in pain and function [31]. To illustrate these issues, we reviewed the systematic reviews published in English within the last 5 years, focusing on injection therapies using CSI for CNCP conditions. We identified the findings and limitations of those reviews, apart from identifying whether they included trials that addressed our review question of comparing LA and steroid with LA alone for CNCP (Table 1). Twenty seven out of forty-two reviews included trials comparing LA and steroid with LA alone [6, 12, 18, 30‐53], but only some reviews have made clear observations on the comparison between LA vs. LA and steroid [18, 33, 38, 41, 45, 48, 51]. Very few conducted meta-analyses [12, 31‐33, 35, 39, 41, 45, 48, 51]. The question of whether the injected steroid has any clinical benefit beyond that achieved from LA alone is an area of active debate, as existing studies across various clinical categories have shown equivalent effects comparing LA and steroid vs. only LA [54‐57]. Findings from our review will help inform physicians, healthcare providers, and CNCP patients on whether the addition of steroid gives any meaningful benefit to LA injection alone.