Chronic Skeletal Muscle Pain Management Abstract: Chronic skeletal muscle pain in the human body is influenced by a variety of factors, and its disposition is very different from acute skeletal muscle pain. Knowledge of the physiology of chronic pain transmission, regulation, and perception is important in the management of pain. Pharmacologic and nonpharmacologic treatments such as psychotherapy and biofeedback can be used in the management of patients with chronic pain. There is now more evidence-based medical evidence for the treatment of chronic pain of all causes. Tramadol, selective tricyclic antidepressants, serotonin reuptake inhibitors, antispasmodic drugs, opioids, and diclofenac have been used in the treatment of pain with reasonable efficacy. However, it should be noted that there is a correlation between the specific efficacy of the drug and the type of disease being treated. Orthopaedic surgeons should be familiar with the characteristics of these drugs in the clinical diagnosis and treatment process, and should apply the drugs to treat chronic musculoskeletal pain in a safe and rational manner. Zhang Yafeng, Department of Spine and Orthopedics, Wuxi Hospital of Traditional Chinese Medicine (Wuxi TCM) Chronic musculoskeletal pain is a huge challenge for orthopedic surgeons in terms of diagnosis, treatment and prognosis. It has been reported that the annual medical cost of chronic pain control in the United States exceeds 100 billion dollars, and the economic losses caused by chronic pain in terms of long-term physical dysfunction, reduced work capacity, and decreased quality of life are immeasurable. Chronic musculoskeletal pain Chronic musculoskeletal pain Chronic pain is a complex, multifaceted physiologic phenomenon that does not have a precise definition. Chronic pain is generally considered to be “pain that persists for 6 months without relief” or “pain that persists longer than the expected time for the pain to improve”. Orthopedic surgeons usually encounter a variety of patients with chronic musculoskeletal pain in their outpatient clinics, such as multiple traumas (80% of patients with chronic pain 1 year after surgery), amputations (more than 50% of patients with chronic pain 1 year after surgery), and hip and knee arthroplasties (more than 10% of patients with chronic pain 1 year after surgery). There is no standardized grading scale for chronic pain, but the description of chronic pain usually includes the location (e.g., lumbar, pelvic, inguinal, etc.) and the cause or nature of the pain (e.g., neurogenic, degenerative, tumorigenic, myofascialigenic). Physiologically, chronic pain symptoms may be the result of the interaction of multiple factors. Most typically, as in patients with low back pain, the source of pain may include, among others, spontaneous lumbar degeneration, neurologic, myofascial, and psychological. There is now strong research evidence suggesting that chronic pain is often comorbid with depression, anxiety, and other psychosomatic disorders, such as somatoform psychosis, which adds to the difficulty of diagnosing and treating chronic pain. Nearly 50% of patients with chronic pain have a mood disorder (e.g., major depression or bipolar disorder), and anxiety is also present in nearly 50% of patients with chronic pain, with some patients having both conditions. In patients with psychiatric disorders, the presence of chronic pain can significantly affect patient outcomes. At the same time, patients with psychiatric disorders tend to exaggerate the degree of chronic pain in their descriptions of chronic pain, and their response to pain treatment is often overly negative, interfering with the physician’s judgment of the efficacy of pain treatment. Patients with somatoform psychiatric disorders usually complain of pain that cannot be described by normal pathophysiology. These patients should be referred to psychiatry for a mental status evaluation prior to pain management. Patients with chronic musculoskeletal pain need to be excluded from other organic pathologies before a diagnosis of chronic musculoskeletal pain can be made. Hypoperfusion, compression neurosis, fibromyalgia, and complex regional pain syndromes can usually be well differentiated, and better outcomes can be achieved with treatment. Pain Pathophysiology The first in vivo mechanisms of pain conduction were reported in the 17th century by philosophers and scientists such as Rene. In his model of conduction, which included a peripheral pain perception system and a central pain receptor system, he visualized that when the skin on the bottom of the foot is burned by fire, pain is transmitted as if a rope is pulled from the bottom of the foot and tied to a bell inside the brain, and when the bell is rung, the pain is transmitted to the brain (Fig. 1). Rene et al. established a model of pain transmission mechanism in the next few hundred years has not been further developed, in the 1960s, scientists found that the way of pain transmission is not a one-way, direct linear conduction, but dynamic, multi-linear signaling mode, pain transmission process regulated by a variety of factors. Nowadays, scientists believe that pain is strictly differentiated into three regions in the body’s conduction process. Figure 2 shows the three regions of pain transmission, and Table 1 shows that different pain medications act on different levels of pain transmission. Traditional Medications NSAIDs, Aspirin, Acetaminophen NSAIDs are the most commonly used pain medications by orthopedic surgeons.NSAIDs and aspirin have analgesic, anti-inflammatory, antipyretic, and COX inhibitory effects. Acetaminophen tablets have similar analgesic and antipyretic effects, but no anti-inflammatory effects. Although these drugs are effective in acute pain, they are less effective in the treatment of chronic pain.The analgesic effects of NSAIDs and aspirin are related to their mechanism of reducing inflammatory factors. C-fiber nociceptors in peripheral nerves are sensitive to prostaglandins and leukotrienes, and the production of these substances can be blocked by the COX-inhibitory effects of NSAIDs. However, these peripheral inflammatory mediators may not be predominant in some chronic pain conditions, making NSAIDs drugs relatively ineffective in the treatment of chronic pain. In a meta-analysis of the use of NSAIDs in patients with low back pain, it was found that NSAIDs drugs were not significantly effective in relieving pain in patients. Symptomatic knee osteoarthritis, however, is different, and the AAOS guidelines on symptomatic knee osteoarthritis also recommend the use of selective, nonselective, and classical NSAIDs for these patients. Based on the available research evidence and guidelines, the use of NSAIDs in patients with osteoarthritis of the knee can result in better pain relief than in the placebo group. Although there are currently conflicting clinical views on the use of NSAIDs for the treatment of chronic pain, a high proportion of patients are still prescribed these medications at the time of their visit to the clinic or purchase similar medications on their own. These drugs are prone to major side effects, such as gastrointestinal reactions, when used for extended periods of time. Recent studies have highlighted the potential cardiovascular risk of some NSAIDs. COX-2 selective inhibitors may reduce gastrointestinal side effects, but their effects on cardiovascular, renal, and cerebrovascular function remain unclear. Opioids Morphine has been used for pain relief for more than 2 centuries. Available research evidence suggests that morphine can act on peripheral, spinal, and supraspinal pain components. Morphine and opioid analogs inhibit presynaptic signaling in C-fibers at the peripheral level. At the spinal and supraspinal levels, morphine reduces the excitatory strength of pain perception and signaling within central structures. Morphine analogs are effective in the treatment of acute pain but less effective in chronic pain. Although the available research evidence suggests that modulation of opioid receptors reduces pain, most of the research evidence suggests that the long-term use of opioids is unsatisfactory for pain management, probably due to drug tolerance that tends to occur during opioid use. A review of the literature has reported finding that opioid addiction can exceed 50% with the use of opioids for the treatment of non-cancer pain; and that the side effects of opioids (constipation, nausea, dyspepsia, headache, euphoria, confusion, drowsiness, lethargy, and urinary retention) are significantly correlated with the duration of their use. Fentanyl patches and oral morphine-based immediate-release medications are less effective in treating chronic pain. The effectiveness of the medications declined significantly after more than 6 months of treating chronic non-cancer pain. Long-term use of opioids is not recommended in clinical practice due to higher drug tolerance, addiction and greater side effects. However, these medications may be considered for persistent chronic pain. Alternative medications Antispasmodics Antispasmodics can cause hyperresponsive neurons to show a sustained attenuation of their responsiveness. Chronic pain may be a consequence of neuronal hyperreactivity in pain transmission and modulation in the dorsal horn of the spinal cord, which can be effectively attenuated by sustained attenuation of antispasmodic drugs such as gamma-aminobutyric acid inhibitors, sodium channel organizers, and other related effects. A recent meta-analysis of chronic pain pharmacotherapy found that gabapentin reduced chronic pain levels by up to 50% or more compared to a placebo group in the treatment of neurogenic pain, intermittent claudication, spinal injuries, and other neurologic conditions. Gabapentin and pregabalin are currently the first-line medications for the treatment of chronic skeletal muscle pain (back pain, neuralgia). Similarly, other high-quality research evidence has found that carbamazepine and others can reduce chronic nerve pain caused by trigeminal nerve and diabetic neuropathy, among others. Antidepressants Antidepressants can increase serotonin, norepinephrine and dopamine concentrations in the central nervous system. Antidepressants such as selective norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors (SSRIs) are usually categorized according to the primary mechanism of action; tricyclic depressants also inhibit the reuptake of serotonin and norepinephrine. These drugs increase the concentration of serotonin and norepinephrine in the central nervous system, which downregulates the conduction of pain across the spinal cord and spinal cord. In addition, in chronic pain patients with mood disorders, antidepressants may also improve chronic pain by alleviating the patient’s psychospiritual disorders. Available evidence in the literature suggests that the therapeutic dose of antidepressants for chronic pain is much lower than their dose for psychiatric disorders. There is also research evidence that improvement in pain symptoms can be obtained with antidepressants alone in patients who do not have depressive symptoms. More in-depth research is needed on the relationship between mental illness and chronic pain at this late stage, and although the relationship is currently not well understood clinically, the available research evidence clearly shows that some tricyclic antidepressants and SSRIs are significantly helpful in improving quality of life, exertion, sleep disturbances, and pain intensity in patients with chronic pain. Tramadol The exact mechanism of action of tramadol is unknown, and studies have shown that it has similar effects to opioids and antidepressants. Similar to opioids, tramadol activates u opioid receptors, leading to downregulation of central nervous system pain transmission; and similar to antidepressants, it has mild CNS serotonin and norepinephrine reuptake inhibitory effects. Tramadol extended-release analogs are effective in the treatment of chronic pain (Table 3). Multiple double-blind randomized controlled trials suggest that tramadol extended-release tablets significantly improve pain symptoms in patients with chronic osteoarthritis and low back pain. Compared with opioids, the efficacy of tramadol extended-release tablets is similar, but its human resistance and side effects, etc. are smaller, but because of the u-receptor agonism of tramadol, it also has certain opioid side effects, such as gastrointestinal tract inhibition, sedation and addiction. Muscle relaxants Cyclobenzaprine is the most thoroughly studied muscle relaxant, and its exact mechanism of action is unknown. However, these drugs have a tricyclic molecular structure similar to that of tricyclic drugs, so scholars believe that their mechanism of action may be similar to that of tricyclic drugs, i.e., to increase the concentration of norepinephrine in the central nervous system, and their side effects are also similar to those of tricyclic drugs. Cyclobenzaprine functions at the spinal cord and supraspinal levels. A systematic analysis including 21 studies found better results in relieving acute pain and muscle spasms than the placebo group, but research evidence is lacking for its prolonged effects. Tizanidine is a class of alpha2 adrenoceptor agonists that inhibit transmitter release from pain interneurons at the spinal cord level. Although there is no clear research evidence to support its long-term use in chronic pain, limited reports in the literature suggest that tizanidine is more effective in the treatment of myofascial-related back and neck pain. Because there is no clear clinical evidence to support the long-term use of antispasmodic medications in chronic pain, we do not recommend these medications as first-line agents for the treatment of chronic pain. Topical pain medications Lidocaine patches block gated sodium channels in peripheral nerve nociceptors. Lidocaine patches provide mild relief of chronic pain caused by osteoarthritis, low back pain, and other neuropathies. Topical pain medication applications can reduce the systemic side effects of intravenous or oral analogs. The use of topical NSAIDs such as diclofenac is now beginning to increase gradually, and their long-term therapeutic effects are satisfactory. Skin application of capsaicin can treat chronic pain. Skin application of capsaicin reduces the release of substance P in the surrounding tissues, thereby reducing peripheral nerve irritation. Meta-analysis in the short and medium term found that topical skin application of capsaicin was effective in relieving pain. Based on the current research evidence, we recommend the use of lidocaine patches and topical NSAIDs analogs as first-line agents for the treatment of chronic skeletal muscle pain. Capsaicin can be an alternative to topical application, especially for chronic pain of neurogenic origin. Menthol and methyl salicylate are two of the more common over-the-counter classes of medications that have been shown to have mild to moderate analgesic effects on chronic pain. It is important to note that topical application of these drugs has toxic cumulative effects, making their long-term application a relative contraindication. Vitamins Although vitamin C does not have an analgesic effect, the use of this medication can be effective in improving the incidence of localized chronic pain in distal radius fractures. However, there is no long-term research evidence to support the long-term use of vitamin C in chronic skeletal muscle pain. A recently published Meta-analysis found that vitamin D was not effective in improving chronic pain in patients and therefore does not recommend the use of vitamin D in pain relief. Non-pharmacological treatments Non-invasive treatments Transcutaneous electrical nerve stimulation (TENS) can be used with different frequencies, intensities, and durations of stimulation to produce different pain-relieving effects. The current of electrical stimulation inhibits peripheral pain receptors, while high intensity electrical stimulation activates pain inhibitory afferent neurons in spinal cord segments. TENS is generally safer and can produce some pain relief in patients with low back pain and neuralgia. A systematic review of analyses found mixed clinical results with the use of TENS in the treatment of chronic pain: 13 cases were reported to be effective and 9 cases were reported to be ineffective. Therefore, TENS cannot be used as a first-line protocol for the treatment of chronic pain, but it does have some efficacy in treating chronic pain. Chiropractic therapy may provide short-term pain relief for acute, nonspecific pain, but its effectiveness in treating chronic spinal pain is not yet clear. Other non-invasive therapies, such as extracorporeal shockwave therapy, are also currently of uncertain efficacy and are therefore not considered first-line treatment options for chronic pain. Other non-invasive therapies such as localized heat therapy, cold therapy, therapeutic ultrasound, hyperthermia, resuscitation, and magnetic therapy are not supported by rigorous, high-quality evidence. Invasive therapies Invasive therapies such as acupuncture, local injections at myofascial sites, and epidural hormone injections have been reported for the treatment of chronic pain. The use of acupuncture in the treatment of chronic pain has now gradually increased, especially among patients with low back pain. However, due to the characteristics of acupuncture treatment, it is not possible to conduct high-quality studies on this. Although current research has concluded that acupuncture is effective in the treatment of chronic pain, acupuncture treatment is not recommended as a first-line treatment option. However, for refractory pain, acupuncture treatment does have some efficacy. Myofascial starting point of local injection treatment of chronic pain is more research, but can not yet draw a definite conclusion. For chronic low back pain, epidural hormone injections are the most commonly used measure. Local use of hormones and anesthetics reduces nerve potentials and C-fiber nerve conduction in peripheral pain. A systematic analysis of studies found that current research evidence supports the use of epidural injections over a long period of time (>6 months) for the treatment of chronic low back pain. There is also evidence that lumbar synovial injections of medications can relieve low back pain for more than 6 weeks, but cervical synovial injection therapy is not currently supported by the evidence. Local anesthetic blocks and radiofrequency ablation of the articular branch nerves may provide long-term pain relief. The etiology of low back pain needs to be clarified before recommending a patient for specific invasive treatments.