levels [10,11]. The precise substrate underlying this phenomenon remains unknown [12]; it has been stated that it might explain the strong association between back pain and digestive disorders [13]. Understanding and awareness of referred pain is key for a precise diagnosis of the pain source [14]. Previous evidence shows that gastrointestinal, biliary, renal, hepatic, heart, and pulmonary disorders may evoke referred pain to the upper quadrant of the body, including the neck region [15]. The discrimination between visceral and somatic sources of pain is not always evident, and if it is not achieved, it may lead to extensive diagnostic procedures and ineffective treatment approaches [16]. Visceral disorders may evoke referred altered sensitivity, e.g., hyperalgesia or allodynia [17]. For instance, the radiation of pain to the neck and/or upper extremity that occurs during acute coronary syndromes [18] is experienced in more than 65% of cases [19]. Eighty-eight percent of patients with colonoscopy-induced splenic injury complain of pain along the C3–C4 dermatomes due to irritation of the diaphragm or distention of the splenic capsule [20] (Figure 1) [21]. That happens during attempts at sheath insertion into the right or middle hepatic vein in liver biopsy as well [22]. Further, it can also be caused by more common, frequently long-lasting, and not so life-threatening conditions, such as hiatal hernias and gastroesophageal reflux disease [23]. Diagnostics 2019, 9, x FOR PEER REVIEW 2 of 24 to somatic tissues, being felt at a site other than the affected viscera [10]. Visceral referred pain (VRP) occurs, as secondary hyperalgesia, in somatic areas neuromerically connected with the affected organs [10]. The overlap of somatic and visceral afferent information into a shared neural pathway seems to be related to a misinterpretation at peripheral, spinal, or supraspinal levels [10,11]. The precise substrate underlying this phenomenon remains unknown [12]; it has been stated that it might explain the strong association between back pain and digestive disorders [13]. Understanding and awareness of referred pain is key for a precise diagnosis of the pain source [14]. Previous evidence shows that gastrointestinal, biliary, renal, hepatic, heart, and pulmonary disorders may evoke referred pain to the upper quadrant of the body, including the neck region [15]. The discrimination between visceral and somatic sources of pain is not always evident, and if it is not achieved, it may lead to extensive diagnostic procedures and ineffective treatment approaches [16]. Visceral disorders may evoke referred altered sensitivity, e.g., hyperalgesia or allodynia [17]. For instance, the radiation of pain to the neck and/or upper extremity that occurs during acute coronary syndromes [18] is experienced in more than 65% of cases [19]. Eighty-eight percent of patients with colonoscopy-induced splenic injury complain of pain along the C3-C4 dermatomes due to irritation of the diaphragm or distention of the splenic capsule [20] (Figure 1) [21]. That happens during attempts at sheath insertion into the right or middle hepatic vein in liver biopsy as well [22]. Further, it can also be caused by more common, frequently long-lasting, and not so life-threatening conditions, such as hiatal hernias and gastroesophageal reflux disease [23]. Figure 1. Pattern of visceral referred pain along the C2–C3–C4 dermatomes. (A) Anterior view; (B) posterior view. When routinely evaluating patients with NP, it is easy to miss manifestations of an underlying disease, and misdiagnose neck disorders of visceral origin [15,24]. Clinical practice guidelines for the management of NP recommend a detailed physical examination to rule out the possibility of VRP in individuals with NP [25]. Hence, clinical trials assessing treatment efficacy in NP should exclude participants with suspected VRP after a comprehensive evaluation. Otherwise, this selection bias would show an underconsideration of that source of NP, and in addition, result in a likely incorrect estimation of the treatment’s effect size. Therefore, the aim of the systematic review was to investigate to what extent the top 15 most cited and the 15 most recent clinical trials published in high impact Figure 1. Pattern of visceral referred pain along the C2–C3–C4 dermatomes. (A) Anterior view; (B) posterior view. When routinely evaluating patients with NP, it is easy to miss manifestations of an underlying disease, and misdiagnose neck disorders of visceral origin [15,24]. Clinical practice guidelines for the management of NP recommend a detailed physical examination to rule out the possibility of VRP in individuals with NP [25]. Hence, clinical trials assessing treatment efficacy in NP should exclude participants with suspected VRP after a comprehensive evaluation. Otherwise, this selection bias Diagnostics 2019, 9, 186 3 of 23 would show an underconsideration of that source of NP, and in addition, result in a likely incorrect estimation of the treatment’s effect size. Therefore, the aim of the systematic review was to investigate to what extent the top 15 most cited and the 15 most recent clinical trials published in high impact journals, by November 2018, that assessed treatment outcomes in patients with NP, took into account VRP when establishing their eligibility criteria. 2. Materials and Methods The present systematic review was performed according to the Preferred Reporting Item for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines [26]. It has been registered in the International Prospective Register of Systematic Reviews (PROSPERO), with registration number CRD42018101987. 2.1. Data Sources and Search Strategy One author (C.G.-G.) conducted a systematic computerized search between November and December 2018 using the Web of Science database. The search used the key terms neck pain and trial, and considered the following limitations: both key terms being included in the title of the article; language—English/Spanish/Italian/French; and having a publication date between January 1995 and November 2018. 2.2. Study Selection In order to obtain the information from high-quality studies, eligible articles were the top 15