Autosomal dominant polycystic kidney disease (ADPKD): Pain syndromes

INTRODUCTION — Over 60 percent of patients with autosomal dominant polycystic kidney disease (ADPKD) have abdominal and flank pain [1]. Abdominal pain is typically related to the kidney cysts but may also be related to liver cysts. Pain may be acute or chronic.

Most patients can be effectively treated, but a minority develop chronic pain that is debilitating [2].

A thorough history provides the best clues to the underlying cause of pain, and radiographic studies are an important adjunct to making the diagnosis. Pain is often not well managed, because there is the reflex response of many clinicians to give narcotics for complaints of pain without understanding the etiology.

This topic provides an overview of the pathophysiology and common presentations of pain in ADPKD and a stepwise approach to its initial management, focusing on pain related to the kidneys.

The general management and the kidney and extrarenal manifestations of ADPKD are discussed separately. (See "Autosomal dominant polycystic kidney disease (ADPKD): Treatment" and "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations" and "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations".)

PATHOPHYSIOLOGY OF KIDNEY-RELATED PAIN — The kidneys and ureters are densely innervated by sympathetic, parasympathetic, and sensory afferent fibers (figure 1) [3-5].

This innervation is extensively cross-connected with nerve fibers to other visceral structures. As a result, pain related to the kidney (as any visceral pain) may be poorly localized and can be associated with nausea due to the proximity of the sensory fibers to the vagus. The pain can also be referred to a distant cutaneous site (resulting in tenderness) since the activated sensory afferent nerves also have receptive fields on the skin in corresponding dermatomes [6]. As an example, stimulation of the renal pelvis produces pain at the costovertebral angle and can also cause referred pain in the testicle or ovary.

Kidney pain may be precipitated by ischemia, inflammation, torsion or traction of the renal pedicle, and distension of the capsule.

PAIN SYNDROMES — ADPKD-associated pain may be acute or chronic [2]. Chronic pain is generally due to the enlarged cystic kidneys causing stretching of the capsule or traction on the renal pedicle [7]. Mechanical pain may also occur due to enlarging cysts that result in lumbar lordosis. Acute pain may be caused by cyst infection, cyst hemorrhage, and movement of a kidney stone (nephrolithiasis). Acute causes must be excluded in all patients with ADPKD who present with abdominal or flank pain. (See 'Evaluation' below.)

Acute pain — The most common causes of acute pain are kidney cyst infection, kidney cyst rupture/hemorrhage, and nephrolithiasis [8]. These conditions may be differentiated to some degree by patterns of pain and associated signs and symptoms (table 1).

Acute pain may also result from infection, hemorrhage, or, less commonly, rupture of hepatic cysts [9]. Discussion of the management of cystic liver disease is presented elsewhere. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations", section on 'Hepatic cysts' and "Diagnosis and management of cystic lesions of the liver", section on 'Polycystic liver disease'.)

Infection — Infected kidney cysts cause the sudden onset of diffuse flank pain that is typically unilateral. Radiation of pain outside of the localized area is uncommon, and the discomfort is not relieved by position change. As with any kidney infection, fever, nausea, malaise, and leukocytosis may be present. If the infected cyst is walled off and does not communicate with the urinary tract, the urine sediment may be bland and the urine culture negative. (See "Acute simple cystitis in adult and adolescent females".)

Acute pyelonephritis and infected cysts may be difficult to differentiate [2]. The diagnosis and management of cyst infection is discussed separately. (See "Autosomal dominant polycystic kidney disease (ADPKD): Evaluation and management of complicated urinary tract infections".)

Cyst rupture/hemorrhage — Patients with ruptured kidney cysts present with the sudden onset of pain, which is thought to be due to an acute increase in cyst size with distention of the kidney capsule [1]. Patients often have point tenderness, in contrast to those with cyst infection, who describe diffuse pain. However, mild diffuse flank pain may occur when a superficial cyst ruptures and causes a subcapsular hematoma [10].

Less commonly, patients describe ipsilateral shoulder pain, particularly when an upper pole cyst ruptures and irritates the diaphragm, or acute abdominal pain when a large hepatic or kidney cyst rupture involves surrounding viscera [11,12].

Approximately 50 percent of ADPKD patients with ruptured kidney cysts have gross hematuria due to the ruptured cyst communicating with the collecting system [13]. Episodes of hematuria usually resolve in two to seven days [2]. However, excessive bleeding can lead to clot formation, with urinary tract obstruction and severe renal colic. (See "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations", section on 'Hematuria'.)

Bleeding is typically managed conservatively with intravenous (IV) volume repletion, topical heat, and judicious narcotic administration [12,14]. Ureteral stenting is usually not necessary, unless obstruction due to clots persists beyond two weeks. Rarely, prolonged and severe bleeding may require percutaneous transarterial embolization or nephrectomy [15]. Embolization itself can cause severe pain related to parenchymal ischemia and can result in loss of kidney function [16]. Therefore, this procedure should only be considered in cases of severe intractable bleeding.

Nephrolithiasis — Kidney stones occur in approximately 20 to 35 percent of patients with ADPKD, and approximately two-thirds are symptomatic [13]. The pathogenesis, diagnosis, and management of nephrolithiasis in ADPKD are discussed separately. (See "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations", section on 'Nephrolithiasis'.)

Chronic pain — Chronic pain is estimated to affect up to two-thirds of patients with ADPKD. It may begin with an acute episode of pain and persist after the cause has been treated or develop gradually over several years [2]. Chronic kidney pain is more common in patients who have enlarged kidneys [17]. Pain is often dull and persistent and is thought to reflect either stretching of the capsule or traction on the renal pedicle [7]. However, the location of pain can vary, and patients can have pain unrelated to the kidneys.

In a review of 171 patients with ADPKD who filled out a questionnaire, the following order of frequency of pain was noted: low back pain, abdominal pain, headache, chest pain, and leg pain [18]. The severity of pain was usually moderate (4 to 5 out of 10). The HALT Progression of Polycystic Kidney Disease (HALT-PKD) trial, involving 1043 ADPKD patients, reported the presence of back and abdominal pain in 50 percent, with 20 percent experiencing daily symptoms. Symptoms relating to abdominal fullness and pain were more frequent in patients with reduced kidney function (estimated glomerular filtration rate [eGFR] 20 to 45 mL/min/1.73 m²), potentially due to both liver and kidney enlargement, especially in women.

Efforts are underway to develop standardized psychometric assessment tools in order to more rigorously study pain in patients with ADPKD [19,20].

Kidney cysts — Enlarging kidney cysts cause chronic pain by compressing surrounding tissues, placing traction on the renal pedicle, or distending the kidney capsule. Although the severity of pain generally correlates with the size of the kidneys, there is often little or no relationship between the severity of pain and the size or number of the kidney cysts: Patients with small cysts may have severe pain [2,21]. There is no correlation between kidney function and pain due to cysts; severe pain may occur among patients who have completely normal kidney function, and, in general, pain tends to start early in the course of disease, before kidney function begins to decline.

Pain related to cyst formation tends to be a steady, nagging discomfort that is exacerbated by walking or prolonged standing. It can also be associated with early satiety if massive cysts compress the greater curvature of the stomach and/or duodenum.

Patients can frequently pinpoint the pain with one finger, which is more often in an abdominal location rather than flank or lumbar. However, in our experience, the location of the pain described by the patient does not always correspond to the largest cyst(s) noted on imaging.

Hepatic cysts — Hepatic cysts may contribute to chronic abdominal or flank pain, although early satiety is much more commonly observed than pain among patients with hepatic cysts, in whom the enlarged cystic liver may occupy the entire abdominal cavity. In general, early satiety is more common among ADPKD patients who have both kidney and hepatic cysts than among those with kidney cysts alone. However, severe pain may occur; among affected patients, pain is generally most severe when the patient is erect, tends to be progressive, and may be resistant to therapy [18]. The management of hepatic cysts is discussed elsewhere. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations", section on 'Hepatic cysts' and "Diagnosis and management of cystic lesions of the liver", section on 'Polycystic liver disease'.)

Mechanical back pain — Among patients with ADPKD, musculoskeletal back pain is probably caused by unbalanced or abnormal load on the spine and lumbodorsal muscles, created by enlarged abdominal viscera (the kidneys, in extreme cases of ADPKD, may weigh as much as 3 to 4 kg, in contrast to the normal weight of 0.3 kg in a 70 kg man) [22]. Consistent with this hypothesis is the observation of paraspinal muscle group hypertrophy on magnetic resonance imaging (MRI) in ADPKD patients with back pain [12].

Mechanical back pain is insidious in onset and tends to worsen over time. Asymmetric cyst enlargement can lead to lateralization of pain and kyphosis, and the increased abdominal girth due to the enlarged kidneys (and possibly liver) can accentuate lumbar lordosis. These chronic alterations in posture can accelerate the development of degenerative changes in the spine and may predispose to spinal stenosis, which can further worsen back pain.

EVALUATION — It is important to determine the etiology of pain in an individual with ADPKD since some causes may result in severe systemic illness (such as cyst infection with septicemia).

Abdominal and/or flank pain — The evaluation of abdominal or back pain in patients with ADPKD differs from that of the general population only in the focus on excluding diagnoses that are more prevalent in this population, including kidney cyst-related causes (hemorrhage, rupture, or infection), pancreatic cysts, hernias, and diverticulitis. The evaluation of abdominal pain in the general population is discussed elsewhere. (See "Evaluation of the adult with abdominal pain" and "Evaluation of the adult with nontraumatic abdominal or flank pain in the emergency department" and "Causes of abdominal pain in adults".)

A systematic history assists in focusing the physical exam and directs the subsequent evaluation; thus, it may prevent unnecessary investigational and imaging studies. The history should elicit the following:

●Location and radiation of pain

●Quality of pain

●Rapidity of onset

●Frequency, intensity, and duration of pain

●Associated symptoms and abnormalities (eg, hematuria, fever)

●Precipitating and relieving factors

●Effect of activity or position on pain

●Relationship with food (eg, early satiety)

The physical exam should be directed at excluding causes of acute illness, such as pyelonephritis, and can be focused on the region affected by the pain. The temperature and pulse should be obtained, and the presence of diffuse or localized abdominal or flank tenderness, or musculoskeletal pain, should be determined. The comprehensive evaluation of patients with abdominal pain, back pain, and headache are discussed separately. (See "Evaluation of the adult with abdominal pain" and "Causes of abdominal pain in adults" and "Evaluation of low back pain in adults" and "Evaluation of headache in adults".)

A urinalysis and urine culture with antimicrobial susceptibility testing should be performed; these tests may distinguish among kidney infection (pyelonephritis or cyst infection), cyst rupture, and nephrolithiasis. (See "Autosomal dominant polycystic kidney disease (ADPKD): Evaluation and management of complicated urinary tract infections", section on 'Diagnosis'.)

Patients with suspected pyelonephritis or cyst infection should be treated with appropriate antibiotics. The evaluation and management of presumed complicated urinary tract infections in patients with ADPKD are discussed elsewhere. (See "Autosomal dominant polycystic kidney disease (ADPKD): Evaluation and management of complicated urinary tract infections", section on 'Management'.)

Among patients without suspected pyelonephritis or cyst infection, imaging tests (ultrasound or noncontrast computed tomography [CT]) are usually performed. A noncontrast CT is more sensitive for the detection of nephrolithiasis and is generally the preferred test for patients with ADPKD and acute onset flank or abdominal pain. A noncontrast CT will not differentiate between cyst infection and hemorrhage, however.

Once acute causes of pain are excluded, the patient may be presumed to have chronic pain associated with cyst enlargement. (See 'Chronic pain' above.)

Back pain — The evaluation of back pain is complex and requires a thorough evaluation that is similar to that for the general population. (See "Lumbar spinal stenosis: Pathophysiology, clinical features, and diagnosis".)

A detailed history of pain location, duration, and associated symptoms will help to differentiate musculoskeletal back pain from pain due to cyst formation. As an example, patients with mechanical back pain may describe exacerbation of pain with movements that increase the load on involved muscle groups (such as bending forward or to the side, or ambulating). Chronic abdominal pain in an anterior location is generally related to kidney or hepatic cyst formation.

For patients with chronic pain suspected to be of musculoskeletal origin who do not have associated symptoms, part of the evaluation may include a trial of simple pain management techniques, which may prove to be diagnostic. (See 'Physical interventions' below.)

Among ADPKD patients who have chronic back pain, magnetic resonance imaging (MRI) may reveal evidence of paraspinal/lumbodorsal muscle hypertrophy [12]. However, MRI is generally not done for this indication.

Recurrent pain — Pain may recur, especially several months after back exercises are discontinued. Recurrent pain may also be related to continuous cyst growth. Generally, the pattern of pain is similar to the initial presentation, and repeat imaging is not necessary. The onset of a different pattern of pain or new associated symptoms may warrant further investigation.

PAIN MANAGEMENT — Chronic narcotic administration is rarely needed and should be used as a last resort. The great majority of patients require no specific therapy for pain other than nonopioid analgesics (possibly including nonsteroidal antiinflammatory drugs [NSAIDs] for a limited duration). However, some patients have persistent pain that is severe enough to diminish the quality of life or to require opiates for pain control [23,24].

The focus of this section is on the management of pain related to cyst enlargement and possibly associated mechanical back pain. The table summarizes the treatment of kidney pain in ADPKD patients (table 1) [25]. The management of kidney infection and nephrolithiasis is discussed separately. (See "Autosomal dominant polycystic kidney disease (ADPKD): Evaluation and management of complicated urinary tract infections" and "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations", section on 'Nephrolithiasis' and "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis".)

There are no trials to provide guidance regarding the optimal management of chronic pain in the setting of enlarging cystic kidneys, and most of the approaches described in this section are standard pain clinic management strategies. These pain management options should be pursued in a sequential fashion, building from low-risk maneuvers and medications for mild intermittent pain to more complex medication regimens and physical or invasive interventions for moderate to severe chronic pain. Invasive interventions are rarely required.

As with the management of chronic pain of any cause, establishing a good rapport with the patient is important. This requires a nonjudgmental attitude on the part of the provider, particularly since pain cannot be objectively measured. We emphasize to our patients that chronic pain often cannot be "cured"; rather, the goal is to adequately control pain in order to reduce interference with the desired lifestyle.

Nonsurgical management

Physical interventions — Among ADPKD patients with chronic back pain, it is critical to maintain mobility, which may be done with physical therapy. If pain is sufficiently severe to limit the efficacy of physical therapy, concomitant medical therapy is indicated. Otherwise, a stepwise approach beginning with physical therapy is appropriate.

There are a variety of physical interventions, which have not been formally evaluated for the treatment of pain associated with ADPKD but are relatively free of risk if appropriately performed. (See "Subacute and chronic low back pain: Nonpharmacologic and pharmacologic treatment", section on 'Exercise therapy'.)

For mechanical back pain:

●Ice massage and heating pads, which may be particularly beneficial for muscle spasms.

●Psychophysical methods to improve body posture and mechanics, such as the Alexander technique [26,27]. The Alexander technique involves individualized, hands-on instruction to improve balance, posture, and coordination, as well as recognition of harmful habits of muscle use in order to avoid painful movements. (See "Exercise-based therapy for low back pain", section on 'Subacute and chronic low back pain: Exercise is beneficial'.)

For pain possibly related to enlarged kidneys pulling on the renal pedicle, wearing a support garment or corset may provide relief.

It is possible that weight control may help treatment of pain in patients with ADPKD. A post hoc analysis of a trial examining blood pressure therapy and targets in patients with ADPKD reported that obesity (ie, body mass index ≥30 kg/m²) was associated with worse back and radicular pain independent of kidney/liver volume, and that mild weight loss was associated with favorable effects on pain [28]. More studies are needed to determine if weight loss may be an effective means of controlling chronic pain in patients with ADPKD.  

Non-narcotic analgesics — The treatment of acute pain among ADPKD patients depends in part upon the underlying estimated glomerular filtration rate (eGFR). Among patients with a normal eGFR, we use acetaminophen, tramadol, and clonidine, alone or in combination. NSAIDs or cyclooxygenase-2 (COX-2) inhibitors may be used for a maximum of five to seven days, and we generally avoid these medications in patients at risk for NSAID- or COX-2 inhibitor-associated acute kidney injury (such as those >65 years of age, with concurrent heart failure, or on either diuretics or renin-angiotensin system inhibitors) [29,30]. (See "NSAIDs: Acute kidney injury" and "Overview of COX-2 selective NSAIDs", section on 'Kidney disease'.)

Among patients with reduced eGFR, we usually treat pain with acetaminophen, given its relatively low toxicity profile. Dosing can start at 650 mg every six hours and be increased to 1000 mg every six hours [30]. However, concomitant chronic alcohol consumption may lead to acetaminophen toxicity with this regimen; thus, alcohol drinking must be limited, or this regimen should not be used in heavy alcohol users [31]. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Clinical factors that may influence toxicity'.)

Among patients who have a reduced eGFR and pain that is not adequately relieved by acetaminophen, we add tramadol as an adjunctive agent. For patients with eGFR >30 mL/min/1.73 m², we suggest a dose of 50 to 100 mg every four to six hours. The dose should be adjusted for patients with eGFR ≤30 mL/min/1.73 m².

For patients with reduced eGFR who cannot take or do not respond to acetaminophen or tramadol, we use clonidine. We begin at 0.1 mg/day and titrate upward over several weeks, as tolerated, in order to achieve pain control. Tricyclic antidepressants used at bedtime can be a helpful adjunctive agent to bring pain under reasonable control.

When added to a local anesthetic for epidural, spinal, or peripheral blockade, clonidine can prolong and intensify anesthesia [32,33]. Oral or transdermal clonidine preparations may also be useful as adjuncts to narcotics for moderate pain, permitting modest dose reduction [34-36]. Clonidine may be safely given with acetaminophen or tramadol. Patients who are on clonidine should be observed closely for hypotension or, if medication is abruptly withdrawn, hypertension.

Anecdotal reports have suggested that gabapentin may be useful for the treatment of chronic pain, although there are no controlled studies that have been conducted in the ADPKD population using this pain medication for pain relief. Dose reduction of gabapentin is required for patients with reduced eGFR. Tricyclic antidepressants may also be useful adjuncts to help control pain. (See "Pharmacologic management of chronic non-cancer pain in adults".)

Opioids — Narcotic analgesics may be required for the management of acute moderate-to-severe pain. Opioids may be more effective when used in combination with other analgesic medications, such as acetaminophen, tramadol, or clonidine. In patients with elevated serum creatinine, opioid drugs must be dosed less frequency to avoid accumulation of active metabolites and meperidine completely avoided. Narcotic administration should be limited in use and used only after every other modality has been thoroughly exhausted. A general overview of opioid use and cautions with kidney function impairment are presented separately. (See "Cancer pain management with opioids: Optimizing analgesia", section on 'Patients with kidney impairment'.)

Intractable chronic pain can be treated with either long-acting oral or transdermal agents (eg, fentanyl patch). It is critical in addressing a chronic pain situation that the goals of therapy are clearly established as the first step in management. The patient MUST be told that curing chronic pain is extremely difficult or impossible. The goal of therapy is to reduce pain as much as possible, so it least interferes with the patient's lifestyle. Setting up the expectation that the patient's pain will be cured leads to failure and frustration in both the patient and the treating clinician.

Other interventions — Although not specifically studied in patients with ADPKD, a variety of other approaches have been used for the management of chronic pain, particularly neuropathic or chronic back pain, or visceral pain due to intra-abdominal cancers.

These interventions may provide temporary benefit and can be tried in patients with chronic pain that persists despite medical therapy, particularly in those settings where surgery does not offer a possible curative result (eg, cyst decompression) or is an extreme measure (eg, nephrectomy).

●Transcutaneous electrical nerve stimulation (TENS) – In our experience, some ADPKD patients with chronic, dull pain may benefit from intermittent TENS, although clinical trials in chronic back pain have not consistently shown benefit.

We suggest a two-week trial of TENS; patients who respond to TENS may use it long term with few side effects.

●Acupuncture – A trial of acupuncture is warranted in ADPKD-related pain as effectiveness has been demonstrated in the management of renal colic [37] and lithotripsy-related pain [38]. Acupuncture performed by an experienced operator is associated with minimal risk.

●Spinal cord stimulation – Spinal cord stimulation may be beneficial in selected patients with moderate-to-severe intractable mechanical back pain or visceral pain due to cyst enlargement. This requires implantation of a device that precludes future magnetic resonance imaging (MRI) studies.

●Celiac plexus blockade – Since both the sympathetic and parasympathetic supply to the kidney pass through the celiac plexus, celiac plexus blockade may be of benefit in the treatment of visceral pain due to cyst enlargement. Temporary celiac plexus block has been applied as a diagnostic maneuver to determine pain relief. In one study, this approach was integrated into an invasive treatment protocol for chronic refractory pain in 44 subjects with ADPKD [39]. In 36 subjects, the diagnostic celiac plexus block resulted in substantial relief on a standard visual analogue scale. Of these 36 subjects, 23 received a major splanchnic nerve block because pain recurred and reported a significant improvement in pain. In eight subjects without relief after the diagnostic block, renal denervation was performed in five subjects, with those subjects reporting a borderline significant change in pain. After a median follow-up of 12 months, the authors note that 81.8 percent of the patients entering this protocol experienced a sustained improvement in pain intensity.

●Neuraxial medications – Opioids and local anesthetics can be administered directly into the epidural or intrathecal space and may be useful in the management of mechanical back pain. However, dose-dependent side effects include motor blockade and urinary retention, and long-term use may result in tolerance and even hyperalgesia [40].

●Tolvaptan – Tolvaptan, an orally available antagonist of the vasopressin V2 receptor, is used to slow the decline of kidney function in selected patients with ADPKD [41,42] (see "Autosomal dominant polycystic kidney disease (ADPKD): Treatment", section on 'Tolvaptan'). Tolvaptan also resulted in a statistically significant decrease in kidney pain as assessed by a questionnaire (five versus seven events per 100 person-years of follow-up). However, we believe that the small potential benefit for treating kidney pain with tolvaptan does not outweigh the risk of adverse effects nor justify the cost of the drug for this off-label usage.

●Catheter-based renal denervation – This approach targets the aorticorenal plexus as a relay for pain signals from the kidney [43]. A case series of five subjects with pain attributable to ADPKD reported the results of percutaneous renal denervation with a single-electrode radiofrequency ablation catheter [44]. This pilot study found an encouraging nonsignificant decrease in the use of analgesic medications from 1.4 to 0 at 12 months postintervention. Larger studies are needed to understand the risks and benefits of such an approach in ADPKD patients. Catheter-based renal denervation was also part of the stepwise invasive treatment protocol described above.

Surgical management — Most patients experience substantial pain relief with noninvasive management. However, pain recurrence is common, and surgical intervention may be required if the pain is persistent, disabling, or controlled only with opiates.

Once acute pain is controlled in a patient with ADPKD considering surgical pain management, we obtain imaging (ultrasonography, computed tomography [CT] scan, or magnetic resonance [MR]) to determine whether a large cyst is present in the area of pain. Ultrasound- or CT-guided aspiration and sclerosis or surgical drainage may be considered. However, aspiration of a cyst(s) is usually not advised, because of reaccumulation of fluid in the affected cyst(s) after aspiration. Injecting a small amount of saline into the suspected culprit cyst can be a helpful diagnostic tool if the patient's pain pattern is reproduced by this maneuver. Unroofing of the cyst (marsupialization) via a laparoscopic approach may be successful in permanent reduction/relief of pain after localizing the exact source for the patient's pain pattern.

SUMMARY AND RECOMMENDATIONS

●Pain syndromes – Pain in the flank and abdomen is common among patients with autosomal dominant polycystic kidney disease (ADPKD). Acute pain suggests a superimposed condition such as cyst hemorrhage or infection or nephrolithiasis. Chronic pain is generally due to the enlarged cystic kidneys causing stretching of the capsule or traction on the renal pedicle, mechanical back pain, or hepatic cyst enlargement. (See 'Introduction' above and 'Pain syndromes' above and 'Hepatic cysts' above.)

●Evaluation of pain – A systematic history helps to focus the physical examination and directs the work-up. A urinalysis is particularly useful in the investigation of acute abdominal or flank pain. Imaging tests are performed if the cause of pain remains unclear after the history, comprehensive physical examination, and urinalysis. (See 'Evaluation' above.)

●Pain management – There are no trials to provide guidance regarding the optimal management of chronic pain in the setting of enlarging cystic kidneys or liver. We use standard pain clinic management strategies that are modified for patients with potentially reduced kidney function. For most ADPKD patients with acute or chronic pain, we suggest the following approach (see 'Pain management' above):

•For the initial management of pain possibly related to cystic kidney enlargement or mechanical back pain, we suggest a trial of physical interventions. (See 'Physical interventions' above.)

•For the treatment of pain in patients with normal kidney function, we suggest acetaminophen, tramadol, and clonidine, alone or in combination. Nonsteroidal antiinflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors may be used for a maximum of five to seven days, although we generally avoid these medications in patients at risk for NSAID- or COX-2 inhibitor-associated acute kidney injury (such as those >65 years of age, with concurrent heart failure, or on either diuretics or renin-angiotensin system inhibitors). (See 'Non-narcotic analgesics' above.)

•For the treatment of pain in patients with reduced estimated glomerular filtration rate (eGFR), we suggest acetaminophen, given its relatively low toxicity profile. High-dose acetaminophen should not be used in heavy alcohol drinkers. For persistent pain, we suggest adding tramadol to acetaminophen. The preferred dose among patients with eGFR >30 mL/min/1.73 m² is 50 to 100 mg every four to six hours. The dose should be reduced among patients with eGFR ≤30 mL/min/1.73 m². Oral or transdermal clonidine may also be used if tramadol is ineffective. We administer clonidine 0.1 mg/day and titrate the dose upward over several weeks. Clonidine may be safely given with acetaminophen or tramadol. Patients who are on clonidine should be observed closely for hypotension or, if medication is abruptly withdrawn, hypertension. (See 'Non-narcotic analgesics' above.)

•Narcotic analgesics may be required to treat moderate to severe pain that is unresponsive to other measures. In patients with elevated serum creatinine, opioid drugs must be dosed less frequency to avoid accumulation of active metabolites and meperidine completely avoided. (See 'Opioids' above and "Cancer pain management with opioids: Optimizing analgesia", section on 'Patients with kidney impairment'.)

•Although not specifically studied in patients with ADPKD, a variety of other interventions have been used for the management of chronic pain. These can be tried in patients with chronic pain that persists despite medical therapy. (See 'Other interventions' above.)

•Surgery may be an option for some patients with ADPKD and persistent pain despite an adequate trial of medical and noninvasive therapies. (See 'Surgical management' above.)