Chronic pain is a significant health problem given its prevalence, impact on quality of life, economic burden, and difficult management. Chronic pain is defined as pain that persists for over 3 months or past the normal time for tissue healing [1]. However, in most cases the duration of the pain is much longer [2,3]. For example, one Canadian study found that over 65% of people with chronic pain have experienced pain for over 5 years [2]. Chronic pain is associated with increased mortality and has major negative impacts on daily living activities and work-related outcomes, such as employment status, days missed from work, and productivity [4]. Depression and anxiety are highly prevalent in the chronic pain population [5]. Individuals living with chronic pain have double the risk of suicide compared with those who do not [6]. Chronic pain is one of the most common reasons for medical visits and is estimated to affect 1.5 billion people worldwide [7-9]. Approximately 30% of adults in the United States and up to 19% of adults in Canada experience chronic pain [10,11]. The direct health care and productivity costs of chronic pain are as high as US $635 billion per year in the United States and Can $43 billion per year in Canada, which exceed the annual costs from cancer and heart disease [11,12]. Pharmacological agents such as antidepressants, anticonvulsants, opioids, nonsteroidal inflammatory drugs, and muscle relaxants are frequently used for pain management [13,14]. Despite the variety of treatments available, they have limited efficacy and dose-limiting adverse effects, leaving a significant unmet need for sufferers [13]. Increases in opioid prescriptions for chronic pain have been associated with increases in opioid-related mortality due to accidental overdose and in the number of individuals requiring treatment for opioid-misuse disorders [15].

Magnesium is the fourth most abundant cation in the human body and plays a fundamental role in a variety of physiological processes [16,17]. Magnesium serves as a cofactor in over 300 enzyme systems necessary for regulating blood pressure, protein synthesis, muscle contraction, and blood glucose [18,19]. In the nervous system, magnesium is important for neurotransmission and neuromuscular coordination [20]. There is evidence supporting the use of magnesium supplementation in a variety of health problems, including preeclampsia or eclampsia, cardiac arrhythmias, migraine headaches, metabolic syndrome, diabetes, hyperlipidemia, asthma, and premenstrual syndrome [19,20]. Treatment with magnesium is inexpensive and has relatively few, usually mild, side effects [17,21]. Magnesium supplementation can be given orally or parenterally and is available in a variety of formulations [17]. This review will consider all magnesium formulations and dosing regimens when used in the treatment of chronic pain.

N- methyl-d-aspartate (NMDA) receptors are active contributors to pain transmission [22,23]. NMDA receptors are found on postsynaptic spinal neurons in the dorsal horn of the spinal cord [24]. Under normal conditions, the NMDA receptor ion channel is blocked by magnesium ions found in nervous tissues [20,25]. However, if there is sustained depolarization of the postsynaptic membrane, such as that from high-frequency pain stimulation or nerve trauma causing abnormal impulse propagation toward the spinal cord, the magnesium plug is removed and calcium enters the cell [13,24]. Increases in intracellular calcium lead to an increase in the intensity of pain through a process termed wind-up [13,24]. In wind-up, the spinal dorsal horn neurons have an amplified and prolonged response to subsequent inputs [23,24]. The influx of calcium can also activate various effector molecules and cause downstream changes [24]. These effector molecules can promote mechanisms of synaptic plasticity, such as long-term potentiation, which can result in elevated sensitivity and activity of dorsal horn neurons [24]. This phenomenon is known as central sensitization and manifests as a heightened response to noxious (hyperalgesia) and normally nonnoxious (allodynia) stimuli [22,24]. Both wind-up and central sensitization are plausible mechanisms for chronic pain states [13]. Magnesium administration modulates NMDA receptor-driven activity by acting as a physiological blocker of the NMDA receptor ion channel [16,26-28]. It is expected that through this mechanism, magnesium administration may prevent wind-up and central sensitization and dampen the activity of the dorsal horn neurons, ultimately reducing the pain experience.

Chronic pain is a common and complex health problem that has a marked negative impact on patients’ quality of life, physical and mental health, family relationships, employment, and economic well-being [29,30]. In North America, clinicians have increasingly prescribed opioids for chronic pain in efforts to improve pain management, despite the relatively modest evidence base and lack of rigorous research demonstrating its long-term effectiveness [31-33]. The high prescribing rates have been accompanied by significant consequences. Deaths from prescription opioid overdoses quadrupled in the last 15 years in the United States, with >200,000 prescription opioid-related deaths since 1999 [31,34]. Although the opioid crisis has been receiving heavy attention from the government and regulatory bodies, which resulted in a decrease in opioid prescriptions since 2013, the prescribing rates still remain very high in various areas across North America [34]. Additionally, continuing efforts to curb the opioid crisis is unlikely to be an effective long-term solution to the chronic pain crisis [35]. The nature of attention given to the opioid crisis may worsen the stigma associated with proper use of prescription opioids, as well as the stigma of those who are successfully finding pain relief from appropriate prescription opioid use, and result in patients being aggressively tapered off prescription opioids without other nonopioid strategies to help control their pain [35,36]. Therefore, the chronic pain crisis should be viewed and dealt with in a larger context in addition to the opioid crisis. This may involve improving public education on chronic pain, reducing stigma of those living with chronic pain, and increasing accessibility of services [35]. Due to the side effects and uncertain benefits associated with opioid use, alongside the limited accessibility of nonopioid therapies, our review will specifically focus on better understanding chronic pain clinically in terms of what nonopioid strategies are effective in the management of chronic pain.

However, finding an alternative treatment for chronic pain remains a major challenge. Many patients with chronic pain are still in pain despite treatment [37]. Growth in chronic pain research in recent decades has led to the advent of some novel agents, but we have yet to address the problem fully [13,37]. Emerging evidence supports the safe use of magnesium in controlling chronic pain, but there is no consensus regarding its clinical effects [17,38]. The findings of this systematic review will help elucidate magnesium’s efficacy and safety as an alternative for controlling pain. This study seeks to improve the quality of life of patients with chronic pain and inform future management strategies for chronic pain.

This paper aims to assess the efficacy and safety of magnesium compared with placebo for the treatment of chronic noncancer pain.