Current Diagnosis & Treatment of Pain, 1st Edition
11. Visceral Pain
Timothy J. Ness MD, PhD
- The hallmark feature is poor localization in the chest, abdomen, or pelvis.
- May be perceived as located within somatic structures (referred pain).
- May sensitize somatic structures (secondary hyperalgesia).
- Often associated with a visceral function, such as eating, voiding, or defecating.
- May represent a neoplastic or a benign process.
- Often associated with strong emotional and autonomic responses.
- Nonspecificity of Symptoms
Chronic pain localized to the chest, abdomen, or pelvis can have multiple etiologies ranging from focal sites of inflammation to idiopathic systemic diseases to processes secondary to cancer. These pains fall within the practice of virtually every medical specialty and are some of the most common presenting symptoms for the primary care physician. When the internal organs of the body are the site of origin of pain sensation, the pain is defined as visceral.
Because of the diffuse nature of the organization of visceral sensory pathways, visceral sensations may be perceived as located within general body regions or within nonvisceral structures (referred pain). Visceral stimuli can evoke stronger than usual emotional responses, but psychological disturbance may also manifest as complaints of abdominal or chest discomfort. Often, organ-specific localization occurs only with direct stimulation of the organ by physical examination. Indirect evidence for an organ's involvement is an association of the pain with a bodily function, such as urination.
The disease states leading to visceral pain are numerous and discussion of all possibilities is beyond the scope of this chapter. Pains due to cancer and ischemic cardiac disease form special cases due to their profound clinical significance and so are discussed more extensively in Chapters 8 and 18. Likewise, gynecologic pains are also unique and are discussed in Chapter 17. Hence, the scope of this chapter will be to focus on pain arising in organs inhabiting the peritoneal cavity, with discussions related to the more common disease states such as kidney stones, chronic pancreatitis, irritable bowel syndrome (IBS), and interstitial cystitis (IC) as well as a cursory description of less common disorders.
- Stimuli Producing Visceral Pain
The visceral stimuli that produce reports of pain fall into four main groupings:
- Chemical stimuli that are secondary to local inflammatory processes.
- Chemical stimuli that are secondary to ischemia.
- Mechanical stimuli that are secondary to compressive and obstructive processes and may be modified by inflammation or ischemia.
- “Functional” stimuli, which are mechanical or chemical stimuli that occur naturally and are typically within physiologic ranges when measured but, for undetermined reasons, lead to profound discomfort.
Cancer, with its diffuse disruption of physiologic processes can produce chemical or mechanical stimuli and be mistaken as functional stimuli. Ischemic stimuli, particularly when recognized as present in cardiac or mesenteric sites, prompt immediate treatment to either reduce metabolic demand or to improve blood and oxygen delivery.
When evaluating symptoms, determining whether the primary pathologic process is potentially life- or tissue-threatening or whether the symptoms indicate syndromes that merely reduce the patient's quality of life is crucial. Symptoms alone cannot distinguish between these differing stimuli that produce visceral pain (TableS 11-1 and 11-2). Many visceral pains are syndromes rather than defined pathophysiologic diseases, so treatments may often be empiric. Hence, evaluation of the distressed patient with chronic visceral pain needs to take into account whether an appropriate, but not necessarily exhaustive, neoplastic work-up has been performed and then perform system-appropriate evaluations to rule
out the presence of readily treatable sources of the pain. A systematic trial of therapeutic options then becomes appropriate.
Table 11-1. Life-or Tissue-Threatening Sources of Visceral Pain.
- General Evaluation of Abdominal and Pelvic Pain
Abdominal pain is a common presenting symptom for the primary care clinician. Initial evaluation includes an interview to assess the acute versus chronic nature of the complaints, exacerbating and ameliorating factors, and history of coexisting disease. Long-term use of medications that alter bowel motility is meaningful. A functionally accurate diagnosis may be determined, based on clinical history, in 75% of patients. Palpation of the abdomen can identify abdominal wall rigidity, suggesting a peritoneal process; distended bowel or underlying masses, suggesting a neoplastic, infectious, or obstructive processes; and localized tenderness, which may suggest a particular organ system. Auscultation of bowel sounds assesses gastrointestinal motility and gives evidence of obstruction.
Rectal and pelvic examinations may give additional information related to local disease. Neurologic examination may demonstrate evidence of neuropathy or localized radiculopathy. Testing for fecal blood, urinalysis, blood cell count with white cell differential, serum amylase and lipase levels, electrolytes, and liver function tests all are considered routine. Determining if performing other tests, such as radiographic evaluations, endoscopic evaluations, ultrasonography, paracentesis or advanced imaging studies, would be helpful depends on the persistence or progression of complaints.
Table 11-2. Quality-of-Life-Related Chronic Visceral Pain Disorders.
Life- or Tissue-Threatening Disorders
Neoplasms can arise in any visceral structure. Symptoms related to these cancers are similar for all sites, with dull and constant pain a common “early” symptom. Pain is generally localized to the chest or upper abdomen for upper gastrointestinal tract lesions and organs located in the upper abdomen. It is generally localized to lower abdomen and perineum for lower gastrointestinal tract lesions and pelvic organs.
Unfortunately, no symptoms or location is pathognomonic for any specific disease site due to the potential presence of metastatic extension prior to diagnosis. Visceral cancers are frequently asymptomatic until obstruction or invasion of other structures occurs. Anorexia, weight loss, fatigue, nausea, and virtually every other nonspecific symptom can be noted at presentation. Anemia, hematemesis, melena, hematuria, and palpable masses on physical examination may direct further investigation. Appropriate imaging and surgical exploration or biopsy are the definitive diagnostic modalities. Sources of cancer-related pain can be multifactorial (Table 11-3) with components due to local tumor effects or more generalized somatic or neuropathic components due to local involvement and metastases.
Treating the cancer may also be pain-producing. Patterns of tumor spread differ between types of tumors, and so general patterns of symptoms related to metastases
also differ. Tumors of the gastrointestinal tract tend to spread through the lymphatics toward the liver and may present with diffuse abdominal complaints. In contrast, prostatic tumors frequently involve the lumbar spine and may present as back pain.
Table 11-3. Cancer Pain Syndromes.
Treatment of the cancer (eg, surgery, chemotherapy, radiotherapy) whether it is curative or palliative is considered a primary treatment for pain. Nerve-killing procedures are an option with the particular site of treatment determined by the site of the symptomatic cancer. For example, celiac plexus blocks may be of benefit for tumors in the upper abdomen, superior hypogastric blocks for tumors in the pelvis, and ganglion of Impar blocks for perirectal and perineal symptoms.
Because various urologic or gastrointestinal structures may become obstructed by neighboring or infiltrating tumor, stenting or diversion of obstructed ureters or bowel segments may be necessary.
Medical treatments are often empirically driven with the aggressive use of opioids, antiinflammatories, antiemetics, and adjuvant medications.
It is notable that when the cancer has responded to treatment but the treatment itself has proved to be pain-producing, there is frequently reticence on the part of clinicians to provide continued aggressive management of symptoms. Neuropathies, radiation enteritis and colitis, postsurgical phantom pain, neuroma formation, altered biomechanics, adhesions and strictures as well as other effects of “scarring” can all act as pain generators or modulators that may require reinvestigation of the primary metastatic process.
Mercadante S et al. Celiac plexus block for pancreatic cancer pain: factors influencing pain, symptoms, and quality of life. J Pain Symptom Manage.2003;26:1140 .
Van Heek NT et al. Palliative treatment in “peri”-pancreatic carcinoma: stenting or surgical therapy? Acta Gastroenterol Belg. 2002;65:171 .
Chronic Mesenteric Ischemia & Ischemic Colitis
Inadequate blood supply to meet the energy demands of abdominal viscera can lead to reports of pain in a way similar to cardiac angina. When ischemia is present in the gastrointestinal system, severe abdominal pain may be precipitated by the ingestion of a meal. As a consequence, a fear of eating with subsequent weight loss and poor nutritional status may further compromise patients already suffering from atherosclerotic disease. Necrosis of gut wall with subsequent perforation and peritonitis are end-stage manifestations with high mortality. More frequent is compromise of the mucosal barrier to absorption of the bacterial endotoxins held within the gastrointestinal tract and the systemic effects of its absorption.
Poor peripheral pulses, abdominal bruits, and arteriographic evidence of stenosis or occlusion in the three main mesenteric arteries are all consistent with the diagnosis of abdominal angina. Similar to cardiac disease, abdominal angina may precede infarction, which has devastating life-threatening consequences. Arterial thrombosis, embolic events, venous occlusion, and low-flow states due to poor cardiac output may all lead to the same disastrous results. Ischemic colitis represents approximately half of the cases of morbidity due to mesenteric vascular disease. Evidence of peritonitis develops in 20% of patients with ischemic colitis; surgical exploration is required in these cases.
Initial presentation of ischemic colitis may be persistent diarrhea, rectal bleeding, or weight loss. Vascular comorbidities increase surgical risks and jeopardize outcome. In addition, angioplasties in this region are technically difficult.
Oldenburg WA et al. Acute mesenteric ischemia: a clinical review. Arch Intern Med. 2004; 164:1054 .
Sreenarasimhaiah J. Diagnosis and management of intestinal is chaemic disorders. BMJ. 2003;326:1372 .
Pancreatitis is life- or tissue-threatening because of nutritional disruption, dehydration due to prolonged nausea and vomiting, and altered electrolyte and peripancreatic environment. The general phenomenon of pancreatitis is divided into acute (isolated episodes with serum amylase and lipase elevations) and chronic (identical symptoms as acute but may lack measurable laboratory abnormalities). Recurrent acute episodes are common early in the development of chronic pancreatitis.
The symptoms of pancreatitis can be associated with pancreatic cell death and with ductal fibrosis and calcification. Whereas acute pancreatitis generally resolves without permanent structural abnormalities, most forms of chronic pancreatitis are associated with permanent abnormalities. However, acute-on-chronic episodes in which an acute necrotic episode may occur in a patient with known chronic changes may be seen. Alcohol abuse
is the primary cause in 70 to 80% of chronic pancreatitis cases in developed nations. Since symptomatic chronic pancreatitis develops in only 5 to 10% of heavy drinkers, there are likely genetic, infectious, and nutritional factors that also contribute to its development. A person with chronic pancreatitis who continues to abuse alcohol has a 50% mortality rate at 5-years' follow-up (versus a 25-year 50% survivability rate if they abstain from drinking). Chronic pancreatitis may also be idiopathic, although other causes include a pancreas divisum, genetic causes (hereditary-type), previous trauma, previous obstructive episodes, hyperparathyroidism, hyperlipidemia, and a1-antitrypsin deficiency. Identifiable disease does not firmly correlate with reports of pain.
- Symptoms and Signs
The primary presenting complaint for chronic pancreatitis is deep, boring pain that is located in the epigastric region with frequent radiation through to the back. At onset, it may be episodic but may advance until it is continuous. Any eating, but particularly consumption of fatty foods, may precipitate pain. Positioning, such as sitting upright or leaning forward, may decrease the pain. It may be coupled with nausea and vomiting, so dehydration, malnutrition, and an inability to take oral analgesics may all become problematic. There are no definitive findings on physical examination. Persons with alcoholic chronic pancreatitis may be cachetic and may have stigmata associated with extensive alcohol use and associated liver failure. It may be possible to palpate an inflammatory mass, but abdominal guarding typically precludes adequate examination.
- Laboratory Findings
Steatorrhea due to pancreatic insufficiency may be present in advanced disease as may glucose intolerance secondary to developing diabetes mellitus. Elevated serum amylase and lipase levels indicate a pancreatic exocrine cell damaging process, but these blood tests are used less frequently since the sensitivity of other diagnostic modalities such as endoscopic retrograde cholangiopancreatography (ERCP) and computed tomography (CT) have improved. Diffuse intraductal calcium deposition is pathognomonic of chronic pancreatitis.
- Imaging Studies
Simple abdominal radiographs will support the diagnosis in 30% of cases. A higher sensitivity (60 to 70% sensitive for intraductal abnormalities) is gained by ultrasonographic evaluation. CT is 90% sensitive. ERCP is the gold standard for chronic pancreatitis based on ductal abnormalities that are graded by severity. A system of stratification or subgroupings of patients by morphologic or functional criteria is still a matter of debate.
Pancreatic cancer must be considered and is not an uncommon incidental finding during surgical treatment of chronic pancreatitis. Peptic ulcer disease, IBS, gallstones, endometriosis, and all other sources of abdominal pain are also possibilities. A first step in the management of an acute increase in pain in patients with chronic pancreatitis is to exclude such complications as pseudocysts or compression of adjacent visceral structures.
Some guidelines do exist for the treatment of pain due to chronic pancreatitis. Unfortunately, most published treatment options are only validated by case reports and retrospective series of patients who underwent treatments assessing a particular method. Few studies of chronic pancreatitis pain have used placebo-controlled methods, and of those, even fewer demonstrated robust effects of the studied treatment. Procedural studies have generally not had controls performed. The symptoms of chronic pancreatitis are episodic with frequent exacerbations and spontaneous resolution. Hence, any “open” study that is initiated during an exacerbation is likely to be deemed effective in some patients due to the natural course of the disease. Therapeutic options for chronic pancreatitis are listed in Table 11-4.
For alcoholic chronic pancreatitis, the initial treatment is abstinence from alcohol. As stated before, if the patient continues to drink, he or she has a high mortality rate. It has been commonly reported that total abstinence from alcohol achieves pain relief in up to 50% of
patients, particularly those with mild to moderate disease. Psychological therapies directed toward developing alternative coping mechanisms and abstaining from alcohol are considered vitally necessary, but outcomes related to substance abuse treatment are mixed and not limited to this specific population.
Table 11-4. Treatment Options for Chronic Pancreatitis Pain.
Opioids, the primary analgesic therapy of advanced chronic pancreatitis, can be supplemented with adjuvant agents such as antidepressants. It is an unfortunate but common experience of clinicians who treat patients with alcoholic pancreatitis that persons who were dependent on alcohol may become dependent on opioids. Therefore, involvement of behavioral medicine specialists with experience in both pain management and substance abuse is of particular benefit in the monitoring and appropriate treatment of these patients. Anti-inflammatory drugs, such as corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs), would seem logical choices in the treatment of a chronic inflammatory process. However, case reports of pancreatitis induced by these agents has temporized their use.
Placebo-controlled medical trials of antioxidants and micronutrients, such as vitamins C and E, beta-carotene, S-adenosylmethionine, and selenium, have produced favorable results. Oral pancreatic enzyme treatments have been used as inhibitors of pancreatic enzyme secretion with a resultant decrease in intraductal pressure. This negative feedback strategy has been effective at reducing pain in some studies, but four of six randomized, prospective, placebo-controlled, double-blind studies failed to observe any effect of this treatment. Inhibition of pancreatic secretion, produced by somatostatin or its analogue octreotide, has been reported to reduce pain but two randomized, prospective, double-blind, placebo-controlled studies failed to see any statistically significant improvement in pain.
- Procedural Therapies
Celiac plexus blocks with local anesthetics have been used for diagnostic purposes but also as primary therapies for chronic pancreatic pain when coupled with corticosteroids. Neurolytic celiac plexus blocks have been performed using alcohol or phenol. Neurolytic celiac plexus blocks for the treatment of nonmalignant pancreatic pain is controversial. Enthusiasm for neurolytic celiac plexus blocks for chronic pancreatitis has been tempered by the apparent limited duration of effect, requiring either retreatment every 2 to 6 months or acceptance of another alternative for care. Sequelae such as chronic diarrhea and the occurrence of uncommon but catastrophic neurologic deficits have also reduced enthusiasm for repeated therapy. Visceral neurolysis via surgical splanch-nicectomy or celiac ganglionectomy has been reported.
Thoracoscopic splanchnic nerve resections have been reported.
Surgical diversion or resection is often viewed as the definitive treatment of chronic pancreatitis despite the absence of prospective randomized studies.
Relief of ductal hypertension or obstruction by surgical means via pancreaticojejunostomy is reported as effective in relieving pain for at least 5 years in 70 to 93% of appropriately selected patients who had dilated pancreatic ducts as demonstrated by ERCP and in 40% of patients with nondilated ducts. Partial or total resection of the pancreas leads to pain relief for at least 5 years in 54 to 95% of patients with 0 to 5% morbidity and mortality. Following total resection, the loss of the endocrine function of the pancreas leads to diabetes mellitus with its own associated morbidity and mortality.
Pancreatic pseudocysts are nonepithelialized sacs of pancreatic fluids, blood, and necrotic debris with apparently inadequate drainage. They enlarge, are frequently painful, and risk rupture of their contents into the peritoneal cavity. Treatments have been predominantly procedural with open or percutaneous drainage, followed by marsupialization (connection of the cyst to nearby gastrointestinal structure) if recurrent. Following surgical drainage of pseudocysts, it has been reported that 96% of patients report short-term relief of pain and 53% remain pain free for many years.
The endoscopic placement of stents, sphincterotomy, dilatation, or stone removal are well-established alternatives to surgery in the treatment of biliary tract diseases, and similar techniques for the relief of chronic pancreatic pain have developed. Ultrasound-guided endoscopic drainage of pseudocysts or performance of neurolytic celiac plexus injections have reported benefit. Extracorporeal shock-wave lithotripsy has been coupled with endoscopic procedures to remove stones from the main pancreatic duct with reported pain reduction in some patients.
It has been proposed that the pain of chronic pancreatitis will eventually “burn out” and subside as the disease process progresses to total organ failure. This process occurs at a variable rate and effectively, for some, does not occur. Hence, delay of treatment in the hopes of disease resolution is neither realistic nor ethical.
Andren-Sandberg A et al. Pain management in chronic pancreatitis. Eur J Gastroenterol Hepatol. 2002; 14:957 .
Cunha JE et al. Surgical and interventional treatment of chronic pancreatitis. Pancreatology. 2004;4:540 .
Stevens T et al. Pathogenesis of chronic pancreatitis: an evidence-based review of past theories and recent developments. Am J Gas-troenterol. 2004;99:2256 .
Pancreatitis Association International http://www.pancassociation.org
Inflammatory Bowel Disease
Ulcerative colitis (UC) and Crohn's disease (CD) are two recurrent gastrointestinal inflammatory disorders with many similarities in symptoms and histopathology; however, they also have significant differences in extent of the disease process, relapse incidence, and associated complications (such as fistula formation). These disorders can be life- and tissue-threatening due to local spread of infection and the severe alterations in nutrient, fluid, and electrolyte levels. The precise causes of inflammatory bowel disease are unknown, but genetic mechanisms are suspected. Inflammatory bowel disease is more common in whites than blacks or Asians and 3 to 6 times more common in Jews than nonJews. UC is 3 to 5 times more common than CD, but recurrent exacerbations are much less frequent. In UC, the gastrointestinal component of the disease process is restricted to the colon; whereas in CD, there is involvement in all portions of the gastrointestinal tract.
Common presenting symptoms include abdominal pain, fever, and altered bowel habits (such as bloody diarrhea). The diagnosis of inflammatory bowel disease is based on biopsy, colonoscopic or endoscopic appearances, or surgical evaluation. Other causes of inflammatory changes such as radiation enteritis or local infection (eg, Shigella, Salmonella, Amoeba, Clostridium difficile) must be ruled out. Local complications of inflammatory bowel disease include the formation of fistulas, abscesses, strictures, perforation, and toxic dilation, all of which are more common in CD than UC. Extracolonic features of inflammatory bowel disease include arthritis, skin changes, and evidence of liver disease.
Dietary alterations may have some acute effects during a “flare” but have not been demonstrated to alter overall disease progression. Neurolysis is typically avoided since symptoms may act as early indicators of life-threatening complications. Although regional anesthetic techniques have possible short-term benefit during a flare, they have the same risks as neurolysis in that they may mask disease complications. Surgery has remained an integral component in the management of inflammatory bowel disease. Pain treatment related to inflammatory bowel disease forms a limited-choice corollary to chronic pancreatitis. Since reports of pain may be associated with life-threatening complications, these patients may have frequent hospitalizations. The use of motility-altering drugs, such as opioids, may be associated with an increased risk of toxic dilation and subsequently an increase in morbidity and mortality. Similar to other diseases with unknown etiologies, genetic influences, immunologic abnormalities, and infectious organisms have all been implicated and used as rationales for treatment. Primary treatment for exacerbations is typically bowel rest; anti-inflammatories (eg, oral sulfasalazine, possible corticosteroids); nutritional, fluid, and electrolyte management; and treatment of complications. No universal consensus appears to exist in relation to preventative treatment. Multiple therapies, such as oral sulfasalazine, oral olsalazine, oral metronidazole, systemic corticosteroids, and mesalamine enemas or suppositories, have been used not only as reactive treatments for exacerbations but as prophylactic measures. Although results related to use of these agents are encouraging for UC, a multicenter study failed to observe any decrease in the recurrence of CD exacerbations even with sulfasalazine. Immunosuppressants such as azothioprine and cyclosporine have been used for a presumed immunologic etiology. Psychological treatments are justified by the presence of a lifelong, recurrent disease process.
With a prolonged clinical course, there is a potential for the development of carcinoma. There is a stated incidence of colon cancer of 0.5 to 1% per year for every year after the initial 10 years of active inflammatory bowel disease. Surgical treatment of inflammatory bowel disease is normally reserved for the treatment of complications, with 20 to 25% of patients with UC and 70% of patients with CD requiring colectomy. Colectomy presumably resolves UC but does not resolve all of the symptoms of CD since the disease process is panenteric.
American Gastroenterological Association Clinical Practice Committee. American Gastroenterological Association medical position statement: perianal Crohn's disease. Gastroenterology. 2003;125:1503 .
Carter MJ et al. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2004;53(Suppl 5):V1 .
A diverticulum is a sac or pouch opening from a tubular organ such as the gut. Diverticuli can occur throughout the gastrointestinal tract but prove to be most common in the colon where they occur typically at the site of penetrating blood vessels, but hypopharyngeal (termed “Zenker diverticulum”), duodenal, jejunal, and ileal
diverticuli are possible. Meckel diverticuli, the remains of the omphalomesenteric duct of the embryo, is a congenital abnormality present in 2% of the population and located on the ileum close to its connection to the cecum. They are notable since they may contain acid-producing gastric mucosa, which may lead to enteral ulcer formation and associated bleeding. Colonic diverticuli are generally pain free; however, severe abdominal pain and infection may result with the development of inflammation and obstruction of the mouth. The condition is then termed “diverticulitis” and may be associated with abscess formation, obstruction, colonic distention, bleeding, and altered bowel habit (ie, diarrhea, constipation). Painful diverticulosis classically presents as recurrent left lower quadrant colicky pain without evidence of inflammation. Like chronic pancreatitis, diverticular disease can produce pain that is episodic and that can have life-threatening consequences if ignored. A bleeding colonic diverticulum is the most common source of lower gastrointestinal tract bleeding, and segmental colonic resection has the highest success rate at stopping bleeding. However, effects on pain are unclear. Reports of pain do not always correlate with observable disease and symptoms can be nonspecific. Consensus panels have not been able to definitively state when surgery was indicated for symptomatic reasons.
Kohler L et al. Diagnosis and treatment of diverticular disease: results of a consensus development conference. The Scientific Committee of the European Association for Endoscopic Surgery. Surg Endosc. 1999; 13:430 .
Familial Mediterranean Fever
An autosomal recessive genetic disease linked to chromosome 16, this disorder begins between the ages 5 to 15 and has an increased incidence in Sephardic Jews, Armenians, Turks, Arabs, and other Mediterranean populations.
Features include periodic febrile episodes without other cause, serous peritonitis, pleuritis, synovitis, and an erysipelas-like rash. Abdominal pain and arthralgias occur in greater than 95% of the episodes, which vary in frequency from twice per week to once per year; the most common variant occurs in 2 to 4 week intervals with acute episodes typically lasting 1 to 3 days. Amyloidosis with associated kidney failure and arthralgia are the most severe associated sequelae. Leukocytosis and elevated sedimentation rate may be present on laboratory examination.
Typical treatment is symptom-driven with the use of systemic analgesics. In controlled studies, colchicine has been demonstrated to decrease the frequency of attacks and risks of amyloidosis. Multiple other prophylactic therapies have been tried without success.
Medlej-Hashim M et al. Familial Mediterranean Fever (FMF): from diagnosis to treatment. Sante. 2004; 14:261. Review French .
The increased formation of porphyrins, or their precursors, occurs in several related autosomal dominant genetic disorders with incomplete penetrance, all characterized by the term “porphyria.” Three subgroups that all have similar symptoms have been identified: acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria.
Acute intermittent porphyria is the most frequently encountered subgroup, with attacks of colicky abdominal pain that are intermittent, may be associated with environmental exposures, and can last for days to months. Certain drugs such as barbiturates, benzodiazepines, alcohol, phenytoin, ketamine, etomidate, meprobamate, and corticosteroids have been particularly implicated as “triggers,” although use of many of these agents without the precipitation of a crisis has been reported.
Vomiting, constipation, and abdominal distention are not uncommon. Neurologic dysfunction may occur principally due to demyelination effects with emotional disturbance a nonspecific symptom. Urine and blood tests related to porphyria may only be diagnostic during crises.
Treatment involves avoiding known triggers. Crises are treated with intravenous fluids, hematin, and increased carbohydrate intake; pain and nausea are managed with safe analgesics and antiemetics. Most opioids are alleged to be nontriggering; a notable exception is the mixed agonist-antagonist pentazocine. Chlorpromazine, promethazine, and droperidol have all been reported to be safe as antiemetics.
Movement of stones within the urinary system (ie, renal pelvis and calices, ureters, bladder, urethra) can produce severe pain (renal colic). If urine flow is sufficiently obstructed, kidney function can be destroyed. Urolithiasis may be frequently recurrent in “stone-formers” and may be continuous when numerous or large renal pelvic (staghorn) calculi are present. Diagnosis is based on history of stone formation or imaging studies (ie, intravenous pyelogram or CT scanning).
The definitive treatment is the removal of the stone by spontaneous passage, which may be assisted by fragmentation using lithotripsy or surgical removal. Drugs producing a relaxation effect in the ureters include NSAIDs, nifedipine, and tamsulosin. Pain treatments used for renal colic are intended to be “temporizing” until stone removal occurs. As such, narcotics and NSAIDs are the mainstay of treatment. As noted above, there may be particular benefit to using NSAIDs because they may produce ureteral relaxation in addition to analgesia.
Conditions other than urolithiasis that may produce lower abdominal or pelvic pain of visceral origin include chronic or recurrent bacterial infections of the bladder, urethra, vagina, prostate, epididymis, or other associated urogenital structures (eg, pelvic inflammatory disease) and anatomic abnormalities, such as asymptomatic urinary tract diverticuli. Similar to treatments for symptomatic urolithiasis, pain-related treatments are temporizing, with the primary goal being resolution of the underlying pathophysiology by surgical, behavioral, or pharmacologic means.
Polycystic Kidney Disease
An autosomal-dominant disease that eventually leads to polycystic kidney disease can also be a cause of visceral pain. Cyst formation, rupture, infection, and secondary compression or traction of neighboring structures can all lead to abdominal, flank, and back pain. Renal stone formation and liver cyst formation are both common comorbidities, and so reports of pain may require an assessment of those etiologies. A general progression from nonpharmacologic methods to non-narcotic analgesics, minimally invasive procedures to progressively more invasive procedures, and use of opioids have been advocated by some clinicians. Procedures unique to polycystic kidney disease include surgical or percutaneous drainage of the cysts with marsupialization to avoid fluid reaccumulation.
Bajwa ZH et al. Pain management in polycystic kidney disease. Kidney Int. 2001;60:1631 .
Loin Pain-Hematuria Syndrome
This is a descriptive diagnosis with the primary symptom of severe flank pain and the laboratory finding of hematuria. It is of obscure etiology and is associated with inconsistent pathology. Loin pain-hematuria syndrome is more common in women than men, and it is predominantly a diagnosis of exclusion. Accepted by some clinicians as a diagnosis that justifies aggressive interventions, including nephrectomy or renal autotransplantation, its very existence as a discrete clinicopathologic entity has been questioned. Recurrence of pain following surgical procedures including extensive surgical sympathectomy of the kidney has been common except in cases where there was meticulous screening of patients for other urologic, nephrologic, or psychiatric etiologies of the pain. Injection therapies have been normally viewed as shortlived. Transcutaneous electrical nerve stimulation has been reported to result in partial pain relief. Due to the limited success of other modalities of treatment, use of narcotic analgesics may be considered.
Pukenas BA et al. Loin pain hematuria syndrome: case series. W V Med J. 2003;99:192 .
Laparoscopy may demonstrate adhesions in postabdominal surgery patients with new onset of abdominal or pelvic pain, but the role of these adhesions in producing pain is a matter of debate. It would appear that unless adhesions are producing bowel obstruction, adhesiolysis appears unlikely to produce reliable benefit. Treatment is episodic and symptomatic, but use of narcotic analgesics may lead to further bowel dysfunction and so may be viewed as a late option.
Gallbladder inflammation, gallstones, and associated diseases of the biliary tract are known sources of acute pain that is typically coupled with dyspepsia and occasionally jaundice (when obstruction is present). However, even
after surgical resection of the gallbladder, pain may continue; this is called postcholecystectomy syndrome.
Typically, the symptoms of postcholecystectomy syndrome are similar to those of cholecystitis: located in the right upper quadrant; associated with nausea; exacerbated by eating; and pain is described as continuous during the day, dull, and frequently colicky. Appropriate work-up will rule out definable disease, such as a retained bile duct stone or secondary pancreatitis. Postcholecystectomy syndrome is a correlate to chronic pancreatitis in that there may be abnormal pressures or motility within the biliary duct. Endoscopic demonstration of elevated sphincter of Oddi pressures suggest sphincter dysfunction as the cause of the syndrome. During ERCP, it may be possible to reproduce the pain by producing intraductal distention.
Endoscopic or surgical sphincterotomy or sphincteroplasty have been beneficial in series reports and calcium channel blockers or long-acting nitrates have been proposed as therapeutic. Other treatment options are dietary alterations, surgical reexplorations, focal injections or neurolysis, and traditional analgesics. In many cases, there is no objective identification of a site of pain generation, so treatment is empiric. Furthermore, the cholecystectomy that presumably started the disorder may also have been an empiric treatment.
Interstitial Cystitis & Painful Bladder Syndrome
Painful bladder syndrome is a term that has been recently advocated for use on a national level to describe a complex of urologic complaints, including pain, that may have a common etiology. Painful bladder syndrome may possibly be an early form of IC, but it has no agreed upon etiology, pathophysiology, or treatment. IC, which has a similarly undefined list of etiologies and treatments, does have a defining pathology; according to a study group of the National Institute of Diabetes, Digestive and Kidney Diseases, IC is either the presence of mucosal ulcers (a Hunner patch) or “glomerulations,” which are small sub-mucosal petechial hemorrhages viewed cystoscopically after sustained distention of the bladder (hydrodistention). Glomerulations are not unique to IC but occur in other forms of cystitis (eg, radiation cystitis) and may be a normal variant, so IC is also a diagnosis of exclusion for those other disorders. There is good evidence that there is a disruption of the normal urothelial barrier in most (if not all) patients with IC. Prevalence of IC is estimated to be 2 in 10,000, with a female to male ratio of 10:1. The frequent association of IC with other chronic diseases and pain syndromes, such as inflammatory bowel disease, systemic lupus erythematosus, IBS, “sensitive” skin, fibromyalgia, and allergies speaks to the fact there may be multiple different pathophysiologies grouped together under one diagnosis.
The etiology of the breakdown in the urothelial barrier in IC and the consequences of this breakdown are as yet unknown. One theory proposes that the breakdown of the urothelial barrier is a failure to maintain adequate formation of glycosaminoglycans, which provide a protective coating to the urothelium. Another theory proposes that IC is a systemic autoimmune disease presenting as a local manifestation with associated abnormal mast cell activity in the bladder, leading to local tissue and neurologic effects. The most mechanistic theory to date relates the breakdown of the urothelial barrier to the presence of a specific peptide present within the urine of patients with IC that impairs urothelial regrowth. The antipro-liferative factor is a low-molecular-weight peptide that is present in bladder urine but not renal pelvis urine of patients with IC, is present in over 90% of patients in whom IC has been clinically diagnosed, is not present in other disorders, and is therefore viewed as the best laboratory diagnostic test for IC. The test itself is not currently available but will likely become available pending further validation as a diagnostic test. Whether antiproliferative factor is present due to rheumatologic, immunologic, infectious, genetic, or neurologic causes has not been determined, but it has been demonstrated to produce a downregulation of genes that stimulate epithelial proliferation and upregulates genes that inhibit cell growth. Independent of the specific reason for a urothelial disruption, the simplest explanation of the consequences of this breakdown is that it allows an exposure of urinary constituents, bacterial products, and cell death products to bladder sensory nerves that normally are protected by an intact barrier. This “toxic urine” exposure produces either direct activation or sensitization of peripheral and central nervous system structures.
- Symptoms and Signs
Urgency, frequency, nocturia, and associated pain are the primary symptoms of IC. Pain may be localized to the lower abdomen, pelvis, groin, and perineum. The onset of the disease is normally abrupt, with rapid progression of symptoms often following an “event” such as a prolonged episode of severe urgency while searching for a
lavatory. Anxiety and depression are frequent comorbidities. Suprapubic tenderness to palpation may accompany a diagnosis of IC. Patients with IC are 10 to 12 times more likely to report childhood bladder problems than the general population. Although a history of frequent urinary tract infection is twice as common in patients with IC than those without IC, most report infrequent urinary tract infections (fewer than 1 per year) prior to the onset of IC symptoms.
- Special Tests
A cystoscopic examination of the bladder wall for a Hunner patch or the development of glomerulations after hydrodistention is necessary to meet the research definition of IC. However, recently the intravesical potassium sensitivity test has been used as an alternative diagnostic procedure. In this test, 40 mL of a potassium chloride solution (40 m Eq in 100 mL water) is administered into the bladder by a catheter and responses observed 3 to 5 minutes later. A positive test is pain and urgency evoked by the potassium solution, but minimal if any symptoms from water instilled into the bladder. As a provocative diagnostic test for IC, the potassium test has good sensitivity (70 to 90%) but may lack specificity; so, at present, this test serves to demonstrate increased urothelial permeability that may accompany multiple painful conditions.
The ultimate goal of therapy is to neutralize the factor or factors responsible for a disease process. In the absence of any known causative factors, the treatments for IC have been guided by prudence, and a given patient's therapy typically progresses from the least invasive treatments to the more invasive. A listing of treatments for IC is given in Table 11-5. Most of these treatments were either identified serendipitously or were “theory-driven” by a presumed mechanism of pathophysiology. For example, dietary modification to avoid foods that exacerbate symptoms (eg, acidic foods such as cranberry juice) has much anecdotal support and goes with the toxic urine mechanism. The working assumption of this therapeutic approach is that certain chemicals from foods are excreted into urine and thereby elicit pain. For the same reason, alkalinization of the urine has been used as an early therapeutic approach. As part of the diagnostic process, hydrodistention is normally performed, and this procedure often proves to be therapeutic with short-term reductions in frequency and pain in more than 50% of patients. Patients with symptomatic improvement for 6 months or more are considered candidates for repeat hydrodistention.
Open trials of tricyclic antidepressants, thought to act upon central neural mechanisms that have been sensitized, have produced reported success rates of 64 to 90%, and oral antihistamines that would counteract histamine released by mast cells have been reported to produce a reduction in symptoms. The oral, renally excreted heparinoid pentosan polysulfate is thought to supplement or replace missing protective glycosaminoglycans on the urothelial surface. The following medications, alone or in combination, have been proposed as possible therapies: intravesical therapy with dimethylsulfoxide, heparin, corticosteroids, bicarbonate, and oxychlorosene (a derivative of hypochlorous acid). The success rates in open trials range from 50% to greater than 90%. Based on the hypothesis that IC is a local manifestation of a systemic autoimmune disease, immunosuppressant therapies such as systemic cyclosporine and intravesical bacillus Calmette-Guérin immunotherapy have been used in open trials with nearly 100% success rates.
Table 11-5. Treatment Options for Interstitial Cystitis.
Neuromodulation via direct sacral (S3) nerve root stimulation has demonstrated benefit on urgency and frequency but has mixed benefits in relation to pain control. Transcutaneous electrical nerve stimulation has been used in open trials and demonstrated to produce good results or remission in 26 to 54% of patients. Behavioral therapies and self-care strategies such as timed voiding have proved valuable in some persons. Series and case reports suggest that sympathectomy produced by lumbar sympathetic or epidural local anesthetic blocks may have
short-term efficacy in up to 75% of patients. Long-term treatment with opioids is an option in patients with IC, but this treatment remains controversial for all nonmalignant processes. Often considered a last resort, surgery in the form of supravesical diversions or cystectomy has also received mixed reports of efficacy.
Epidemiologically, IC is most prevalent in young to middle-age females implying that there may be a resolution of symptoms that occurs with time. It has been reported that up to 50% of patients in whom IC has been diagnosed have spontaneous remissions, with durations of 1 to 80 months. There have been reports of patients with continued bladder pain despite the surgical resection of the bladder.
Chancellor MB et al. Treatment of interstitial cystitis. Urology. 2004;63(3 Suppl 1):85 .
This syndrome is characterized by pain with urination that is coupled typically with urinary urgency, increased frequency, suprapubic or back pain, and an absence of laboratory evidence of infection or inflammation. Urodynamic studies may demonstrate a pulsatile (staccato) or prolonged flow phase and increased external sphincter tone. An absence of other causes of symptoms (including local anatomic causes) is required for the diagnosis. Urethral syndrome is most common in women in their reproductive years and has a high rate of spontaneous remission. Conservative therapy using muscle relaxants, electrostimulation, and behavioral techniques have also been reported to be successful.
Irritable Bowel Syndrome (Functional Bowel Disorders)
Like other functional bowel disorders (eg, noncardiac chest pain and functional dyspepsia), IBS is a diagnosis of exclusion that is based on symptoms. It is associated with abnormalities of motility and sensation in different sub-populations. IBS is a common diagnosis and is the reason for 40 to 70% of referrals to gastroenterologists. IBS frequently accompanies other disorders without identifiable histopathology, such as fibromyalgia, noncardiac chest pain, functional dyspepsia, IC, and mixed headaches. It has been associated with significant neuroses and psychoses such as anxiety and depression.
There are many diverse hypotheses related to the etiology of IBS including: pain may be psychosocial in origin, pain may be due to motility dysfunction at one or multiple sites in the gut, or pain is a neuropathic process with associated visceral hypersensitivity (the equivalents of somatic hyperalgesia and allodynia). Alternatively, hypersensitivity could be due to peripheral sensitizers such as those contained within and released by mast cells. Like many diagnoses of exclusion, it is likely that multiple pathophysiologies are present in different subgroups and that all of these hypotheses may be correct for different subgroups.
- Symptoms and Signs
IBS typically presents in the third or fourth decades of life and has a female to male ratio of 2:1. There are at least three different clinical presentations of IBS, two of which have no pain or pain as a minor component: (1) watery diarrhea group and (2) alternating constipation-diarrhea group. The third subgroup has abdominal pain as the primary symptom and altered bowel movements as a secondary or exacerbating complaint. In this group, pain is typically in the left lower quadrant or in the suprapubic region and may be precipitated by food ingestion and a need to defecate. Bloating, mucus in the stools, and flatulence are often prominent; anxiety may exacerbate symptoms. Although there is great variation between patients, the particular symptom complex for a given patient generally remains constant. Generalized abdominal tenderness to palpation is common. The classic physical finding is a tender, palpable mass (the sigmoid colon) in the left lower quadrant.
- Special Tests
As a diagnosis of exclusion, imaging and laboratory findings should show no evidence of neoplasm, inflammatory bowel disease, infection, diverticulosis, or other intra-abdominal process. Colonoscopy and barium enema radiography should not demonstrate focal lesions. Stool samples should not have occult blood or infectious organisms present. It is generally agreed that the colons of most patients with IBS are exceptionally reactive to physiologic stimuli such as eating. Unfortunately, the finding is not pathognomonic, and so acts only as supportive evidence for the diagnosis. Although there are no absolute criteria for the diagnosis of IBS except for a report of abdominal pain and altered bowel habit in the absence of identifiable pathology, the ROME criteria have been proposed to facilitate a “positive” diagnosis (Table 11-6). Motility studies and sensation evocation with a
distending balloon in the rectum or sigmoid colon may prove valuable in the identification of patients as members of different subgroups.
Table 11-6. Diagnostic Criteria for Irritable Bowel Syndrome.
IBS has exacerbations and spontaneous resolution of pains, so open trials are of limited value due to placebo rates of 40 to 70%. Procedural treatments have not been a major component of therapy because there is no structural disease to treat. Life-threatening disease may be simply ruled out without an exhaustive investigation, and the patient needs to be assured that their symptoms are believed.
Therapeutic options for IBS are listed in Table 11-7. As part of a diagnostic and therapeutic trial, patients are generally advised to engage in dietary modifications, such as avoiding milk products, avoiding excessive legume consumption (associated with gas production), increasing fiber and bran in cases of constipation, avoiding caffeine- or sorbitol-containing foods, and establishing a stable dietary pattern in hopes of establishing a stable evacuation routine. Anticholinergics and antidiarrheals have been extensively studied and used clinically, but unfortunately their benefit is anecdotal. Traditional advice has been to keep analgesic therapy to a minimum; the use of opioids is particularly discouraged because of concerns related to altered motility.
Tricyclic antidepressants have been shown in controlled studies to be effective, but whether the efficacy is due to their antidepressant, sedative, anticholinergic, or analgesic effects is unclear. Gastrokinetic agents, antidiarrheals, osmotic laxatives, opioid antagonists, cholecystokinin antagonists, and peppermint oil have all been proposed as effective. Injection therapies have not been generally used in the treatment of IBS. The newest pharmaco therapy is the use of drugs acting as serotonin receptors such as alosetron (5-HT3-receptor antagonist used for diarrhea predominant IBS) and tegaserod (5-HT4-receptor agonist used for constipation predominant IBS). Behavioral treatments such as hypnotism, cognitive therapy, and supportive psychotherapy have proved valuable, especially if pain is intermittent and a psychiatric comorbidity (such as anxiety or depression) has been identified.
Table 11-7. Treatment Options for Irritable Bowel Syndrome.
Due to the typically stable nature of a patient's symptom complex, once significant disease has been ruled out, additional or repeat investigation is not necessary unless the symptom complex were to change.
Drossman DA. The functional gastrointestinal disorders and the ROME II process. Gut. 1999;45 Suppl 2:II1 .
Spiller R. ROME II: the functional gastrointestinal disorders. Diagnosis, pathophysiology and treatment: a multinational consensus. Gut. 2000;46:741B .
Pain localized to the testes has a wide differential diagnosis. Possible causes include local processes, such as tumor; infection, such as epididymitis; varicocele, hydrocele, spermatocele; and testicular torsion, which are all potentially acute and chronic sources of pain. Although trauma (including iatrogenic types such as inguinal hernia repair, vasectomy) can lead to chronic inflammatory processes, most causes of altered sensation and pain are idiopathic. Neuropathic etiologies ranging from diabetic neuropathy and entrapment neuropathies to spinal disc disease may all present with testicular pain. Scrotal pain
should be differentiated from testicular pain since the nerve supplies differ and may represent differing sites of disease along sacral versus thoracolumbar pathways. Due to the “personal” nature of the site of pain, concerns related to psychological etiologies or sequelae of this chronic pain are maintained.
Treatment of chronic orchialgia has traditionally started with anti-inflammatories or antibiotics. Surgical procedures including epididymectomy, orchiectomy, or denervation procedures have been recommended; however, long-term outcomes are unknown, and retrospective series have suggested limited benefit, particularly in subsets of patients with other pain disorders. There may be benefit from the use of antidepressants, anticonvulsants, membrane-stabilizing agents, opiates and, in some patients, sympatholytic treatments. Because of the wide differential diagnosis of testicular pain, no specific treatment will be universally effective.
Ness TJ. Chronic urologic pain syndromes. Curr Pain Headache Rep 2001;5:27 .
Defined as episodic spasms of pain localized to the rectum and anus occurring at irregular intervals and without identifiable cause, proctalgia fugax is highly prevalent, occurring in 14 to 19% of healthy persons. Episodes are normally brief (seconds to minutes) and infrequent (normally fewer than 6 per year). They may be precipitated by bowel movements, sexual activity, stress, and temperature changes and may lead to avoidance behavior on the part of the patient. No cause or method of treating or preventing proctalgia fugax has been universally accepted, although spasm of the sigmoid colon, levator ani, and pelvic floor musculature have been postulated as sources of the pain. Local anorectal disease, such as fissures or abscesses, are typically ruled out as alternate sources of pain and spasm. Most reactive pharmacologic treatments have usually proved inadequate due to the brief nature of most episodes. However, clonidine, nitro-glycerin, antispasmodics, and calcium channel blockers have all been reported as effective, and inhaled salbutamol was reported to shorten the duration of severe pain. Heat or pressure applied to the perineum, consumption of food or liquids, dilation of the anal sphincter, and assumption of a knee-chest position have been anecdotally reported as beneficial.
This disorder is defined as pain attributed to the prostate in the absence of identifiable disease. Also termed “non-bacterial chronic prostatitis” or “male chronic pelvic pain syndrome,” it has the hallmark symptoms of dysuria, urinary urgency, poor urinary flow, and perineal discomfort. Laboratory findings should not show evidence of bacteria or white blood cells in prostatic fluids. No strikingly successful treatment options have been described, and so treatments may be empiric trials of medications used in the treatment of chronic pain. Antibiotics are commonly prescribed despite the absence of evidence for a microbiologic infection. If urodynamic measures indicate abnormalities, α-adrenergic-blocking agents (eg, tamsulosin) have been suggested as therapeutic.