#98703: Chronic Pain Syndromes: Current Concepts and Treatment Strategies

Guidelines by the Australian and New Zealand College of Anaesthetists emphasize the utility of protective analgesia, an approach that uses pre- and postsurgical analgesia to reduce risk of sensitization [49]. Efficacy in reducing chronic postsurgical pain has been found with combinations of gabapentin, opioids, clonidine, NSAIDs, and the N-methyl-D-aspartate (NMDA) antagonists ketamine and dextromethorphan, with greatest benefit coming from low-dose IV ketamine added to epidural analgesia.

A systematic review of perioperative gabapentin or pregabalin evaluated efficacy in preventing chronic (two or more months) postsurgical pain. Eleven RCTs involving 930 patients were analyzed. All three pregabalin trials found a very large reduction in chronic postsurgical pain (pooled odds ratio [OR]: 0.09; P=0.007), while six of eight gabapentin trials demonstrated a moderate-to-large reduction in chronic pain development (pooled OR: 0.52; P=0.04) [50].

Patients are considered opioid tolerant after receiving ≥60 mg oral morphine (or equianalgesic dose of another opioid) daily for one week or longer. Patients not meeting this threshold are considered opioid naïve. Principles for treating pain in opioid-naïve patients include [23]:

For opioid-naïve patients with mild pain, a trial of NSAIDs or acetaminophen is indicated before titrating a short-acting opioid (e.g., hydrocodone or codeine). If pain is moderate, the National Comprehensive Cancer Network recommends using oral morphine (5–15 mg) as the first-line short-acting opioid [23].

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].

For opioid-tolerant patients with breakthrough pain level ≥4 or pain level <4 with inadequate pain control and function, the rescue dose may be increased by 10% to 20% of the total opioid amount given in the previous 24 hours. Then, assess every 15 minutes after IV dose or 60 minutes after oral dose. If the pain remains unchanged or worsens, administer 50% to 100% of the previous opioid rescue dose [23]. If the pain decreases to a level of 4–6 after the rescue dose, repeat the same opioid dose and reassess after 60 minutes for oral or 15 minutes for IV dose. If the pain score decreases to 0–3, the current opioid dose should be continued as needed for the ensuing 24 hours. If the pain level is unchanged (moderate-to-severe pain) after two to three opioid cycles, change the route or change the overall strategy [23].

A 2013 meta-analysis compared rapid-onset oral fentanyl preparations against oral morphine in onset and effectiveness of breakthrough cancer pain. The results strongly indicated more rapid and superior pain control with fentanyl and suggest buccal tablet, sublingual, or oral transmucosal fentanyl products be considered in place of standard oral morphine therapy for these patients [57].

Subsequent treatment is based on continued patient pain rating score. It is important to remember that all pain levels require regular-dose and rescue-dose opioids, and the approach will depend on the type of pain experienced (Table 2). For persistent moderate pain, continue opioid and adjuvant analgesic titration and consider specific pain syndrome problems and pain specialist consultation. For example, antidepressants and anticonvulsants are first-line adjuvant analgesics for cancer-related neuropathic pain and can improve pain control with partial response to opioids. If persistent pain is severe, also re-evaluate the diagnosis, opioid titration, and adjuvant selection and consider specialist consult.

Complementary approaches may be useful adjuncts to pharmacotherapy. A systematic review was performed of RCTs comparing drug therapy plus acupuncture with drug therapy alone in the treatment of cancer pain. A significant difference was found in pain reduction when acupuncture was combined with pharmacotherapy [58]. Acupuncture typically provides pain relief 15 to 40 minutes after stimulation. Relief seems to be related to the release of endorphins and a susceptibility to hypnosis [59]. The efficacy of acupuncture for relieving pain has not been proven, as study samples have been small. However, acupuncture has been found to be of some benefit for cancer-related pain when the therapy is given in conjunction with analgesic therapy [58].

Massage, which can be broadly defined as stroking, compression, or percussion, has led to significant and immediate improvement in pain in the hospice setting [60]. Both massage and vibration are primarily effective for muscle spasms related to tension or nerve injury, and massage can be carried out with simultaneous application of heat or cold. Massage may be harmful for patients with coagulation abnormalities or thrombophlebitis [59].

Focused relaxation and breathing can help decrease pain by easing muscle tension. Progressive muscle relaxation, in which patients follow a sequence of tensing and relaxing muscle groups, enables patients to feel more in control, provides distraction from pain, and may lessen the level of ambient discomfort [59]. This technique should be avoided if the muscle tensing will be too painful.

Other nonpharmacologic interventions reportedly helpful for some patients but lacking a strong evidence base include manipulative and body-based methods (such as application of cold or heat and positioning), yoga, distraction, and music or art therapy. The application of cold and heat are particularly useful for localized pain and have been found to be effective for cancer-related pain caused by bone metastases or nerve involvement, as well as for prevention of breakthrough incident pain [59]. Alternating application of heat and cold can be soothing for some patients, and it is often combined with other nonpharmacologic interventions.

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.

Changing the patient's position in the bed or chair may help relieve pain and also helps minimize complications such as pressure ulcers, contractures, and frozen joints. Members of the healthcare team as well as family members and other informal caregivers can help reposition the patient for comfort and also perform range-of-motion exercises. Physical and occupational therapists can recommend materials, such as cushions, pillows, mattresses, splints, or support devices.

Hatha yoga is the branch of yoga most often used in the medical context, and it has been shown to provide pain relief for patients who have osteoarthritis and carpal tunnel syndrome but it has not been adequately studied in patients with cancer-related pain. Yoga may help relieve pain indirectly in some patients through its effects on reducing anxiety, increasing strength and flexibility, and enhancing breathing [61]. Yoga also helps patients feel a sense of control.

Methods to provide distraction from pain come in a wide variety of methods, including reciting poetry, meditating with a calm phrase, watching television or movies, playing cards, visiting with friends, or participating in crafts. Music therapy and art therapy are also becoming more widely used as nonpharmacologic options for pain management. Listening to music has been shown to decrease the intensity of pain and reduce the amount of opioids needed, but the magnitude of the benefit was small and the review was withdrawn [62]. Research suggests that art therapy contributes to a patient's sense of well-being [63]. An art therapist can help with reflection on the implications of the art work. Art therapy is especially helpful for patients who have difficulty expressing feelings with words, for physical or emotional reasons.

Opioids are associated with many side effects, the most notable of which is constipation, occurring in nearly 100% of patients. The universality of this side effect mandates that once extended treatment with an opioid begins, prophylactic treatment with laxatives must also be initiated. The recommended first-line treatment is a stimulant laxative with or without a stool softener and/or polyethylene glycol. If inadequate, use metoclopramide and/or a saline enema. Finally, if the constipation is still persistent, methylnaltrexone or naloxegol should be considered. If refractory, consider neuraxial analgesics, neuroablative techniques, or other interventions to decrease pain, alleviate constipation, and/or reduction of opioid dose [23].

Nausea may occur alone or with vomiting, a neuromuscular reflex. Nausea and vomiting can exacerbate pain and contribute to insomnia, fatigue and weakness, and anorexia. It can also limit activities and cause distress for the patient and family. Nausea is the result of stimulation of one of several pathways: the chemoreceptor trigger zone (located in the medulla), the cortex of the brain, the vestibulocochlear nerve, or the GI tract. Prochlorperazine, thiethylperazine, metoclopramide, or haloperidol should be used to address this complication. If nausea and vomiting persist, add therapies that target different mechanisms of action, such as corticosteroids or the 5-HT3 receptor antagonists granisetron or ondansetron. Tolerance to nausea and sedation usually develops within three to seven days. Opioid rotation should be considered if nausea or vomiting remains a problem despite treatment [23].

Other possible side effects include pruritus, sedation, and delirium. Pruritus is generally addressed using diphenhydramine or promethazine, although low-dose naltrexone or nalbuphine may be added in severe or intractable cases. If pruritus continues despite treatment, switch opioids. Sedation may be treated with methylphenidate, dextroamphetamine, modafinil, or caffeine. First-line choices for delirium include haloperidol, olanzapine, or risperidone. Persistent delirium may require a switch to another opioid [23].

The pathophysiology underlying the transition from acute to chronic nonspecific LBP is not yet fully explained, but several likely mechanisms have been identified. These include interaction between inflammatory and neuropathic processes, patient-specific factors, factors related to the precipitating injury or trauma that induce peripheral sensitization, and central sensitization [26].

Muscle tissue shows a high innervation density of nociceptors containing the neuropeptide substance P, calcitonin gene-related peptide (CGRP), and somatostatin, released with nociceptor activation by noxious stimuli. Substance P and CGRP induce local vasodilatation and edema, triggering the release of bradykinin from plasma proteins and increasing the excitability of nociceptor nerve endings. Soft tissue overuse, ischemia, or inflammation elevates tissue concentrations of bradykinin and serotonin (5-HT) to induce the release of arachidonic acid from cell membranes by phospholipase A2. Prostaglandin E2 is released, and a proinflammatory cascade is triggered that results in muscle nociceptor sensitization. Prolonged transmission of nociceptive stimuli to the dorsal horn results in dorsal horn neuron hyperexcitability caused by the release of substance P and glutamate from the spinal terminals of muscle afferents and by the ensuing activation of NMDA channels in dorsal horn neurons. This leads to expansion of the receptive field of the muscle nerve and central sensitization. Transition from acute to chronic LBP involves structural changes that perpetuate the functional changes. Numerous mechanisms are involved, including cell death, primarily in inhibitory interneurons due to bombardment by intense nociceptive stimuli. Decreasing the population of these neurons promotes chronic disinhibition and continuous generation of pain by nociceptive neurons with or without the presence of noxious stimuli [65,67,76].

Most persons with degenerative spine changes such as disk herniation, spinal stenosis, and foraminal stenosis do not have pain. In patients who do have pain with disk herniation and associated radiculopathy, it is thought to be primarily due to chemical inflammation and not merely mechanical compression. Inflammatory mediators play an important role in the pathogenesis of lumbar radicular pain and LBP in lumbar degenerative diseases. The cytokine interferon gamma (IFN-γ) contributes to the biochemical cascade, triggering pain in lumbar radicular pain [77]. Epidural corticosteroid injection is effective in suppressing the functional activity of inflammatory mediators such IFN-γ and phospholipase A2, decreasing pain from inflammation in the epidural space and surrounding nerve roots [65].

Pain resulting from injury or lesion to a peripheral nerve, dorsal root ganglion, or dorsal root arising from trauma, compression, inflammation, or ischemia represents peripheral neuropathic pain. In CLBP with a peripheral neuropathic pain component, mechanisms that alter the structure and function of peripheral nerves and their central terminals include [78]:

The onset of LBP is described as discomfort in the vicinity of the low back ranging from a dull ache to a sudden, sharp, shooting or stabbing pain and may include limited flexibility and/or range of motion or inability to stand straight [79]. Although the symptoms of back pain can originate anywhere from the thoracic spine to the sacrum and coccyx, most cases originate in the lumbar spine, as this is the site of support for upper body weight [79].

With LBP, the clinical presentation varies according to etiology. In general, radicular pain suggests nerve root involvement, while axial pain suggests disk degeneration, facet arthropathy, sacroiliac (SI) joint arthropathy, or myofascial pathology of the spine.

Nonspecific LBP

Up to 85% of LBP in patients presenting to the primary care setting is nonspecific, meaning that it lacks a clear origin and is not caused by specific local or systemic disease or spinal abnormality [1]. Nonspecific LBP is a diagnosis of exclusion made after ruling out serious causes of the back pain. Although pain can originate from ligaments, facet joints, muscle, fascia, nerve roots, the vertebral periosteum, or outer portions of the disk, the effective management of nonspecific LBP does not require a precise anatomic diagnosis [66]. The pain is usually unilateral and may radiate to the buttocks or posterior thigh but not past the knee. This can lead to incorrect diagnosis of radiculopathy or disk herniation. However, true radicular symptoms radiate below the knee in a dermatomal distribution and can involve sensory loss, weakness, or reflex changes. Painful spasm may be present, and pain may be worsened by movement, while lying flat decreases the pain. Complaints of numbness, weakness, or bowel or bladder dysfunction are absent [80]. Degenerative changes revealed by lumbar imaging should usually be considered nonspecific, because they poorly correlate with symptom severity [21,81].

Lumbosacral Radiculopathy

Lumbosacral radiculopathy is a clinical diagnosis of nerve root irritation and compression, resulting in a symptom distribution of the affected lumbar or sacral nerve root such as numbness, weakness, or paresthesia. Sciatica is the most common symptom of lumbar radiculopathy and refers to pain that radiates down the leg below the knee in the distribution of the sciatic nerve to indicate nerve root compromise from mechanical pressure or inflammation [21].

Causes of lumbar radiculopathy include disk herniation, arthritic degeneration, cord compression, spinal stenosis, tumor, and infection. With herniated disk, the pain is described as a deep, aching, axial midline pain concurrent with radicular pain. Discogenic pain results from a tear in the outer disk layer (annulus fibrosis) that causes the inner gelatinous material (nucleus pulposus) to prolapse, inflame, and compress a nerve root [80]. The resulting pain from pressure and nerve irritation improves with the resolution of local inflammation, and the disk protrusion may spontaneously remit with time. Although disk herniation and radiculopathy are often viewed as causally linked, herniation is often asymptomatic and only occasionally the cause of sciatica [80].

Lumbar Spinal Stenosis

Lumbar spinal stenosis refers to the frequently age-related narrowing of the spinal canal that may result in bony constriction of the cauda equina and the emerging nerve roots [21]. Spinal stenosis can produce pain in the low back that radiates down the back of both legs, often worsened with standing or walking. To make the pain more bearable, patients often walk a short distance with a hunched back, and then sit down for relief. The pain will then dissipate after several minutes. Congenital lumbar canal stenosis is a predisposing factor. Patients show less tenderness over the lumbar spine than those with acute lumbar disk herniation, and the straight leg-raising test may be normal [65].

Most persons 60 years of age and older exhibit varying degrees of spinal stenosis from disk herniation, osteophytes, or degenerative spondylolisthesis. Fortunately, clinical pain manifests in less than 30% and, just as with degenerative disk disease, there is poor correlation between symptom severity and extent of spinal canal stenosis revealed by magnetic resonance imaging (MRI) [80].

Myofascial Pain

Myofascial pain of the low back or neck is common, especially following trauma or repetitive motion injury. This is thought to result from strain or sprain to the muscles and ligaments. Myofascial pain is described as a deep, aching, poorly localized discomfort made worse by activity. It can be limited to discomfort in the paraspinal muscles or may extend to the buttocks and upper thigh areas [82].

Epidural Compression Syndrome

Epidural compression syndrome is an umbrella term that encompasses spinal cord compression, cauda equina syndrome, and conus medullaris syndrome. While these conditions differ in the level of neurologic deficit at presentation, they are otherwise similar in symptoms, evaluation, and management. Massive herniation of a midline disk, typically at the L4 to L5 disk level, is the most common cause of epidural compression syndrome. Tumor, epidural abscess, spinal canal hematoma, or lumbar spine spondylosis represent other causes [80].

In these patients, neurologic status at diagnosis is the greatest predictor of ultimate neurologic outcome and underscores the importance of early accurate diagnosis. The dominant symptom is back pain with accelerating pain severity. Pain from epidural spinal cord compression is made worse with recumbent positioning, and unilateral or bilateral radiculopathy may develop over time. For many patients, leg pain or neurologic symptoms are more dominant than back pain. Also common at diagnosis is symmetrical lower extremity weakness that may have progressed to gait disturbance or paralysis. Decreased lower extremity reflexes are associated with cauda equina syndrome [80].

Lumbar Facet Joint Syndrome

Lumbar facet joint syndrome is seen in as many as 35% of patients with LBP and is frequently associated with arthritis or lumbar facet joint injury [65]. Dominant symptoms include unilateral LBP that may radiate down the back or front of the thigh and morning stiffness with isolated facet arthropathy [83]. Tenderness is usually found over the lumbar paraspinal muscles and facet joints. Back pain is worsened with back extension and lateral rotation to the side of the pain, and the leg-raising test is negative. MRI and computed tomography (CT) findings of facet joint arthropathy do not correlate with clinical findings [65].

Sacroiliac Joint Syndrome

SI joint syndrome typically manifests as localized pain in the lower back or upper buttock area that overlies the SI joint. Pain is intensified by attempts to walk upstairs, and while pain may be referred to the posterior thigh, extension below the knee is unusual [79]. Tenderness over the SI joint is often found in physical examination, and pain is aggravated by the Patrick test or single-leg standing [65]. The onset of SI joint pain is usually gradual (over months to years), and although etiology is often elusive, trauma, infection, and tumor represent infrequent yet known causes of SI joint pain [79].

Spinal Cord Injury

Spinal cord injury (SCI) occurs in 17,810 persons every year in the United States (78% of new cases are men), and an estimated 294,000 patients are living with SCI [84]. Less than 1% of persons with SCI experience complete neurologic recovery by the time of hospital discharge [84]. One study found that, among patients with SCI, 86% report that pain persists six months after discharge and 27% report that pain is severe enough to interfere with most daily activities [85]. SCI pain may develop at or below the level of spinal injury and does not correlate well with the magnitude or location of the lesion nor the presence of myofascial pain syndrome. However, injury from gunshot is associated with more severe pain [65].

Neuropathic, musculoskeletal, and/or visceral pain can contribute to SCI pain. Central neuropathic pain can develop weeks to months following injury and is described as a burning, sharp, or shooting pain at or below the level of injury in areas with partial or complete loss of sensation to touch. Segmental pain around the trauma site often develops within the first couple of months post-injury and can manifest as allodynia (pain induced by light touch) and hyperalgesia, potentially resulting in severe pain if nerve root entrapment is involved [65]. Muscle spasm below the level of SCI and arthritis in disused joints may contribute to pain, described as dull or aching pain intensified with movement and relieved by rest. Constipation and urinary retention secondary to sphincter dysfunction reflects visceral involvement, in which case patients often complain of cramping, burning, and near-constant discomfort [65].

Failed Back Surgery Syndrome

More than 900,000 spinal surgeries are performed annually in the United States, primarily for lumbar and cervical disk herniation [86]. Of these, failed back surgery occurs in 13% to 35% of cases, with up to 74% continuing to experience pain following surgery [87]. The level of pain is widely variable and may occur with neurologic deficits. Contributors to pain and the clinical features of failed back surgery syndrome include recurrent disk herniation, epidural abscess, scar tissue formation around nerve roots, facet joint syndrome, and muscle spasm [65]. Patients with this syndrome should be questioned to identify new or persistent problems needing further evaluation. A frequent source of late-onset back pain following previous fusion surgery involves wear and tear to the facet joints and disks directly above and below the fused segment(s). Patients with persistent radicular pain, usually from chronic nerve injury, greatly benefit from treatment that addresses the neuropathic pain [65].

Most patients with acute low back pain have ligamentous or muscle strain syndrome, follow a benign course, and show significant improvement within two to three weeks. The challenge for clinicians is to recognize early the possibility of serious disease, such as spinal metastatic cancer or vertebral and epidural space infection, and then to identify those with herniated disk, radiculopathy, or spinal stenosis.

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].

Patients should also be assessed for "yellow flags," or risk factors for poor prognosis and chronicity [66,67]. Areas to explore include maladaptive beliefs, attitudes, and behaviors regarding the back pain and recovery, such as passivity or reluctance to self-manage, dependency on the provider to "cure," fear avoidance beliefs, and beliefs that harm will come from activity and discomfort. Other areas include depression, anxiety, maladaptive coping response to stress, social withdrawal or isolation, and lack of social support. Adverse economic and work environment circumstances, such as job dissatisfaction, excessive and inflexible physical workplace demands, high levels of work-related stress, poor workplace social support, and adversarial or dysfunctional workplace relationships should also be noted [66]. Early detection and intervention (if indicated) for problematic motivational, emotional, or social dysfunction are important because these factors influence the selection and effectiveness of therapeutic interventions.

In the absence of red flags, use of imaging and diagnostic tests for acute LBP is discouraged, as imaging findings rarely change clinical management [81]. Overuse of lumbar imaging in LBP correlates with, and likely contributes to, the two- to threefold increase in surgical rates for LBP over the last 10 years [86]. Assigning significance to imaging anomalies requires skill at the specialist level to integrate historical, clinical, and imaging findings. Imaging abnormalities are essentially normative by 40 years of age; for instance, 80% of persons 60 years of age and older exhibit a protruding disk, which is symptomatic for only a fraction of patients. Incorrect communication of imaging findings to the patient may lead to patient fixation, contribute to fear-avoidance behaviors, and increase the risk of iatrogenic aggravation of chronic LBP. Guidelines suggest that physicians without advanced training defer imaging tests to qualified specialists [88].

However, imaging and other testing should be performed in patients with new-onset or progressive neurologic deficits and those with suspicion of serious underlying conditions. In patients with persistent pain and symptoms consistent with radiculopathy or spinal stenosis, MRI should be performed only when such patients are candidates for surgery or epidural steroid injection. CT scanning is an alternative option to first-line MRI [89,90].

The Subgrouping for Targeted Treatment (STarT) Back Screening Tool is a nine-item standardized, validated screening tool that can be used in the initial assessment to identify patients with LBP at risk of progression to chronicity. This tool has been shown to accurately stratify patients to treatment based on risk, increase the efficiency in physical therapy referrals, improve clinical outcomes, and reduce costs [91,92].

Although acute LBP improves in most patients within three to six weeks using conservative therapy, up to 33% of patients with LBP report pain of moderate or greater severity at one-year follow-up and 20% report ongoing pain severe enough to limit activity [21]. With chronicity, LBP may become disabling and impose a severe emotional and functional burden. The management goals for chronic LBP are to minimize pain and disability, improve functional status, and facilitate restoration of normal activity, while limiting the use of marginally effective or inappropriate medication [21,81].

Many pharmacologic therapies and minimally invasive or invasive procedures have been utilized in a strategy designed simply to relieve pain—with variable results. However, there is little evidence these focused pain approaches are comparable or superior to interventions that focus primarily on restoration of function instead of pain relief. This contradicts the biomedical model in medicine that emphasizes escalation of costly and invasive therapies to achieve "pain cure" in patients lacking response to lower-intensity approaches [64,88]. It is now recognized that treatment for conditions such as CLBP persisting in the absence of a unique underlying pathologic lesion must address potential contributory factors such as affective disorders, maladaptive beliefs and coping skills, and interpersonal and occupational dysfunction. Dysregulated cortical, pre-frontal, and higher neural level mechanisms associated with CLBP are being identified and may represent therapeutic targets in functional restoration-based approaches. As with other chronic pain syndromes, greater understanding of pain pathway alterations will better inform therapy selection.

Virtually universal among practice guidelines for CLBP is the emphasis on a multidisciplinary, multi-modal approach that includes exercise and activity, cognitive restructuring of maladaptive attitudes and coping skills, a behavioral component addressing fear avoidance, physiotherapy and manual therapy, and analgesics as indicated [18,21,81,88,93,94,95]. This is often best accomplished by consultation or referral to an established pain treatment center. Multidisciplinary functional restoration programs, which are intensive (>100 hours) biopsychosocial interventions whereby physical rehabilitation is combined with cognitive-behavioral therapy and delivered by an interdisciplinary team, embody this recommendation. Moderate-to-strong evidence supports their efficacy in CLBP. They have been found effective in reducing pain and improving physical function, work readiness, and return to work. Weaker outcomes are found in programs that are less intensive or lacking a behavioral component. Patients who do not improve with less intensive therapy options and have high levels of pain, distress, and disability should be considered for multidisciplinary functional restoration programs [66].

The following treatment recommendations are based on practice guidelines by the American Pain Society, the American Society of Anesthesiologists, the American Society of Regional Anesthesia and Pain Medicine, the American College of Physicians, the National Institute for Health and Clinical Excellence, the American College of Occupational and Environmental Medicine, the Institute for Clinical Systems Improvement, and several published reviews and systematic reviews [18,64,65,88,93,94,95].

Persistent Nonspecific LBP

For persistent nonspecific LBP lasting longer than 12 weeks, patients should be offered education material on self-care developed from evidence-based guidelines and should be informed of the generally favorable outcome and natural time course of recovery [21,93]. Maintenance of activity is important, and bed rest should be avoided. A structured, tailored exercise program may be established that includes aerobic activity, movement instruction, muscle strengthening, postural control, and stretching [88,95]. Ice and/or heat should be applied to the painful area, with avoidance of prolonged exposure to extreme cold or heat (to the extent that tissue could be damaged). The pharmacologic approach for patients with persistent nonspecific LBP consists of acetaminophen or NSAIDs as needed [81]. Spinal manipulation, manual therapy, and/or acupuncture should be considered.

For patients unresponsive to less intensive therapy and who display high disability and/or psychological distress levels, referral to a multidisciplinary functional restoration program is indicated [88,95]. If acetaminophen or over-the-counter NSAIDs are ineffective, use a COX-2 inhibitor [81]. Moderate-quality evidence shows that TCAs are not effective for CLBP compared with placebo [81]. Clinicians should only consider opioids as an option in patients who have failed other therapies and only if the potential benefits outweigh the risk for individual patients [81].

Patients with persistent nonspecific LPB despite optimal care may be considered for spinal fusion [88,95]. However, appropriate care for any significant psychological distress should be pursued before surgery is considered. In the first three months of LBP onset, the only patients to benefit from surgery are those with severe spinal disease or debilitating symptoms and evidence of specific nerve root compromise on imaging studies [88,95].

Chronic Low Back Pain

According to the Institute for Clinical Systems Improvement, clinicians should advise patients with acute and subacute low back pain to stay active and continue activities of daily living within the limits permitted by their symptoms.

(https://www.icsi.org/guideline/low-back-pain Last Accessed: August 19, 2022)

Strength of Recommendation/Level of Evidence: Strong Recommendation/Moderate Quality Evidence

For all pharmacotherapy recommendations for CLBP, clinicians must weigh the potential benefits against potential risks and consider patient comorbidity. Some risks can be mitigated; for example, the use of proton pump inhibitors to prevent GI side effects in patients using NSAIDs [88,95]. All minimally invasive and invasive interventional therapies are recommended only for symptomatic pain relief, with full discussion of potential benefits, risks, and evidence for each suggested approach. In addition, all patients with chronic back pain, independent of additional therapies, should be involved in multi-modality therapy [81,88,95].

All patients with CLBP should be provided evidence-based information and encouraged to remain active and to use self-care options [21,81]. Medications with proven benefits should be used in conjunction with patient education and self-care. For most patients, first-line medication options are acetaminophen or NSAIDs [21,81]. In patients not improving with self-care, consider multidisciplinary rehabilitation, exercise therapy, acupuncture, massage therapy, spinal manipulation, yoga, cognitive-behavioral therapy, or progressive relaxation. When patients with CLBP do not respond to these interventions, further assessment to determine etiology should be considered, with further treatment then based on these findings (Table 3).

Tapentadol is a newer opioid available for the treatment of chronic moderate-to-severe pain. The mechanism of action involves a novel mu-opioid receptor (partial) agonist combined with norepinephrine reuptake inhibition. Its efficacy for CLBP is demonstrated by the results of a randomized, double-blind trial that compared tapentadol ER (100–250 mg twice daily) against oxycodone CR (20–50 mg twice daily) and placebo in 958 patients with CLBP (baseline pain "severe" in 88.5%) [96]. After 12 weeks maintenance therapy, tapentadol was superior to the other treatment arms by the following measures among responders: patients with ≥30% and ≥50% pain intensity reduction; patients who were "very much improved" or "much improved;" and patients with significant improvement in function and quality of life. No differences were found between oxycodone and placebo in response rate, ≥30% pain reduction, or ≥50% pain reduction.

A meta-analysis of yoga effectiveness for LBP evaluated 10 RCTs enrolling 967 patients with CLBP. Strong evidence was found that practicing yoga is associated with significant improvement in near-term pain relief, back-specific disability, general improvement, and long-term pain control. Moderate evidence supported findings of significant long-term improvement in back-specific disability. The authors concluded that yoga should be recommended for patients with CLBP [97].

The changes that follow whiplash injury are heterogeneous and complex, and several pathogenic mechanisms are thought to account for the clinical findings. Evidence suggests the contribution of initial structural injury combined with the secondary effects on sensory and motor function [99]. Injuries are most likely to occur in cervical spine structures, especially the zygapophyseal joints. Augmented central pain processing mechanisms are the likely basis of persistent chronic post-injury pain. Muscle strain and associated dysfunction likely account for disturbances in movement and neuromotor control. Kinesthetic deficits, loss of balance, and loss of eye movement control are the result of disturbances in sensorimotor control, which likely contributes to symptoms of dizziness [108]. Cerebrospinal fluid (CSF) leak has also been suggested as a contributing factor [109].

Alteration in peripheral and central pain processing is considered important in the pathogenesis of chronic WAD. CNS hyperexcitability contributes to sensory hypersensitivity (both generalized and expressed in unaffected tissue remote from the injury site). This is initiated by alteration in spinal cord neuron excitability secondary to peripheral nociceptive signaling bombardment. It is sustained by NMDA receptor activation and resultant release of COX-2 in the spinal cord and by glial cell activation. Dysregulation in the balance between descending facilitatory and inhibitory pathways, originating within cortical centers, also contributes to central hyperexcitability [110].

Peripheral sensitization is augmented by the inflammatory response to structural injury, which releases inflammatory mediators such as substance P, prostaglandins, and bradykinin. This amplifies the intensity and prolongs the duration of nociceptive signaling, which in turn alters peripheral nerve fiber characteristics in such a way as to perpetuate primary hyperalgesia [110].

The relative lack of published research on treatment efficacy in WADs has resulted in an overall paucity of evidence-based treatment guidelines. Identifying and comparing studies on treatment outcome is further complicated by the absence of uniform patient classification by symptom severity [98]. Nonetheless, a systematic review to evaluate the strength of evidence for various WAD therapies was published in 2010 [98,100,101,111]. The authors evaluated 83 studies, including 40 RCTs, published between 1980 and 2009. Their recommendations, along with those from practice guidelines, systematic reviews, and clinical trials form the basis for the treatment of acute, post-acute, and chronic-phase WAD [88,108,110,112,113,114,115,116,117]. The conclusions for most minimally invasive and surgical interventions are based on single published trials and should be viewed with caution given this limited evidence base [111].

Behavioral and Lifestyle Interventions

Patient education that addresses therapeutic barriers, therapy compliance, and prevention of chronicity should be offered in all phases of WAD. Lifestyle and behavioral changes are the first (and often only necessary) treatments for patients with mild-to-moderate whiplash-related pain [99]. Exercise programs are effective in reducing short-term pain intensity in all WAD phases [111]. However, the results of one systematic review found a lack of significant improvements in long-term pain and disability in individuals with WAD who participated in general exercise interventions [118]. Vestibular rehabilitation can be offered for dizziness in chronic-phase WAD. Of greatest benefit in improving pain and function during the acute phase are range of motion, neck and scapular strengthening, and neck stabilization exercises. One study investigated ventral neck muscle interactions in 26 individuals with chronic WAD randomized to neck-specific exercise or a wait list for three months [119]. The researchers used real-time, non-invasive ultrasound measurements and calculations of the deformed area and deformation rate in the neck muscles. After three months, significant improvements were observed in neck muscle interactions and pain intensity in the neck-specific exercise group compared to the wait list group, demonstrating that non-invasive ultrasound may be a useful diagnostic tool for muscle impairment and may be used to evaluate exercise interventions in WAD [119]. Aggressive strengthening programs may worsen symptoms and should be avoided [111].

Encouraging the patient to maintain good range of motion is important. Soft-collar cervical immobilization should be discouraged as active mobilization during acute phase WAD can actually reduce pain intensity [99]. Multimodality therapy programs that include joint mobilization, relaxation therapy, electrotherapies, exercise, and a cognitive-behavioral component that address pain and functional deficits are effective in patients with subacute or chronic WAD who have not improved with simple activity-related approaches [99]. Patients with severe symptoms should be enrolled as soon as is feasible following injury. However, patients with cold hyperalgesia and/or widespread allodynia may not respond to this intervention. Early referral to a pain clinic is advisable for patients at risk of developing chronic symptoms [111]. Patients should also be assessed and monitored for symptoms of anxiety and depression, then treated accordingly.

Pharmacotherapy

Prompt, effective pain control should be achieved early, because high pain levels can interfere with recovery. There is little available guidance on the effectiveness of specific opioid and non-opioid analgesics. Some recommend initiating acetaminophen or NSAIDs for pain and adding codeine if appropriate and necessary [111]. If a patient remains symptomatic despite optimal analgesia, adding a TCA, such as amitriptyline, may be beneficial [99].

Methylprednisolone infusion may improve recovery in moderate-to-severe acute WAD. In addition, intra-articular dextrose and lidocaine injections may reduce pain and disability [111].

Medial branch block of the cervical zygapophyseal joints effectively reduced sensory hypersensitivity in a small group of patients with chronic WAD, but these results need larger-scale prospective replication [111]. Supportive evidence is equivocal for botulinum toxin injections and lacking for intra-articular or selective nerve root block or corticosteroid injections in chronic WAD [111].

Surgical Interventions

Moderate evidence indicates that radiofrequency neurotomy is effective in reducing pain in chronic WAD, although relief is not permanent [111]. Some patients benefit from occipital nerve decompression, carpal tunnel decompression, and cervical discectomy and fusion. In addition, combined surgical fasciectomy and spinal accessory nerve neurolysis is effective in patients with severe, refractory WAD with spinal accessory nerve entrapment and/or chronic compartment syndrome of the trapezius muscle.

Patients with chronic WAD often complain of headache, dizziness, and nausea, symptoms also experienced by patients with CSF leak. Ishikawa et al. explored the relationship between chronic WAD and CSF leak and investigated the efficacy of epidural blood patch in chronic WAD [109]. Of 66 patients (mean duration of WAD: 33 months) imaged with radioisotope cisternography, CSF leak was detected in 37 patients who then received epidural blood patch. Compared with baseline, symptom reduction one week after epidural blood patch was noted in most patients, including improvements in headache (100% vs. 17%), memory loss (94% vs. 28%), dizziness (83% vs. 47%), visual impairment (81% vs. 25%), and nausea (78% vs. 42%). Treatment response remained at six-month follow-up, and work status was also significantly improved at follow-up. The authors concluded that in some cases of chronic WAD, the possibility of CSF leak should be assessed, and that epidural blood patch may be beneficial for patients with positive findings. There are no other published studies confirming these observations.

Alternative Therapies

Massage therapy, chiropractic, physical therapy, and occupational therapy constitute adjunctive modalities that may be of benefit in all phases of WAD [111]. Acupuncture has also been shown to reduce pain in chronic WAD, although evidence of functional improvement is lacking [88,111,112]. Pulsed electromagnetic field therapy can decrease pain intensity and increase cervical range of motion in acute WAD. Myofeedback training may be beneficial for some patients with chronic WAD [88,111,112,120].

An RCT of 51 patients with chronic nonspecific neck pain compared a self-help exercise program with Iyengar yoga [121]. Following a nine-week trial of both yoga and neck pain interventions, yoga resulted in significantly greater improvement than home-based exercise for pain, pain intensity, disability, mental health-related quality of life, and neck muscle functional status. Patients randomized to yoga were further evaluated one year after completing the nine-week formal protocol [122]. Statistically significant improvements from baseline were found in pain intensity, neck-related disability, and bodily pain. Sustained yoga practice was the strongest predictor of long-term effectiveness.

Optimal treatment of WAD continues to be a challenge, which may be related to the need for better understanding of the subjective experiences and perceptions of patients living with the condition. In one study, researchers conducted individual telephone interviews with patients with WAD and then analyzed the transcribed audio tapes. Two main themes emerged from the interviews. First, the participants described what it was like to navigate the healthcare system to understand their injury, interpret therapeutic recommendations, and find the right healthcare practitioner to help with the process. Additional navigational complexities were related to compensation and funding systems. Second, participants described a journey of trial and error in establishing self-management strategies to prevent and relieve pain. This included the gradual realization that they could be faced with an ongoing residual deficit. Early identification of the patient's expectations for recovery and validation of their injury by the healthcare practitioner can aid the recovery process [123].

According to the American Academy of Orthopaedic Surgeons, oral acetaminophen is recommended to improve pain and function in the treatment of knee osteoarthritis when not contraindicated.

(https://www.aaos.org/globalassets/quality-and-practice-resources/osteoarthritis-of-the-knee/oak3cpg.pdf Last Accessed: August 19, 2022)

Strength of Recommendation: Strong (Evidence from two or more "high" quality studies with consistent findings for recommending for or against the intervention.)

Altered central pain processing and central sensitization are involved in osteoarthritis pain. Treatment approaches are beginning to address this CNS origin of pain. Cognitive-behavioral therapy and neuroscience education potentially reduce emotional sensitization and descending pain facilitation, while centrally acting drugs such as duloxetine may increase endogenous analgesia by enhancing descending pathway inhibition [131,132].

With no currently available cure for osteoarthritis, treatment focuses on symptom relief, functional improvement, and prevention of disease progression through a combination of patient education, physical therapy, weight control, and pharmacotherapy [124,133]. The 2019 guidelines from the American College of Rheumatology (ACR) represent the practice guidelines with the highest level of scientific rigor and broadest clinical applicability [133]. These guidelines depart from previous ACR recommendations, and from those of other organizations, by abandoning the sequenced order of interventions for patients failing to respond to recommended initial therapies, as this management strategy has not received empirical validation. The selection of interventions and the order in which interventions are used will vary among patients. No specific hierarchy of one option over another is implied other than on the basis of strength of the recommendation [133].

The ACR guidelines for initial management of osteoarthritis are organized according to affected joint (Table 4, Table 5, and Table 6).

An important point is that patient failure with conservative therapies may be due to lack of adherence to self-management or medication. Many of these cases can be identified through the patient history [134].

In the treatment of osteoarthritis, no clear advantage based on side effect profile has been shown with any non-opioid oral analgesic. Given the different adverse event profiles of each agent, treatment decisions should be guided by patient factors, such as age, comorbidity, and concomitant medication [135].

Regarding chondroitin sulfate and glucosamine, clinical trials have shown comparable but not superior benefits relative to NSAIDs for pain relief and function improvement. With most of the studies performed outside the United States and involving pharmaceutical-grade preparations, the results may not generalize to the United States with over-the-counter preparations [135].

Operative Treatment

Operative treatment for osteoarthritis should be delayed until all possible nonoperative options have been exhausted [136]. In general, the indications for operative treatment are debilitating pain and major limitations in function and activities of daily living [136]. Proper patient selection and adherence to precise surgical procedure are critical to success [137].

In an effort to delay total knee or hip replacement, many have recommended arthroscopic lavage and debridement, but several studies, systematic reviews, and meta-analyses have shown that there is no evidence to support the efficacy of this approach for treatment of osteoarthritis of the knee [137,138,139,140,141]. In addition, comparisons between the use of intra-articular corticosteroids and joint lavage showed no differences between the two treatments with respect to efficacy or safety [142,143]. Arthroscopic lavage and debridement may be useful for removing unstable tissues (e.g., loose bodies, meniscal tears, loose cartilage) that are causing mechanical symptoms [136,138].

The American Academy of Orthopaedic Surgeons (AAOS) updated its guideline on surgical management of knee osteoarthritis in 2015 [144]. This guideline states that moderate evidence supports no difference between unicompartmental knee arthroplasty or valgus-producing proximal tibial osteotomy in outcomes and complications in patients with symptomatic medial compartment osteoarthritis of the knee [144]. The AAOS recommends against performing arthroscopy with debridement or lavage in patients with a primary diagnosis of symptomatic osteoarthritis of the knee [144]. The AAOS notes that arthroscopic partial meniscectomy or removal of loose bodies is an option for patients who have failed physical therapy or other nonsurgical treatments [145]. In addition, the AAOS found that arthroscopic partial meniscectomy can be used in patients with osteoarthritis of the knee with a torn meniscus [144].

Experts have described satisfactory outcomes after arthroscopic debridement of the elbow [146,147]. The ideal candidate for the procedure is younger than 60 years of age, is active, and has impingement pain at the extremes of the range of motion but not at the midpoint of the arc of motion or at rest [146,148]. Compared with open debridement, the arthroscopic procedure is associated with decreased intraoperative bleeding and less postoperative pain. The procedure is technically demanding but is safe when performed by an experienced surgeon familiar with the technique [146].

Debridement (through arthroscopy or arthrotomy) of the ankle has relieved pain, decreased swelling and stiffness, and improved activity levels in more than half of patients [149]. Improvement is most likely when debridement is done to remove osteophytes, smooth unstable chondral surfaces, and remove loose bodies [149].

Rheumatoid arthritis is diagnosed clinically but may be classified according to the 2010 ACR and European League Against Rheumatism classification criteria for rheumatoid arthritis (Table 7). For classification purposes, a patient has definite rheumatoid arthritis if he or she scores at least 6 points using the established system.

Early diagnosis and DMARD treatment are extremely important for suppression of synovitis and prevention of bone erosion in the joints, as this greatly reduces the risk of permanent disability. The 2010 criteria were developed to improve sensitivity in detecting early-stage rheumatoid arthritis by including tender and swollen joint count, acute phase reactants, anticitrullinated peptide antibodies or rheumatoid factor, and symptom duration. Also, the former criterion requiring six weeks of symptom duration was eliminated. The criteria are intended for use following differential diagnosis of synovitis in patients with at least one swollen joint, and patients showing bone erosion are automatically classified as rheumatoid arthritis [161].

Pain is common for many patients with rheumatoid arthritis, even with optimal therapy addressing the pathophysiology. Patients with rheumatoid arthritis report that pain control is their greatest priority. The treatment goals for all patients with rheumatoid arthritis are control of pain and inflammation and ultimately the induction of disease remission or greatly diminished disease activity [158]. Pharmacologic treatments are the backbone of therapy and fall into three general categories: corticosteroids, NSAIDs, and DMARDs, including biologic, conventional synthetic, and targeted synthetic DMARDs [156,158,162].NSAIDs and corticosteroids have a short onset of action, while DMARDs can take several weeks or months to demonstrate a clinical effect [163]. In contrast to the 2015 guideline recommendations, the 2021 ACR guideline recommendations for the treatment of rheumatoid arthritis (Table 8) considers current disease activity, prior therapies used, and the presence of comorbidities as the factors most relevant to treatment decisions [162].

The 2021 ACR treatment guidelines also include recommendations for patients with specific comorbidities, including those with subcutaneous nodules, pulmonary disease, heart failure, hepatitis B infection, nonalcoholic fatty liver disease, and previous serious infection [162].

Corticosteroids (e.g., methylprednisolone, prednisone, prednisolone) are prescribed orally for rheumatoid arthritis to reduce inflammation and subsequent joint pain and swelling through receptor binding at inflammation sites. These agents inhibit movement of inflammatory cells, neutrophil function, and prostaglandin production. However, while they may control symptoms, they do not impact disease progression [158,163].

Oral DMARDs are heterogeneous agents grouped together on the basis of slow action and ability to improve symptoms, reduce or prevent joint damage, and preserve structure and function in patients with inflammatory disease. They include methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine [158,163].

Biologic DMARDs are an injectable form of DMARD that differ from oral agents in the selectivity of immune system target. Adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab block proinflammatory-mediating cytokines through TNF inhibition [156]. The other biologic DMARDs include anakinra, an interleukin-1 receptor antagonist; abatacept, an immunosuppressant that interferes with T lymphocyte activation; rituximab, which removes circulating B cells; and tocilizumab, an interleukin-6 (IL-6) antagonist [158].

Oral tofacitinib received FDA approval in 2012 for the treatment of rheumatoid arthritis in patients who have failed a trial of methotrexate. Tofacitinib is the first recent nonbiologic, small-molecular treatment for rheumatoid arthritis. Tofacitinib is a Janus kinase (JAK) inhibitor. Inhibition of JAKs reduces production of and modulates the proinflammatory cytokines central to rheumatoid arthritis [156]. Extensive evaluation has shown it superior to placebo, comparable to the anti-TNF agent adalimumab, efficacious in patients not responding to other anti-TNF agents, and superior to methotrexate. As with methotrexate, patients receiving tofacitinib are at risk for myelosuppression and should be monitored for cytopenias [36,164,165]. In 2018, the FDA approved a second JAK inhibitor, baricitinib as a second-line treatment for rheumatoid arthritis in patients with moderately-to-severely active disease who have had an inadequate response or intolerance to one or more TNF antagonists [36,156,166]. Baricitinib may be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs [156]. It should not be used in combination with biologic DMARDs or immunosuppressant agents (e.g., azathioprine, cyclosporine) [156,166]. Baricitinib is dosed at 2 mg once daily [36]. Another JAK inhibitor, upadacitinib, was approved by the FDA in 2019 for treatment of rheumatoid arthritis in patients with moderately-to-severely active disease who have had an inadequate response or intolerance to one or more TNF blockers [36,167]. The recommended dose of oral upadacitinib is 15 mg once daily [36,167].

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].

In patients with longstanding active disease, biologic DMARDs offer greater likelihood of remission than oral agents and therefore are often the approach used [135,158,163]. Combining two biologic DMARDs does not improve disease activity, functional capacity, or symptom response, yet it does increase the risk of serious adverse events. However, if oral DMARDs are used, a combination of two or three agents is more effective than monotherapy [135,158].

In patients with longstanding active disease requiring a change in therapy, biologic DMARDs are preferred over oral DMARDs [135,158,162]. The combination of a biologic DMARD and methotrexate provides greater symptom reduction than either agent alone without increasing the risk of serious adverse events.

Recognition of the substantial burden imposed by persistent rheumatoid arthritis pain prompted the development of recommendations for pharmacologic pain control in rheumatoid arthritis by the 3e (evidence, expertise, exchange) Initiative (Table 9). The guideline was initially developed in reference to the broad category of inflammatory arthritis, but most of the evidence in the final report pertains to rheumatoid arthritis [141].

Other pain control options are being studied and may be considered in intractable cases. Nefopam hydrochloride is a benzoxazocine analgesic widely used in Europe for rheumatic disease and moderate-to-severe pain as an opioid alternative [174]. Nefopam blocks voltage-sensitive sodium channel activity in CNS neuron membranes to inhibit presynaptic glutamate release and postsynaptic neuronal excitation following glutamate receptor activation [175]. Following activation of voltage-sensitive calcium channels, nefopam inhibits calcium influx, cyclic guanosine monophosphate formation, and NMDA receptor-dependent neurotoxicity [176]. A published review of neuromodulator therapy in rheumatoid arthritis found two RCTs of nefopam showing significant pain reduction after two weeks [177]. However, this agent remains investigational in the United States.

An RCT of capsaicin found significant pain reduction at one and two weeks, with a 2% dropout from side effects [177]. Capsaicin may be considered as adjunctive therapy in patients with persistent local pain and inadequate response or intolerance to other analgesic approaches [178].

Gout is perhaps the most easily treated, and preventable, form of arthritis. This is due to widespread understanding of its underlying mechanisms and the availability of effective treatment [181]. It is managed by controlling the current acute attack and preventing future attacks. Medications addressing the underlying pathophysiology include the xanthine oxidase inhibitors (XOIs) allopurinol and febuxostat and the uricosuric agents probenecid, fenofibrate, and losartan [181,188]. (Note: The use of fenofibrate and losartan for the treatment of gout is off label.)

The American College of Rheumatology conditionally recommends that patients with gout limit their consumption of purine-rich foods (e.g., meat and seafood), alcohol, and high-fructose corn syrup (particularly in sweetened soft drinks and energy drinks).

(https://www.rheumatology.org/Portals/0/Files/Gout-Guideline-Final-2020.pdf Last Accessed: August 19, 2022)

Certainty of Evidence: Low or very low

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].

The acute pain of gout may be treated with NSAIDs, a COX-2 inhibitor, systemic corticosteroids, or oral colchicine monotherapy in mild-to-moderate disease (≤6 on a 10-point pain scale). Combination therapy (i.e., colchicine and NSAIDs, oral corticosteroids and colchicine, or intra-articular steroids with each of the other options) may be used in cases of severe disease with intense pain and polyarticular presentation. Intramuscular triamcinolone acetonide is recommended in patients unable to take oral medication or likely to be poorly adherent to the multidose oral regimen [188].

An inadequate response to therapy after escalation (<20% pain reduction within 24 hours or <50% pain reduction after ≥24 hours) should prompt reconsideration of the diagnosis. If gout is confirmed, switching to another form of monotherapy or adding a second agent may prove effective [184,188].

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].

Clinicians may also consider screening for the HLA-B*5801 allele, which is associated with high risk of severe allopurinol hypersensitivity reaction. High-risk persons include Koreans with an estimated glomerular filtration rate <60 mL/min/1.73 m2 or those with Han Chinese or Thai ancestry [36].

Anti-inflammatory prophylaxis (against precipitating an acute flare) is recommended when initiating urate-lowering therapy in asymptomatic patients [189]. Colchicine was once the treatment of choice but is now less commonly used than NSAIDs because of its narrow therapeutic window and risk of toxicity [190]. To be effective, colchicine therapy is ideally initiated within 36 hours of onset of the acute attack [179]. In the case of colchicine intolerance or contraindication, prednisolone may be used [189]. Prophylaxis should continue after achieving target serum urate level for three months in patients without tophi, for six months in patients with resolved tophi, and with any remaining signs of gout activity in all patients [189].

Patients with intermittent symptoms or chronic synovitis with tophi (chronic tophaceous gouty arthritis) should be treated with a single-agent XOI, such as allopurinol, at a dose to achieve and maintain the serum urate level within normal range [184,188]. If the serum urate target is not achieved or disease activity persists, a uricosuric agent may be added to the XOI. Pegloticase therapy should be considered if the serum uric target is not achieved, disease activity persists, more than seven attacks occur per year and no tophi, two or more attacks per year and tophi, or chronic tophaceous gouty arthritis is present [36,189].

Migraine is a complex heterogeneous disorder with pathogenic mechanisms that are only now being elucidated [199]. A likely primary pathway leading to migraine-associated pain involves trigeminovascular system activation. This system is comprised of nociceptive nerves from the first or ophthalmic region of the trigeminal ganglia, major blood vessels that regulate cerebral blood flow, and smaller vessels in the pain-sensitive meninges. In the trigeminal ganglion, Aδ and C fibers transmit nociceptive impulses from meningeal blood vessels to the caudal brain stem or high cervical cord, resulting in headache pain. Sensitization and excitation of trigeminal nerves, the result of inflammatory mediator release from CNS dysfunction, promote neurogenic inflammation and generation of pain stimuli. This trigeminal nociceptor activation triggers neuropeptide release, including calcitonin gene-related peptide, substance P, and neurokinin A, from primary sensory neurons involved in the transmission of pain signaling [199,201,202].

Aura is believed to be related to cortical spreading depression, a process that transiently compromises cortical function resulting from a spreading (2–6 mm/min) wave of neuronal excitation in cortical gray matter. This cellular depolarization and resultant aura activate trigeminal fibers to initiate headache. The basis of cortical spreading depression involves the release of potassium or glutamate from neural tissue, which depolarizes adjacent tissues that release more neurotransmitters to propagate cortical spreading depression [203]. Cortical spreading depression may be responsible for the upregulation of genes, such as those encoding for metalloproteinases. The activation of these enzymes leads to leakage of the blood-brain barrier, allowing potassium, nitric oxide, adenosine, and other products to reach and sensitize the trigeminal afferent endings. Increased net activity of matrix metalloproteinase-2 has been demonstrated in patients with migraine [199].

As with most conditions, the foundation of migraine headache treatment is patient education and self-care [195,199]. The history, or a log kept by the patient, may reveal one or more environmental, food, or medication sources that act as "triggers" of a migraine attack [193]. Common triggers include intense temperature, an odor, bright light, stress, poor sleep, foods containing monosodium glutamate or nitrates (e.g., aged cheeses, beer, red wine), citrus, aspartame, oral contraceptives, estrogen therapy, nifedipine, and nitroglycerin. Resting in a quiet, dark room can help alleviate some migraines. Regular aerobic exercise and smoking cessation are encouraged. Patients should also keep a headache diary in order to identify triggers and assess treatment efficacy [193]. Acute medication should not be used more than nine days per month, which should be possible with adherence to the prophylactic treatment regimen. For persons who experience troublesome nausea with their attack, it is helpful to keep on hand a prescription antiemetic such as metoclopramide, prochlorperazine, or promethazine [193]. Caffeine may also be a useful adjunct.

Acute Attacks

For patients experiencing mild symptoms of a migraine, initial treatment consists of over-the-counter NSAIDs or aspirin (with or without caffeine) [193,195]. Triptans (e.g., naratriptan), lidocaine nasal spray, or sumatriptan/naproxen sodium combination therapy may also be used. In 2013, the FDA approved a sumatriptan iontophoretic transdermal system for acute treatment of migraine with or without aura in adults [204].

For moderate symptoms, guidelines recommend the use of NSAIDs, triptans, lidocaine nasal spray, dihydroergotamine mesylate (DHE), or combination acetaminophen, isometheptene, and dichloralphenazone [193,195]. Severe symptoms may be treated with prochlorperazine, chlorpromazine, DHE, ketorolac IM, magnesium sulfate IV, or triptans. If the migraine is known to be related to menstruation and does not respond to first-line therapies, use of frovatriptan or zolmitriptan is indicated [193].

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.

Intractable migraine pain may be managed with an opioid (not meperidine) or dexamethasone. If at all possible, clinicians should avoid opioids. The brief pain-relief window, induction of inflammatory neurochemical release, and vasodilatation are counterproductive to treatment issues and migraine pathophysiology. Meperidine is not recommended because its neurotoxic metabolite normeperidine may promote seizures [195].

Prophylactic Treatment

The criteria for migraine prophylactic treatment are three or more severe migraines per month with inadequate response to symptomatic therapy, less frequent but prolonged attacks that are disruptive to quality of life, and patient desire [195,199]. Several classes of drugs with established efficacy are available, the selection of which depends on individual patient response and tolerance [195,205,206]:

If the patient's response is unsatisfactory, it may help to switch to an alternate class, combine a beta blocker with a TCA, or add a second-line medication [195]. Second-line agents are considered probably effective according to available evidence and may be employed for patients who do not respond to initial therapy. These medications include [195,205,206]:

Good studies have demonstrated the effectiveness of the herb butterbur (Petasites hybridus) in preventing migraines [199]. Butterbur may be useful to patients with migraine to reduce the frequency and severity of migraine attacks. Patients on butterbur require monitoring of liver enzymes [206]. Additionally, the AAN/AHS found moderate evidence of effectiveness for riboflavin, magnesium, and feverfew [206].

Muscular and psychogenic factors contribute to tension-type headache etiology. Patients with chronic tension headaches (longer than five years) have shown lower cortisol levels, likely due to hippocampal atrophy resulting from the effects of chronic stress [207]. Combined myofascial dysfunction and central nociceptive dysregulation is also thought to contribute to tension-type headache, with increasing central nociceptive alteration resulting in progression of tension-type headache from episodic to chronic [208,209].

The treatment of acute tension headache generally consists of over-the-counter pain relievers, including NSAIDs, acetaminophen, aspirin, and combination medications [193,195,196]. Patients who experience more than 15 tension headaches per month require prophylactic treatment with venlafaxine XR, amitriptyline, or another TCA [193]. Acupuncture has also been shown to improve symptoms. Codeine and stronger opioids are not indicated, and botulinum toxin is ineffective [193,195,196].

Although the underlying pathophysiology of cluster headache is incompletely understood, an underlying mechanism in cluster headache is thought to involve trigeminovascular nociceptive pathway activation and reflex cranial autonomic activation. Central sensitization induces alteration in trigeminal-facial neuronal circuitry and dysregulation in serotonergic raphe nuclei-hypothalamic pathways. Functional imaging has confirmed the highly specific activation of hypothalamic gray in cluster headache attacks, suggesting its involvement in initiating the pain process [210,211].

Sensory-motor impulses generated in the maxillary and ophthalmic divisions of the trigeminal nerve are relayed to the sphenopalatine ganglion and interior carotid perivascular sympathetic plexus. This signaling is propagated by substance P neurons, and somatostatin inhibits substance P to reduce the duration and severity of cluster headache. Vascular dilatation, secondary to primary neuronal discharge, contributes to cluster headache pathogenesis, and the sudden release of histamine (or serotonin) seems to play a role [212,213].

Acute cluster headache is treated with subcutaneous sumatriptan or intranasal zolmitriptan, interventions proven highly effective for these patients [195,196]. Some have studied 20-mg sumatriptan nasal spray, but this route is not recommended. Other possible approaches include DHE and supplemental oxygen [195]. A 2014 literature review of six studies (five randomized-controlled studies) found that flow rates of 7–12 L/min effectively treated cluster headaches in approximately 80% of participants [214]. Oxygen inhalation is highly effective when delivered at the onset of an attack with a nonrebreathing facial mask at a flow rate of 7–15 L/min [195]. Analgesics, ergotamine tartrate, and orally administered triptans are ineffective and should not be used [193,195,196].

Galcanezumab, a humanized monoclonal antibody, was approved by the FDA in 2018 for migraine prophylaxis. It acts by blocking the CGRP pathway by targeting the ligand itself [36]. Studies have shown galcanezumab to be efficacious in reducing monthly migraine headache days, monthly migraine headache days with acute medication use as well as improving response rates and functional and disability scores [215,216]. Other monoclonal antibodies targeting the CGRP pathway include fremanezumab (approved in 2018) and eptinezumab (approved in 2020), which target the ligand, and erenumab (approved in 2018), which blocks the receptor [217]. These three agents, as well as galcanezumab, are approved for migraine prevention [36]. Galcanezumab is the only agent shown to be efficacious in cluster headache as well [218].

Bridge treatment for quick suppression of attacks until maintenance treatment reaches therapeutic level consists of corticosteroids, oxygen, and occipital nerve block. For sustained suppression of attacks over the expected cluster cycle, the first-line medications are verapamil, corticosteroids, lithium carbonate, divalproex sodium, and topiramate [195,196,212]. Antihistamines may also be helpful. Patients should also be advised to avoid alcohol, tobacco smoke, and certain foods during the cluster cycle [212].

Lifestyle and dietary interventions have been recommended for all women with endometrial pain. Preliminary evidence supports a diet emphasizing vitamins, minerals, salts, lactic ferments, and fish oil as a postsurgical intervention. Fish oil supplementation (for omega-3 fatty acids) has also been suggested. Some studies have found positive results with a gluten-free diet, but confirmation with RCTs is necessary [222,229,230,231,232].

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.

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].

Adding laparoscopic uterine nerve ablation to laparoscopic removal of endometriosis is considered ineffective. Presacral neurectomy may benefit a small number of women, but potential harms outweigh benefits [222,229,230,231,232].

Some patients with CRPS find NSAIDs effective, although certain NSAIDs may have greater efficacy [305]. Ketoprofen is likely to produce a substantial antibradykinin and antiprostacyclin effect along with the expected antiprostaglandin effect.

A demonstration of modest benefit with IV immunoglobulin suggests potential efficacy in targeting immune function and inflammation in CRPS [305]. Thalidomide, a TNF-α and interleukin-1 and 6 inhibitor, has also shown modest benefit.

Oral corticosteroids are the only anti-inflammatory intervention with support from RCTs. However, most studies involve early/acute cases, when inflammation is prominent [305]. It is unclear if corticosteroids are beneficial for chronic CRPS, in which pro-inflammatory cytokine levels are lower. Chronic steroid use is contraindicated due to serious adverse effects.

Gabapentin has shown efficacy in CRPS, while pregabalin has not yet been evaluated. Carbamazepine 600 mg/day over eight days has been found to substantially reduce pain versus placebo [305]. Oxcarbazepine is often used in place of carbamazepine because of a more favorable side effect profile, and although not yet studied in CRPS, it may be beneficial [305]. Phenytoin is a third-line agent to consider, especially in cases involving ectopic nerve firing.

Tricyclic and heterocyclic antidepressants can be highly beneficial in the treatment of CRPS, and side effect profile determines their selection. For example, doxepin may be a good choice in anxious, depressed, underweight, or insomniac patients, while the greater noradrenergic selectivity of desipramine may be a better choice in overweight or hypersomnolent patients.

SSRIs are ineffective in CRPS and are not supported [305]. Data are lacking for combined SNRIs.

Neuropathic pain in CRPS does not predictably respond to opioids to the same extent as acute nociceptive pain, often resulting in dose escalation with no added pain relief but accruing adverse effects. However, opioids are a reasonable second- or third-line treatment option in CRPS [305]. Use of short-acting opioids is often inappropriate, and when indicated, therapy should involve extended-release delivery systems and "pure" (not containing acetaminophen) formulations. Short-acting opioids should be reserved for breakthrough pain only.

Methadone has the theoretical advantage of NMDA antagonism and is inexpensive [305]. Likewise, tramadol is theoretically appealing due to its dual serotonin/norepinephrine reuptake blockade. Long-term high-dose use of opioids can exacerbate allodynia and/or hyperpathia.

The NMDA receptor antagonists MK-801, amantadine, and dextromethorphan have been evaluated in neuropathic pain and CRPS, but toxicity at effective doses has generally been too high. Oral dextromethorphan may be better tolerated and may augment the effect of opioids to decrease opioid dosing requirements. Ketamine has been used topically, orally, and intravenously and is one of the very few therapies demonstrating substantial and durable pain reduction of treatment-refractory CRPS pain [306]. Ketamine trials have effectively controlled side effects with higher-dose co-administration of midazolam or lorazepam, combined with either the a2-adrenergic agonist clonidine or the 5-HT3 antagonist ondansetron [307,308,309,310].

The most dramatic treatment response involved induction of anesthetic-dose ketamine treatment in 20 patients with CRPS unresponsive to all other pain management approaches, including lower-dose 5-day inpatient or 10-day outpatient ketamine protocols. Over five days, patients were infused with ketamine 7 mg/kg/h, midazolam 0.15–0.4 mg/kg/h, and clonidine 0.1 mg. Complete remission from CRPS was observed in all patients at one month, 17 of 20 at three months, and 16 of 20 at six months. Of the 20 patients, 10 remained completely pain free from 5 to 11 years and no longer required any form of pain medication [311]. Consensus guidelines developed by the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists caution that larger studies are needed to quantify efficacy, improve patient selection, refine the therapeutic dose range, and develop a better understanding of the long-term risks of repeated ketamine treatments [312].

Nifedipine, a calcium channel blocker, has a strong theoretical basis for use in CRPS, and doses up to 60 mg/day can be useful in some patients [305]. Phenoxybenzamine and phentolamine are considered third-line agents for CRPS. Efficacy of phenoxybenzamine is supported, but it is more effective in syndromes under three months in duration. Phentolamine is used much less often due to cost and administration by continuous IV infusion.

Calcitonin is one of the few CRPS treatments validated by RCTs, and intranasal doses of 100–300 U per day are efficacious for CRPS-related bone pain [305]. Bisphosphonates such as alendronate, ibandronate, risedronate, zoledronate, etidronate, and pamidronate can ease bone pain in CRPS by slowing bone resorption. Alendronate is the most studied in this class [305].

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.

Interventional approaches supported for use in patients with CRPS are placed in a three-level sequence. Inadequate or partial response should initiate a stepwise progression moving from less to more invasive, in conjunction with non-interventional therapies [305]. This approach consists of [305]: