Chronic Pain Syndromes: Current Concepts and Treatment Strategies

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Self-Assessment Questions

    1 . Nociceptive pain is
    A) a physiologic response to tissue injury.
    B) the result of central nervous system injury.
    C) strictly pathologic and has no adaptive function.
    D) a perception that arises from activation of the immune response.

    BACKGROUND

    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.

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    2 . Which of the following is an example of a centralized pain syndrome?
    A) Cancer pain
    B) Fibromyalgia
    C) Postsurgical pain
    D) Postherpetic neuralgia

    BACKGROUND

    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].

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    3 . The most common diagnosis for patients seeking primary care attention for chest pain is
    A) trauma.
    B) costochondritis.
    C) unstable angina.
    D) musculoskeletal chest pain.

    VISCERAL AND REFERRED PAIN

    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].

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    4 . Which of the following pharmacotherapies is NOT effective for the treatment of acute exacerbations of chronic functional abdominal visceral pain?
    A) Opioids
    B) Probiotics
    C) Tricyclic antidepressants (TCAs)
    D) Nonsteroidal anti-inflammatory drugs (NSAIDs)

    VISCERAL AND REFERRED PAIN

    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].

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    5 . In patients with cancer, hepatic distension syndrome is categorized as
    A) acute treatment-related pain.
    B) a chronic nociceptive pain syndrome.
    C) an acute pain syndrome related to bisphosphonate use.
    D) a chronic pain syndrome resulting from visceral involvement of the neoplasm.

    CANCER PAIN

    COMMON CANCER PAIN SYNDROMES

    Tumor-Related PainTreatment-Related Pain
    Acute pain
    Vertebral collapse and other pathologic fractures
    Acute obstruction of hollow viscus
    Headache from intracranial hypertension
    Hemorrhage into tumor
    Chemotherapy
    • Painful oropharyngeal mucositis

    • Painful peripheral neuropathy

    • Bone/muscle pain from colony-stimulating factors or chemotherapies

    Radiation therapy
    • Painful oropharyngeal mucositis

    • Radiation enteritis and proctocolitis

    • Early-onset brachial plexopathy

    • Painful dermatitis

    • Hormone therapy

    • Bone pain flare

    • Arthralgia, myalgia

    Nociceptive pain syndromes (chronic pain)
    Bone and joint/soft tissue pain syndromes
    • Multifocal or generalized pain (focal metastases or marrow expansion)

    • Base of skull metastases

    • Vertebral syndromes

    • Pain syndromes of bony pelvis or hip

    • Tumor invasion of joint or soft tissue

    Paraneoplastic pain syndromes (e.g., hypertrophic osteoarthropathy)
    Tumor-related gynecomastia
    Painful osteonecrosis
    • Radiation- or corticosteroid-induced necrosis of femoral or humeral head

    • Osteoradionecrosis of other bones

    Painful lymphedema
    Painful gynecomastia
    Chronic abdominal pain
    • Due to intraperitoneal chemotherapy

    • Due to radiation therapy

    Radiation-induced chronic pelvic pain
    Visceral involvement of neoplasm (chronic pain)
    Hepatic distension syndrome
    Rostral retroperitoneal syndrome
    Chronic intestinal obstruction
    Peritoneal carcinomatosis
    Malignant pelvic and perineal pain
    Chronic ureteral obstruction
    Neuropathic pain syndromes (chronic pain)
    Painful peripheral mononeuropathies
    Painful polyneuropathies
    Plexopathy
    • Cervical

    • Brachial

    • Lumbosacral

    • Sacral

    Postsurgical neuropathic pain syndromes
    • Postmastectomy syndrome

    • Post-thoracotomy syndrome

    • Postradical neck dissection syndrome

    • Postnephrectomy syndrome

    • Stump pain/phantom limb pain

    Postradiotherapy pain syndromes
    • Radiation fibrosis of cervical, brachial, or lumbosacral plexus

    • Radiation-induced neoplasm

    • Radiation myelopathy

    Postchemotherapy pain syndromes
    Bisphosphonate-related pain (chronic pain)
    Bone pain
    Osteonecrosis
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    6 . The initial treatment of opioid-naïve patients with severe cancer-related pain is
    A) IV 2–5 mg morphine or equivalent.
    B) IV 0.25–0.5 mg morphine or equivalent.
    C) 20–50 mg morphine or equivalent orally.
    D) Either A or C

    CANCER PAIN

    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].

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    7 . The recommended adjuvant analgesic for cancer-related pain attributed to nerve compression or inflammation is
    A) duloxetine.
    B) gabapentin.
    C) a trial of NSAIDs or corticosteroids.
    D) a topical agent (e.g., lidocaine patch 5%).

    CANCER PAIN

    ADJUVANT ANALGESICS FOR CANCER-RELATED PAIN

    Type of PainRecommended Adjuvant Analgesic
    Neuropathic pain
    Antidepressants (first-line: amitriptyline, imipramine, nortriptyline, desipramine; second-line: duloxetine, venlafaxine)
    Anticonvulsants (first-line: gabapentin, pregabalin)
    Topical agents (lidocaine patch 5%, diclofenac gel 1%, or diclofenac patch 180 mg)
    Corticosteroids (if neural structures or bones are involved)
    Nerve compression or inflammationTrial of NSAIDs or corticosteroids
    Bone pain without oncologic emergency
    NSAIDs
    Bisphosphonates or other bone-modifying agents
    For diffuse bone pain: hormone therapy or chemotherapy, corticosteroids, and/or systemic radioisotopes
    For local bone pain: local radiation therapy, nerve block, vertebroplasty, or kyphoplasty
    Painful lesions likely to respond to antineoplastic therapiesTrial of radiation, hormones, or chemotherapy
    NSAIDs = nonsteroidal anti-inflammatory drugs.
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    8 . For patients with cancer-related pain, cold therapy
    A) should always be avoided.
    B) should be avoided in patients with bleeding disorders.
    C) is recommended for use in those with peripheral vascular disease.
    D) provides relief for pain related to muscle spasms induced by nerve injury.

    CANCER PAIN

    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.

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    9 . Among primary care patients with back pain, the most common etiology is
    A) nonspecific.
    B) herniated disk.
    C) spinal stenosis.
    D) ankylosing spondylitis.

    PAIN OF SPINAL ORIGIN

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

    • Nonspecific LBP: 85%

    • Herniated disk: 4%

    • Compression fracture: 4%

    • Spinal stenosis: 3%

    • Cancer: 0.7%

    • Ankylosing spondylitis: 0.3%

    • Cauda equina syndrome: 0.04%

    • Spinal infections: 0.01%

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    10 . Which of the following is considered a "red flag" when assessing the patient with chronic low back pain?
    A) Prior history of cancer
    B) Fear avoidance beliefs
    C) Depression and anxiety
    D) Reluctance to self-manage

    PAIN OF SPINAL ORIGIN

    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].

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    11 . Which risk factor is the strongest indicator of poor recovery from whiplash-associated disorders?
    A) Delayed onset neck pain
    B) Crash impact at the rear of the vehicle
    C) High initial levels of pain and/or disability
    D) Ability to be ambulatory without interruption

    PAIN OF SPINAL ORIGIN

    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].

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    12 . The increase in cytokine release that accompanies joint inflammation and pathologic structural changes characteristic of osteoarthritis results in
    A) bone marrow lesions.
    B) peripheral sensitization.
    C) bilateral pain distribution.
    D) pain with unusual movements.

    ARTHRITIC PAIN CONDITIONS

    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].

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    13 . Which of the following approaches to the initial management of knee osteoarthritis has the strongest recommendation for use?
    A) Tai chi
    B) Oral NSAIDs
    C) Exercise
    D) Intra-articular corticosteroid injections

    ARTHRITIC PAIN CONDITIONS

    HAND OSTEOARTHRITIS, INITIAL MANAGEMENT

    Strength of RecommendationRecommended Approaches
    Nonpharmacologic recommendations
    Strong recommendationsa
    Exercise (strongly recommended for all patients with OA, but more evidence for its benefit for knee/hip OA)
    Patient participation in self-efficacy, self-management programs
    Hand orthoses for patients with first CMC joint OA
    Conditional recommendationsb
    Cognitive-behavioral therapy
    Hand orthoses for patients with OA in joint of the hand other than first CMC joint
    Acupuncture
    Thermal interventions (e.g., moist heat, diathermy, ultrasound, hot/cold pack, paraffin)
    No recommendations
    Balance training
    Weight loss
    Tai chi, yoga
    Pharmacologic recommendations
    Strong recommendationsaOral NSAIDs
    Conditional recommendationsb

    One or more of the following:

    • Topical NSAIDs

    • Intra-articular glucocorticoid injection

    • Acetaminophen

    • Duloxetine

    • Tramadol

    • Chondroitin sulfate

    Strong recommendations against usinga
    Bisphosphonates
    Glucosamine
    Hydroxychloroquine
    Methotrexate
    Biologics (e.g., tumor necrosis factor inhibitors)
    Conditional recommendations against usingbIntra-articular therapies
    No recommendations
    Ultrasound-guided intra-articular glucocorticoid injection
    Intra-articular botulinum toxin
    Prolotherapy
    Platelet-rich plasma
    Stem cell injection
    CMC = carpometacarpal, NSAID = nonsteroidal anti-inflammatory drug, OA = osteoarthritis.
    aCompelling evidence of efficacy with benefits that clearly outweigh harms and burdens
    bQuality of evidence proved low or very low and/or balance of benefits versus harms and burdens was close, requiring shared decision-making between patient and clinician.
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    14 . Which of the following is NOT one of the possible courses of rheumatoid arthritis?
    A) Polycyclic
    B) Regressive
    C) Progressive
    D) Monocyclic

    ARTHRITIC PAIN CONDITIONS

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

    • Monocyclic: A single episode ending within two to five years of initial diagnosis without recurrence. This outcome may be attributable to early diagnosis and/or aggressive treatment.

    • Polycyclic: Characterized by a fluctuating level of disease activity throughout the course of the condition.

    • Progressive: The disease progressively increases in its severity and is unremitting.

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    15 . For patients with early rheumatoid arthritis (less than six months in duration), first-line therapy is
    A) corticosteroids.
    B) oral DMARDs.
    C) topical capsaicin.
    D) biologic DMARDs.

    ARTHRITIC PAIN CONDITIONS

    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].

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    16 . Dietary modification involved in the treatment of gout should include avoidance of
    A) vegetables.
    B) organ meats.
    C) non-fat dairy products.
    D) All of the above

    ARTHRITIC PAIN CONDITIONS

    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].

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    17 . Urate-lowering therapy should be initiated in patients with gout and
    A) one or more tophi.
    B) no history of urolithiasis.
    C) stage 1 chronic kidney disease.
    D) fewer than two attacks per year.

    ARTHRITIC PAIN CONDITIONS

    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].

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    18 . After 15 years of suffering migraines, approximately what percentage of women no longer have migraine attacks?
    A) 22%
    B) 30%
    C) 40%
    D) 63%

    HEADACHE

    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].

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    19 . If migraine symptoms persist for more than 72 hours, the treatment of choice is
    A) triptans.
    B) prochlorperazine.
    C) over-the-counter NSAIDs.
    D) dihydroergotamine mesylate (DHE).

    HEADACHE

    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.

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    20 . Tension-type headaches that occur on 14 days per month are classified as
    A) chronic.
    B) episodic.
    C) infrequent chronic.
    D) infrequent episodic.

    HEADACHE

    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].

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    21 . In patients with endometriosis, the usual endometrial responsiveness to progesterone is
    A) blunted.
    B) heightened.
    C) unchanged.
    D) highly variable.

    ENDOMETRIOSIS

    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].

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    22 . Which of the following statements regarding the treatment of endometriosis is TRUE?
    A) Danazol is the first-line agent of choice.
    B) Opioids should be considered first for severe pain.
    C) First-line pharmacotherapy includes the use of NSAIDs.
    D) Laparoscopic surgical removal of ectopic endometrial tissue should be avoided, if possible.

    ENDOMETRIOSIS

    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]:

    • Opioids

    • Gonadotropin-releasing hormone (GnRH) agonists with add-back hormone replacement

    • Levonorgestrel-releasing intrauterine system

    • Depot progestins

    • Aromatase inhibitors

    • Selective progesterone receptor modulators

    • GnRH antagonists

    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].

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    23 . Sickle cell disease is found predominantly in persons of
    A) African descent.
    B) Saudi Arabian descent.
    C) Mediterranean descent.
    D) Northern European descent.

    SICKLE CELL DISEASE

    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].

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    24 . During the prodromal phase of an acute sickle cell disease attack, what symptoms are present?
    A) Lethargy and mild localized pain
    B) Hyperactivity and moderate pain
    C) Moderate pain, alterations in mood, and decreased hemoglobin
    D) Severe pain and laboratory changes, including dramatically increased C-reactive protein levels

    SICKLE CELL DISEASE

    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]:

    • Prodromal: Lethargy and mild localized pain may develop, but hematologic changes have not yet occurred.

    • Initial infarctive: Pain intensity increases from mild to moderate, hemoglobin decreases, and alterations in mood develop. Laboratory findings lag behind patient self-report of symptoms. Prompt physician attention to patient report of symptom onset is essential to initial management.

    • Post-infarctive/inflammatory: Severe pain peaks, with intensity that causes patients to seek emergency department or hospital care for pain relief. Laboratory changes include increases in reticulocyte count, lactate dehydrogenase, and C-reactive protein. During crisis, C-reactive protein levels can rise to 70 mg/L, compared with an average 32.2 mg/L in patients with sickle cell disease not in crisis and 10 mg/L in persons without sickle cell disease.

    • Resolution: Pain during crisis returns to a moderate intensity following adequate fluid hydration and intravenous analgesics.

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    25 . What pharmacologic option is most often used for prevention of acute pain episodes in patients with sickle cell disease?
    A) Morphine
    B) Hydroxyurea
    C) Hydromorphone
    D) Blood transfusion

    SICKLE CELL DISEASE

    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.

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    26 . Which of the following is NOT a risk factor for the development of postherpetic neuralgia?
    A) Male sex
    B) Depression
    C) Severe rash
    D) Immunocompromise

    POSTHERPETIC NEURALGIA

    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]:

    • Intensity of zoster pain at onset

    • Severity of the rash

    • Presence and duration of pain before onset of rash

    • Psychosocial factors, such as depression

    • Female sex

    • Immunocompromise

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    27 . The most important strategy for the management of postherpetic neuralgia is
    A) the incorporation of lifestyle changes.
    B) early treatment of herpes zoster outbreaks.
    C) prevention of herpes zoster with the VZV vaccine.
    D) the use of strong analgesics to prevent breakthrough pain.

    POSTHERPETIC NEURALGIA

    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].

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    28 . Among persons with limb amputation, what proportion experience phantom limb pain?
    A) 6% to 8%
    B) 15% to 30%
    C) 20% to 40%
    D) 60% to 80%

    POST-AMPUTATION PAIN

    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].

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    29 . Mirror therapy consists of
    A) using a mirror to perform daily affirmations.
    B) viewing the reflection of the residual limb while completing exercises with the intact limb.
    C) viewing the reflection of the intact limb while performing exercises with the amputated limb.
    D) reprocessing emotional memories via eye movement desensitization and reprocessing techniques.

    POST-AMPUTATION PAIN

    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].

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    30 . To reach efficacy, patients with phantom limb pain may require a daily tramadol dose of
    A) 323 mg.
    B) 523 mg.
    C) 830 mg.
    D) 1,000 mg.

    POST-AMPUTATION PAIN

    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].

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    31 . The most common sites of painful diabetic neuropathy are the
    A) neck or trunk.
    B) hands or arms.
    C) feet or lower legs.
    D) back and buttocks.

    DIABETIC NEUROPATHY

    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].

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    32 . Diabetic focal neuropathy presents as
    A) changes in sexual function.
    B) autonomic symptoms such as resting tachycardia and sweating.
    C) sudden-onset pain or loss of motor function involving the head, torso, or leg.
    D) unilateral pain in the thighs, hips, buttocks, or legs that results in lower extremity weakness.

    DIABETIC NEUROPATHY

    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].

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    33 . According to the American Academy of Neurology, the first-line pharmacologic approach to the treatment of diabetic neuropathy pain is
    A) TCAs.
    B) opioids.
    C) pregabalin.
    D) venlafaxine ER.

    DIABETIC NEUROPATHY

    PRACTICE GUIDELINE RECOMMENDATIONS FOR THE PHARMACOLOGIC TREATMENT OF DIABETIC NEUROPATHY PAIN

    ApproachRecommended Pharmacotherapy by Recommending Organization
    American Academy of NeurologyToronto Expert Panel on Diabetic NeuropathyEuropean Federation of Neurological Societies Task Force
    First-linePregabalin
    TCAs
    SNRIs
    Anticonvulsants
    Opiates
    Membrane stabilizers
    Alpha-lipoic acid
    Capsaicin
    Pregabalin
    Gabapentin
    Duloxetine
    TCAs
    Venlafaxine ER
    Second- or third-line
    Opioids (e.g., morphine tramadol, oxycodone CR)
    Venlafaxine
    Duloxetine
    Amitriptyline
    Gabapentin
    Valproate
    Capsaicin
    Dextromethorphan
    Opioids (e.g., morphine, tramadol, oxycodone CR)
    Spinal cord stimulation
    Opioids
    Tramadol
    Spinal cord stimulation
    CR = controlled release, ER = extended release, SNRI = serotonin-norepinephrine reuptake inhibitor, TCA = tricyclic antidepressant.
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    34 . What is the only pain therapy for diabetic neuropathy that potentially addresses the underlying pathophysiologic process?
    A) SNRIs
    B) Insulin
    C) Capsaicin
    D) Alpha-lipoic acid (ALA)

    DIABETIC NEUROPATHY

    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].

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    35 . What is the cardinal feature of complex regional pain syndrome (CRPS)?
    A) Changes in cardiovascular function
    B) Pain experienced in a part of a limb that has been amputated
    C) Allodynia and hyperalgesia in the neck region and possibly remote peripheral sites
    D) Continuous and progressively severe intense pain disproportionate to the severity of the initial injury

    COMPLEX REGIONAL PAIN SYNDROME

    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].

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    36 . All of the following are common trophic changes characteristic of CRPS, EXCEPT:
    A) Tremor
    B) Fibrosis
    C) Osteoporosis
    D) Abnormal nail growth

    COMPLEX REGIONAL PAIN SYNDROME

    COMMON CLINICAL CHARACTERISTICS OF CRPS

    Autonomic AbnormalitiesMotor AbnormalitiesTrophic Changes
    Distal extremity swelling, especially in acute phase
    Hyper- or hypohidrosis
    Vasodilatation or vasoconstriction
    Changes in skin temperature
    Weakness
    Coordination deficits
    Tremor
    Neglect-like symptoms of disturbed body perception of affected limb
    Dystonia
    Abnormal nail growth
    Increased or decreased hair growth
    Fibrosis
    Thin, glossy skin
    Osteoporosis
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    37 . The analgesic of choice for recurrent or treatment-resistant CRPS in the presence of depression and insomnia is
    A) anticonvulsants.
    B) calcium channel blockers.
    C) systemic or targeted steroids.
    D) sedative analgesic antidepressants.

    COMPLEX REGIONAL PAIN SYNDROME

    ANALGESIC SELECTION FOR RECURRENT OR TREATMENT-RESISTANT CRPS

    Reason for Inability to Begin or ProgressAction
    Mild-to-moderate painSimple analgesics and/or blocks
    Excruciating, intractable painOpioids and/or blocks or more experimental interventions (if continued non-response)
    Inflammation/swelling and edemaSteroids, systemic or targeted (acutely), or NSAIDs (chronically); immune modulators
    Depression, anxiety, insomniaSedative analgesic antidepressant/anxiolytics and/or psychotherapy
    Significant allodynia/hyperalgesiaAnticonvulsants and/or other sodium channel blockers and/or NMDA receptor antagonists
    Significant osteopenia, immobility, and trophic changesCalcitonin or bisphosphonates
    Profound vasomotor disturbanceCalcium channel blockers, sympatholytics, and/or blocks
    NMDA = N-methyl-D-aspartate, NSAID = nonsteroidal anti-inflammatory drug.
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    38 . Which topical treatment has often been found intolerably painful and unacceptable by patients with CRPS?
    A) Capsaicin
    B) 5% lidocaine patch
    C) Dimethyl sulfoxide cream
    D) None of the above

    COMPLEX REGIONAL PAIN SYNDROME

    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.

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    39 . Which of the following is NOT a sign/ symptom of fibromyalgia?
    A) Morning stiffness
    B) Sleep disturbances
    C) High pain threshold to thermal stimuli
    D) Sensitivity to loud noises or bright lights

    FIBROMYALGIA

    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]:

    • Morning stiffness

    • Tingling or numbness in the extremities

    • Headache that may include migraine

    • Irritable bowel syndrome

    • Sleep disturbances

    • Cognitive and memory dysfunction (referred to as "fibro fog")

    • Dysmenorrhea

    • Restless legs syndrome

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

    • Hypersensitivity to painful stimuli applied to somatic structures, including painful and non-painful sites and normal control areas

    • Low pain thresholds to thermal, mechanical, electrical, and chemical stimuli

    • Pain increases with repeated stimulation (enhanced temporal summation)

    • Temperature sensitivity

    • Sensitivity to loud noises or bright lights

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    40 . Which of the following medications is FDA-approved for the treatment of fibromyalgia?
    A) Duloxetine
    B) Gabapentin
    C) Amitriptyline
    D) Cyclobenzaprine

    FIBROMYALGIA

    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].

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