Nociceptive pain is a physiologic response to tissue injury, the perception that arises from intense stimulation of specialized peripheral sensory neurons (nociceptors) that respond only to noxious (pain) stimuli. Nociceptive pain is subgrouped by location of involved tissues into somatic pain (muscle or connective tissue) and visceral pain (visceral structures) [23]. Nociceptive pain is considered adaptive during tissue healing but maladaptive and pathologic when it persists after healing has occurred.

Centralized pain results from heightened nociceptive sensitivity in the absence of detectable peripheral stimulus and with negligible peripheral inflammatory pathology. The mechanism is poorly understood and is regarded as strictly pathologic as it lacks any evident adaptive function. Centralized pain disorders include conditions such as fibromyalgia, tension headache, and irritable bowel syndrome [14,23,25].

Chest pain is the second leading reason for emergency department visits annually in the United States with approximately 53% of adult visits seeking care for chest pain each year [30]. In one review, the most common diagnoses were musculoskeletal chest pain (20.4%), reflux esophagitis (13.4%), costochondritis (13.1%), stable angina pectoris (10.3%), and unstable angina or possible myocardial infarction (1.5%) [31]. NCCP is frequently observed in the healthcare setting, with as many as 30% of patients undergoing coronary angiography for chest pain showing normal coronary arteries. The prevalence of NCCP is distributed evenly between men and women, but it is over-represented in patients with a diagnosis of gastroesophageal reflux disease [30].

NSAIDs are ineffective for acute exacerbations of chronic functional abdominal visceral pain because peripheral sensitization and visceral nociceptor hyperalgesia are the pain mechanisms rather than acute inflammation. Opioids, tricyclic antidepressants (TCAs), and probiotics represent available agents with demonstrated efficacy. Newly approved and investigational agents with efficacy include peripherally acting serotonergic agents such as the 5-HT3 antagonist alosetron, the 5-HT4 agonist tegaserod, and the kappa-opioid receptor agonist asimadoline [38].

The initial treatment for opioid-naïve patients with severe pain is rapid titration of a short-acting opioid, specifically IV 2–5 mg morphine or equivalent. If the patient is morphine intolerant, IV hydromorphone, oxymorphone, or fentanyl should be substituted. Patients are reassessed every 15 minutes after an IV dose or every 60 minutes after an oral dose. If the pain is unchanged or worse, the dose may be increased by 50% to 100%. If the pain decreases to level 4–6, repeat the same opioid dose and reassess again after 60 minutes for oral or 15 minutes for IV dose. If the pain score decreases to 0–3, the current opioid dose is then continued as needed for the initial 24 hours. Insufficient relief of moderate-to-severe pain at reassessment after two to three opioid cycles should result in a change in route or a change in strategy [23].

Cold therapy can be applied through wraps, gel packs, ice bags, and menthol. It provides relief for pain related to skeletal muscle spasms induced by nerve injury and inflamed joints. Cold application should not be used for patients with peripheral vascular disease. Heat can be applied as dry (e.g., heating pad) or moist (e.g., hot wrap, tub of water) and should be applied for no more than 20 minutes at a time, to avoid burning the skin. Heat should not be applied to areas of decreased sensation or with inadequate vascular supply or for patients with bleeding disorders.

Among primary care patients with back pain, the prevalence of LBP etiology is [21,71,72]:

The proper assessment of the patient with back pain requires vigilance and careful attention for factors and warning signs suggestive of serious or life-threatening disorders. A thorough history and physical examination should be performed on all patients, during which the patient is assessed for the presence of warning signs or ''red flags." Red flags represent alarm symptoms or signs that warrant prompt, specific diagnostic testing, urgent treatment, or referral to a specialist. Among these are weight loss, prior history of cancer, nocturnal or rest pain, age older than 50 years, recent trauma, fever and chills, history of injection drug use, chronic corticosteroid therapy, difficulty urinating, bowel or bladder incontinence, and neurologic deficits such as saddle anesthesia, perianal or perineal sensory loss, or motor weakness in the extremities [67,80]. As an example, there is a common association between spontaneous vertebral fracture and any combination of age older than 70 years, female gender, recent trauma, and prolonged corticosteroid use. There is also a moderate to highly significant predictive value for age older than 50 years, history of prior cancer, unexplained weight loss, and failure of conservative therapy in identifying spinal malignancy [67].

A variety of more complex symptoms and signs is seen in as many as 20% to 30% of affected individuals. These include allodynia and hyperalgesia in the neck region and possibly in remote peripheral sites; cold hyperalgesia (a negative prognostic indicator); spinal cord hyperexcitability demonstrated by heightened flexor withdrawal responses; substantially reduced neck movement; and motor control deficits such as abnormal muscle recruitment in the neck and shoulder girdles. For many patients, these difficulties eventually resolve following recovery from injury; for others, they do not, and over time they contribute to chronic pain and disability. Collectively, the persistent discomfort and other associated syndromes described are referred to as whiplash-associated disorders or WAD [28,99,104]. Chronic pain following whiplash injury is aggravated by cervical spine motion, tension, sitting, or reading and by push/pull activities such as vacuuming. Prolonged or repetitive use of the shoulder girdle muscles, such as when carrying items or washing dishes, may induce radiating pain in the upper extremities [28,99] High initial levels of pain and/or disability represent the strongest indicator of poor recovery. Low risk factors for developing protracted post-whiplash symptoms include crash impact at the rear of the vehicle, ability to sit instead of lie down in the emergency department, ability to be ambulatory without interruption, delayed neck pain onset, and absence of midline cervical spine tenderness. The greatest gains in recovery occur during the first three months, following which symptom reduction tends to plateau [28].

Traditionally, osteoarthritis was thought to affect primarily the articular cartilage of synovial joints; however, pathophysiologic changes also are known to occur in the synovial fluid, as well as in the underlying (subchondral) bone, the overlying joint capsule, and other joint tissues [127]. Nociceptor innervation is found in the intra-articular and periarticular structures of the joint, including the menisci, adipose tissue, synovium, and periosteum; cartilage is aneural [127]. The increase in cytokine release that accompanies joint inflammation and pathologic structural changes characteristic of osteoarthritis results in peripheral sensitization that manifests as primary hyperalgesia, spontaneous pain, and pain with normally innocuous movement. Bone marrow lesions, synovitis, effusions, and possibly meniscal abnormalities represent the specific pathologic features that contribute to pain in osteoarthritis [127].

Although the natural history of rheumatoid arthritis shows marked variability among patients, it is believed the disease follows at least three courses [154]:

Sarilumab injection received FDA approval in 2017 for the treatment of rheumatoid arthritis in patients with moderately-to-severely active disease who have had an inadequate response or intolerance to one or more DMARDs [36,162,168,169]. Approval of sarilumab was based on the results two trials [156]. In the first trial, patients treated with sarilumab plus methotrexate had reduced signs and symptoms and improved physical function and demonstrated significantly less radiographic progression of structural damage compared with placebo plus methotrexate [170]. The second trial produced similar results as the first trial [171]. Sarilumab may be use as monotherapy or in combination with methotrexate or other conventional DMARDs. The usual dose is 200 mg subcutaneously once every two weeks [36,168]. For patients with early rheumatoid arthritis (less than six months in duration) who have never taken a DMARD, oral DMARD monotherapy (preferred agent: methotrexate) is recommended as first-line treatment [162]. Sulfasalazine is similarly effective, and leflunomide may provide comparable results [135,158,163]. In methotrexate-naïve patients with early rheumatoid arthritis, symptom response is similar between methotrexate and adalimumab or etanercept, and improvement in functional capacity is similar between methotrexate and adalimumab [163]. Adding prednisone reduces radiographic progression and joint erosion but increases risk of adverse events. Biologic DMARDs are more effective than oral DMARDs in limiting radiographic evidence of progression [135,158].

Updated guidelines for the management of gout were published by the ACR in 2020 [184,188,189]. The initial steps include patient education, testing to rule out other causes of hyperuricemia, and evaluation of the disease burden to determine appropriate treatment. All patients with hyperuricemia and established gout should be advised to begin dietary modification. This involves avoiding organ meat high in purine content, high-fructose corn syrup, and excessive alcohol use. Portions of high purine-content seafood, sugar, and salt should be limited. The ideal diet will include low- or non-fat dairy products and vegetables. Other lifestyle modifications can also assist in managing gout, including weight loss in overweight patients, regular exercise, smoking cessation, and adequate hydration [184,188,189].

Urate-lowering therapy should be initiated in all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares [189]. Therapy should be started within 24 to 36 hours of the onset of an acute gout attack unless otherwise contraindicated. Urate-lowering therapy is not recommended for patients experiencing their first flare, or for patients with asymptomatic hyperuricemia (serum urate >6.8 mg/dL) with no prior gout flares or subcutaneous tophi [189]. Allopurinol (≤100 mg/day) is the preferred first-line agent. Febuxostat (≤40 mg/day) is an acceptable alternative [189]. Probenecid may be used as an alternative to allopurinol or febuxostat if there is contraindication or intolerance to these preferred agents. However, probenecid should be avoided in patients with a history of urolithiasis [184,188,189].

The severity and frequency of migraine attacks tend to diminish with increasing age. After 15 years of suffering migraines, approximately 30% of men and 40% of women no longer have migraine attacks [199]. Comorbid conditions may occur with migraine, including anxiety and mood disorders, allergies, other chronic pain disorders (e.g., fibromyalgia, low back pain), hypertension, and epilepsy. Migraine with aura is also a risk factor for ischemic stroke, especially in women with frequent attacks [199]. Negative prognostic factors include early age at onset, psychosocial stressors, and psychiatric comorbidity [199].

If symptoms persist for more than 72 hours, the treatment of choice is DHE; however, DHE should never be given within 24 hours of ingesting any triptan or ergot derivative [193,195]. Other absolute contraindications to DHE use include pregnancy, history of ischemic heart disease, history of variant angina, severe peripheral vascular disease, cerebrovascular disease, hemiplegic or basilar-type migraine, and onset of chest pain following DHE test dose. In these cases, treatment consists of chlorpromazine, valproate sodium IV, magnesium sulfate IV, or prochlorperazine.

Tension-type headache is further subtyped based on frequency of symptoms. These headaches are classified as episodic tension-type headache (<15 headache days/month) or chronic (≥15 day/month for 3 months) [193].

The pain of endometriosis is in part caused by a chronic, localized inflammatory disorder involving dysregulated immune and endocrine function. Significant immune system alterations have been found that facilitate survival and growth of displaced endometrial tissue. In brief, the immune response is elicited by displaced endometrial tissue that fails to clear the menstrual debris yet retains the capacity to generate proinflammatory cytokines and chemokines that stimulate ongoing inflammation. Under these conditions, endometrial cells exhibit a hypersensitivity to inflammatory stimuli, which serves to propagate tissue growth within the peritoneal cavity [221,226]. In addition, the usual endometrial responsiveness to progesterone is blunted, resulting in the loss of local immunosuppressive activity of this steroid and disordered communication between endocrine and immune systems. It is unclear whether progesterone resistance is the cause or effect of disease progression. It is possible that, in some women, altered immune function produces progesterone resistance, while in others, resistance represents an endometrial phenotype that promotes the persistence and progression of the inflammatory state [220].

First-line pharmacotherapy often includes the use of NSAIDs and/or acetaminophen for acute pain relief. However, a series of Cochrane analyses found no evidence that NSAIDs are effective in managing pain caused by endometriosis and that they may cause unintended effects [233]. A comparative review of eight widely used guidelines found agreement on the use of combined oral contraceptive pills and progestins (e.g., medroxyprogesterone acetate, norethisterone, dienogest) [234]. If this approach is not effective in managing painful episodes, second-line options include [221,222,229,230,231,232]:

Third-line therapies, reserved for women who do not respond to first- and second-line approaches, include gestrinone (not available in the United States) and danazol [36,222,229,230,231,232]. However, a Cochrane review found no benefit from ovulation suppression in subfertile women with endometriosis who wish to conceive [235].

Several complementary therapies have been assessed for efficacy in addressing symptoms of endometriosis. Both acupuncture and high-frequency transcutaneous electrical nerve stimulation (TENS) have shown promise. Two randomized studies evaluated specific versus sham acupuncture for endometriosis pain and both reported significantly better pain relief with true acupuncture [236,237]. No RCTs supporting the utility of TENS have been published [222,229,230,231,232]. Chinese herbal medicine may be helpful, although almost all supporting evidence has been published in Chinese journals and may be difficult to replicate.

Surgery

The guidelines agree that laparoscopic surgical removal of ectopic endometrial tissue is first-line therapy for painful endometriosis [222,229,230,231,232]. Laparoscopic surgery is preferred over laparotomy in most cases. Lesions should be excised after identification, especially in cases of deep endometriotic lesions. Laparoscopic excision is preferred for ovarian endometriomas to minimize recurrence of endometrioma and pain. However, the best surgical approach to deep endometriosis is not known. Highly specialized surgical expertise is required for surgery of deep endometriosis and should only be performed within specialized centers [222,229,230,231,232].

In the United States, an estimated 100,000 people are afflicted by sickle cell disease and 2,000 infants are born with sickle cell disease annually [238,239]. Sickle cell disease is predominantly found in persons of African descent; other groups with heightened risk include those of South or Central American, Caribbean, Mediterranean, Indian, and Saudi Arabian descent (typically areas in which malaria is endemic) [239,240]. The condition is chronic and lifelong and is associated with a decreased lifespan. Median survival in the United States is 42 years for men and 48 years for women, although innovations in disease management are improving long-term survival [241].

Pain is the primary reason that medical care is sought by persons with sickle cell disease, usually during an acute pain crisis. Acute pain crises are commonly triggered by dehydration, infection, stress, and changes in body temperature and unfold in four distinct phases [238]:

For prevention of acute pain episodes, hydroxyurea is most often used [240]. This agent acts by ribonucleotide inhibition and induction of fetal hemoglobin, which possesses superior affinity for oxygen binding. It is FDA-approved for use in adults and children 2 years of age and older and is the only treatment for sickle cell disease that modifies the disease process. Hydroxyurea is effective in reducing pain crises, painful symptoms, need for blood transfusion, and mortality. As such, it represents the backbone of sickle cell disease management. The usual daily oral dose is 15–35 mg/kg [36,240]. Inconsistent adherence reduces its efficacy, and patient adherence can be challenged by the three- to six-month delay between treatment initiation and the onset of clinical response. More frequent follow-up contact with support and encouragement may be needed in some patients.

Although difficult to estimate, 500,000 to 1 million people are believed to be currently afflicted with postherpetic neuralgia [249]. The risk of developing postherpetic neuralgia following acute zoster is strongly associated with age. The incidence of postherpetic neuralgia is 5% in those younger than 60 years of age, 10% in those 60 to 69 years of age, and 20% in those 80 years of age or older [250]. Other risk factors for postherpetic neuralgia include [248,251]:

The most important strategy for postherpetic neuralgia is prevention of herpes zoster and neuralgia with the VZV vaccine, approved by the FDA in 2006 and indicated for use in adults 50 years of age and older with a history of chickenpox. A second, more effective vaccine was licensed by the FDA in 2017, also for use in adults 50 years of age and older [248]. Two doses of the vaccine decreases the incidence of herpes zoster by 98% and reduces the incidence of severe varicella by 100% [248]. Moreover, the vaccine also reduces the incidence and severity of postherpetic neuralgia by two-thirds in patients who do develop zoster after vaccination [248]. However, the vaccine remains seriously underused due to provider and patient unawareness and other factors. With postherpetic neuralgia potentially leading to severe, life-altering chronic pain, the vaccine should be offered to every patient older than 50 years of age with a history of chickenpox [248,254].

Of individuals with limb amputation, 60% to 80% experience phantom limb pain [263]. Post-amputation pain can manifest in the residual limb or be referred from a site in the former limb. Phantom-limb pain is commonly confused with pain in the area adjacent to the amputated body part, which is referred to as residual limb pain or stump pain. Residual limb pain and phantom limb pain can co-occur. It is important to note that the term "residual limb pain" is not strictly a diagnosis, as it does not acknowledge the underlying mechanism [264].

Psychotherapy has been found effective in reducing pain from amputation and can inform the pain physician of the underlying mechanism (e.g., muscle spasm or vascular insufficiency) and thus assist in pharmacologic selection [263]. Mirror therapy, which involves the patient viewing the reflection of their intact limb as he or she performs exercises with the amputated limb, is efficacious in upper and lower extremity phantom limb pain; however, most experts agree that further research is needed [271,272,273,274]. A pilot study evaluated pain outcomes in 10 patients with phantom limb pain using eye movement desensitization and reprocessing, a psychological treatment directed at reprocessing emotional and somatosensory memories. At three-months follow-up, four were pain-free and four had reduced pain. At 2.8-years (mean) follow-up, three were pain-free and two had reduced pain (and four dropped out). These encouraging results require larger-scale replication [268].

No single drug has shown universal effectiveness in phantom limb pain control [269]. However, evidence of morphine and tramadol efficacy is robust and consistent, and both received an efficacy rating of "A" by the European Federation of Neurological Societies Task Force [256]. Patients with phantom limb pain may require higher-dose morphine and tramadol; the daily effective dose was found to be 70–300 mg and 523 mg, respectively [269].

Among patients with diabetes, as many as 50% of patients have mild-to-severe nerve damage (diabetic neuropathy), and roughly 50% of those 40 years of age and older have impaired foot sensation [278]. Pain with diabetic neuropathy, termed painful diabetic neuropathy, usually involves sensory-motor neurons and is experienced as burning, shooting, or stabbing pain. The feet or lower legs are almost always the sites of pain, and when pain occurs in the arms or hands, it is usually preceded by leg symptoms. Some patients may experience tingling, numbness, or loss of feeling in the extremities [279,280]. In one study, the prevalence of painful diabetic neuropathy in adults with type 2 diabetes was found to be 26.4% [281]. Another study found a prevalence of 21%; however, painful symptoms, with or without diagnosed neuropathy, occur in one-third of all patients with diabetes [282].

Diabetic focal neuropathy appears as sudden-onset pain or loss of motor function that involves the head, torso, or leg. Pain may become severe, but the neuropathy usually improves over several weeks or months and does not create long-term nerve or tissue damage [279]. Focal neuropathy that occurs in an extremity is also considered to be peripheral [280].

Alpha-lipoic acid (ALA) bears special mention as the only pain therapy for diabetic neuropathy that potentially addresses the underlying pathophysiologic process (i.e., reduction of oxidative stress) [295]. One study randomized 460 patients with diabetes to oral ALA 600 mg once daily or placebo [296]. Four-year follow-up found significantly greater numbers of ALA patients reporting symptom improvement with fewer showing progression. A 2006 study found that five weeks of oral ALA 600–1,800 mg once daily resulted in significant improvement compared to placebo in stabbing and burning pain, paresthesia and numbness, and overall patient rating of efficacy [297]. However, these studies did not specifically evaluate changes in nerve conductivity. A 2012 systematic review evaluated 15 RCTs of ALA (mostly from Chinese-language journals) that used nerve conduction velocities as an end point for assessing the effectiveness of therapy on the underlying neuropathologic condition [298]. The pooled outcomes indicate that treatment with ALA (300–600 mg/day IV for two to four weeks) can lead to significant improvement in motor nerve conduction velocity, sensory nerve conduction velocity, and painful symptoms. A 2015 randomized withdrawal trial demonstrated painful symptom reduction from an average total symptom score of 8.9 to an average total symptom score of 2.5 over a 20-week period with a 600 mg/day ALA dose [295].

The cardinal feature of CRPS is continuous and progressively intense pain that is substantially disproportionate to the severity of the initiating injury or illness. An example is finger or toe injury that results in widespread pain involving the entire arm or leg or that transfers to the opposite extremity. Pain is usually comprised of stimulus-evoked mechanical and thermal allodynia and hyperalgesia and deep somatic allodynia [303]. Emotional stress can exacerbate the pain response [299].

A 5% lidocaine patch may have efficacy in some local or focal CRPS phenomena such as allodynia [305]. Dimethyl sulfoxide (50% cream for two months) has been found to significantly reduce pain compared with placebo [305]. Topical capsaicin is often found intolerably painful and unacceptable by patients with CRPS.

The cardinal features of fibromyalgia are widespread pain and tenderness in multiple regions of the body that are not attributable to another condition. In addition to pain and tenderness, patients with fibromyalgia often experience [314,315]:

Abnormal reactivity to sensory input is also characteristic of fibromyalgia. This includes [316]:

The three FDA-approved drugs for fibromyalgia—duloxetine, milnacipran, and pregabalin—have been found superior to placebo on many measures, the exceptions being duloxetine for fatigue, milnacipran for sleep disturbance, and pregabalin for depressed mood [323]. Comorbid depression may not respond to the primary agent or the dose used to treat fibromyalgia, and separate antidepressant therapy may be required [322]. A 2012 Cochrane review of monoamine oxidase inhibitor efficacy in fibromyalgia found statistically significant improvement with pirlindole versus placebo in pain, tender points, and patient and physician assessment [324].