Chronic Pain in Musculoskeletal Diseases: Do You Know Your Enemy?

Abstract

Musculoskeletal pain is a condition that characterises several diseases and represents a constantly growing issue with enormous socio-economic burdens, highlighting the importance of developing treatment algorithms appropriate to the patient's needs and effective management strategies. Indeed, the algic condition must be assessed and treated independently of the underlying pathological process since it has an extremely negative impact on the emotional and psychic aspects of the individual, leading to isolation and depression. A full understanding of the pathophysiological mechanisms involved in nociceptive stimulation and central sensitization is an important step in improving approaches to musculoskeletal pain. In this context, the bidirectional relationship between immune cells and neurons involved in nociception could represent a key point in the understanding of these mechanisms. Therefore, we provide an updated overview of the magnitude of the musculoskeletal pain problem, in terms of prevalence and costs, and summarise the role of the most important molecular players involved in the development and maintenance of pain. Finally, based on the pathophysiological mechanisms, we propose a model, called the "musculoskeletal pain cycle", which could be a useful tool to counteract resignation to the algic condition and provide a starting point for developing a treatment algorithm for the patient with musculoskeletal pain.

Keywords: chronic pain; interdisciplinarity; musculoskeletal diseases; musculoskeletal pain; nociceptive stimulation; sensitization.

Figure 1

Main risk factors associated with musculoskeletal pain. Some risk factors may promote the musculoskeletal pain onset directly or by influencing lifestyle and work activity. Smoking and a diet high in animal protein and fat are factors that amplify the chronic pain associated with musculoskeletal disorders by stimulating immune cells to release inflammatory mediators. Depression, which can lead to substance and drug abuse and suicide risk increase, is also associated with musculoskeletal pain onset. Finally, a sedentary lifestyle, correlated with reduced muscle mass and strength, fracture risk increase and obesity, is among the main factors promoting chronic pain development.

Figure 2

The pain development process occurs through a bidirectional crosstalk between immune cells and nociceptive neurons. During inflammation, cells of the immune system secrete a wide variety of molecular mediators responsible for nociceptive stimulation. These include lipid mediators, such as prostaglandin E2 (PGE2) and leukotriene B4 (LTB4); cytokines, such as interleukin-1 beta (IL1β), interleukin-6 (IL-6), tumour necrosis factor-α (TNFα), and interleukin-17A (IL-17A); growth factors and neurotransmitters, such as nerve growth factor (NGF), histamine, serotonin (5-HT), and bradykinin (BK). All these mediators interact with their receptors on peripheral nerve terminals, causing sensitization to pain.

Figure 3

Musculoskeletal pain cycle. Some musculoskeletal disorders are characterised by an increased inflammatory state and tissue damage, which leads to the release of chemical mediators responsible for the nociceptive response. Consequently, the release of neuropeptides such as calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP) occurs, with a potent vasodilatory action that promotes the extravasation of immune cells to the site of damage. In a pathological context, this chain of events takes on the characteristics of a vicious circle leading to prolonged nociceptive stimulation. The resulting musculoskeletal pain leads to the exacerbation of important risk factors, such as sedentariness and depression, which not only promote musculoskeletal pain but also exacerbate the pathological state by promoting the reinforcement of the cycle.

Figure 4

Possible management algorithm for the patient with musculoskeletal pain. An understanding of the musculoskeletal pain cycle may be the starting point for the development of an appropriate management algorithm for the musculoskeletal pain patient. If the patient understands the risks of a superficial and inconsistent approach, he/she will be more cooperative in accepting the therapy provided by a multidisciplinary team. Particularly, an algologist or pain specialist should play the role of team leader of a specialist team, such as an orthopaedist or bone specialist, a physiatrist or specialist in physical and rehabilitation medicine, a neurologist or nerve specialist, a psychologist and a psychiatrist or mental health specialists, and a rheumatologist or specialist of joints and musculoskeletal system. In addition, if therapy proves ineffective, knowledge of the pain cycle may reduce the likelihood of counterproductive and self-defeating behaviour, promoting greater adherence to therapy.