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Pain Management in Patients With Comorbidities
Introduction
Pain is defined by the International Association of Pain (IASP) as “an unpleasant sensory and emotional experience associated with, or resembling that associated with actual or potential tissue damage.” Given that pain is not only a symptom but also an independent disease, it is highly likely that patients with chronic pain may also have other medical comorbidities and disorders that will influence the scope of treatments that are recommended. In any patient with chronic pain, the severity, frequency, and tolerance to the condition are variable and are influenced by a variety of factors, including one’s cultural background, expectations, behaviors, and physical and emotional health. In patients with comorbid conditions such as renal and hepatic diseases, diabetes, and the elderly, an understanding of how these conditions may influence pain treatment is of utmost importance. The appropriate selection of non-pharmacologic, pharmacologic, and interventional treatments based on the underlying comorbid conditions has the potential to improve physical functioning, emotional wellbeing, and overall quality of life. The scope of this chapter is to understand how pain management strategies need to be understood and tailored to specific comorbid medical conditions, including renal disease, liver disease, diabetes, and the frail/elderly population.
Renal Disease
Prevalence
Chronic kidney disease (CKD) is a global public health problem that is increasing in incidence and prevalence and is associated with poor patient outcomes and high medical costs. CKD is defined as the progressive and gradual loss of the kidneys to concentrate urine, excrete wastes and metabolites, secrete hormones, and conserve electrolytes. There is a distinction between CKD and end stage renal disease (ESRD), which is the deterioration of kidney function to the point where renal dialysis or transplantation is required for survival. Patients with CKD and ESRD experience a high severity and prevalence of physical symptoms related to their diseases. The symptom burden in these populations is greater than that of the general population, and despite this well-described complication, many patients have underrecognized, underestimated, and undertreated symptoms related to their CKD and ESRD. Pain is one of the most common symptoms encountered in CKD and ESRD, with the reported prevalence of pain ranging from 30 to over 58%. In patients with ESRD who are on hemodialysis (HD) or peritoneal dialysis (PD), the prevalence of acute and chronic pain has recently been shown to be up to 80%. Of these patients who report pain, it has been shown that over half report pain as moderate to severe in intensity. , , ,
Etiologies
Similar to the underlying disease processes present in CKD and ESRD, the pain experienced by patients with kidney disease is often multifactorial. Etiologies of pain can be either straightforward or complex and related to a multitude of issues ( Table 47.1 ). Symptoms can be caused as a direct result of the primary underlying kidney disease process, such as pain related to autosomal dominant polycystic kidney disease, or they can be related to associated underlying systemic and comorbid diseases such as diabetes, peripheral vascular disease, and various musculoskeletal processes. Pain may also be experienced as a direct result of HD or PD procedure itself. , It is also important to remember that additional pain related diagnoses such as anxiety, depression, and sleep problems may coexist with the chronic pain syndromes experienced by CKD/ESRD patients and that these conditions may feed into the challenges that coincide with treating chronic pain in these populations.
TABLE 47.1
Pain Origins in Chronic Kidney Disease and End Stage Renal Disease
| Pain Origin | Examples |
| Intrinsic Kidney Pathologies | CalciphylaxisRenal osteodystrophy (bone pain)Limb ischemia because of dialysis access steal syndromeDialysis related amyloid arthropathy |
| Underlying or Comorbid Disease Processes | Autosomal dominant polycystic kidney diseaseUrinary tract infectionsVascular peripheral neuropathyDiabetic peripheral neuropathyAmyloidosisPhantom limb painDermatologic conditionsMalignancyOsteoporosis |
| Dialysis Related | AV fistula/graft surgical creationNeedlestick cannulation of HD AV accessInstillation of PD fluidPD associated peritonitis, low back painMuscle cramping from dialysis ultrafiltrationPruritisHeadacheChest pain associated with intradialytic hypotensionDyspneaInfected HD catheter |
| Pain Unrelated to Kidney Disease | OsteoarthritisMalignancyDegenerative disc diseaseRadiculopathiesMigrainesGoutFibromyalgiaRestless leg syndromeEntrapment neuropathies |
Clinical Presentation and Assessment of Pain in CKD/ESRD.
As in any patient with acute or chronic pain, determining the type and severity of the pain can provide an excellent roadmap for outlining treatment plans. Listening to the patient about their symptoms and experiences surrounding their pain provides a great opportunity to provide them with compassion and validation of the significance of their problem and is an important piece of the therapeutic relationship.
Acute and chronic pain can be classified as nociceptive, neuropathic, nociplastic, or mixed pain. By definition, nociceptive pain arises from actual or threatened damage to non-neural tissue and results from the activation of nociceptors, while neuropathic pain is a clinical description that requires a definite lesion or a specific disease process that affects the somatosensory nervous system. The persistence of nociceptive stimuli can lead to several functional and structural changes in the central nervous system, known as central sensitization. Many chronic pain conditions are characterized by central sensitization, widespread pain, and altered descending pain modulation. The IASP has recently introduced a new term, nociplastic pain, defined as conditions that arise from altered nociception, without clear evidence of actual or threatened tissue damage or lesions, or disease of the somatosensory nervous system. Patients with ESRD may suffer from nociceptive, neuropathic, nociplastic, or mixed pain states. Ascertaining the mechanism of chronic pain is essential in the choice of mechanism-based analgesic therapies. ,
A thorough and complete pain assessment includes determining several attributes that contribute to acute and chronic pain, such as pain severity, pain quality (described in the previous paragraph), eliciting and attenuating factors, impact of pain on daily activities and physical functioning, pain interference with mood and sleep, and effects of pain on quality of life. No instruments have been specifically designed and validated for pain assessment in CKD/ESRD patients. However, several approaches can be used. One-dimensional scales are instruments used to identify pain severity, while multidimensional scales can be utilized to reflect the biopsychosocial model of pain that integrates social and psychological paradigms with the biologic mechanisms of pain.
The most commonly used one-dimensional scale for pain assessment is the 11 point numeric rating scale (NRS), where zero indicates no pain and ten is the worst imaginable pain, and the 10 cm (100 mm) continuous visual analog scale (VAS), which is anchored by the two verbal descriptors for each extreme (“no pain” and “pain as bad as it could be”). Many of the same assessment tools that exist for patients with non-kidney disease pain are valid and reliable in the CKD/ESRD population. The McGill pain questionnaire (MPQ) and the brief pain inventory (BPI) are the most common multidimensional scales used to assess pain. The MPQ has been in use since 1975 and is a widely used instrument to evaluate pain and helps determine both quantitative and qualitative aspects of pain, such as location, grade, temporal characteristics, and intensity. The BPI, initially developed for cancer patients but validated for use in chronic non-cancer pain, uses an 11 point NRS for pain intensity, requests the patient to draw the site(s) of pain on a body diagram, and uses an 11 point NRS to assess pain interference in seven domains, including general activity, mood, walking ability, work, relations with other people, sleep, and enjoyment of life.
Assessment tools such as the modified Edmonton symptom assessment system (m-ESAS v. 2), and palliative care outcome scale-renal (POS-renal) are renal-specific screening tools that may be more appropriate for routine clinical screening for pain in renal patients. These assessments identify the presence of pain and provide opportunities for discussions about appropriate palliative and supportive care treatment options.
Barriers to Pain Management in Kidney Disease
As mentioned previously, chronic pain is very common in patients with CKD and ESRD. However, it has historically been underrecognized and often poorly managed. It is well known that poorly controlled pain leads to decreased quality of life, poor physical functioning, reduced mobility, increased healthcare utilization, and longer hospital stays. Numerous reasons have been reported for insufficient pain management in CKD and ESRD, including inadequate pain assessment, concerns about analgesic-related adverse effects, and misconceptions. , ,
As described in the previous section, an adequate pain assessment requires an accurate medical history, thorough physical examination, and the application of validated tools for the identification of pain intensity and quality. The presence and severity of pain should be regularly assessed in patients with CKD and ESRD, and if applicable, during each HD session. Pain is generally undertreated in patients with CKD and ESRD because of the fear of the potential toxicity of analgesic drugs. Overtreatment, overdose, and inadequate analgesia can result from inappropriate dosing of non-opioid and opioid analgesics. Unfortunately, quality data or guidelines on the pharmacokinetics, clinical efficacy and safety of many common analgesics in this population are lacking. Indeed, the translation of pharmacologic pain management methods used in non-CKD/ESRD populations can be dangerous, as patients with CKD and ESRD have reduced renal function and altered pharmacokinetics. Alterations in metabolism and excretion may lead to significant adverse toxicities and side effects. Renal dose adjustments are required for most analgesics.
Setting Expectations
At the initiation of any pain management treatment program, the provider must discuss with the patient the expectations of therapy. These expectations should include the identification of reasonable therapeutic goals, including the level of pain that is acceptable for a patient’s quality of life, the risks and benefits of the treatment(s), the potential duration of pharmacologic therapy, and if applicable, the components of a pain contract for continued care. The overall goal of both immediate and long term pain management should be to improve the functional status. Moreover, a discussion that the patient should not expect to be pain-free is of importance and that a reasonable expectation should be that pain may not be completely resolved or controlled and that a 30% reduction in pain symptomology is often identified as clinically meaningful.
Pain Management Approach in Patients With CKD and ESRD With or Without Hemodialysis
General Principles
Pain treatment should be tailored to each individual according to the type and severity of pain. In general, non-pharmacologic options should be used first. Non-pharmacologic treatment options can be broadly categorized as psychosocial/behavioral interventions (e.g. cognitive behavior therapy (CBT), mindfulness) and physical interventions (e.g. exercise, physical therapy, yoga, acupuncture, electrical stimulation). Although most of these have not been specifically tested in CKD/ESRD, they have been proven to be effective in other chronic pain states and thus provide an encouraging approach for the treatment of pain in this population, either alone or as an adjunct to pharmacologic treatment.
Pharmacologic analgesic therapy should be based on the type of pain, severity of pain, and when the benefits of medications are cautiously weighed against possible side effects, drug-drug interactions, and coexisting medical morbidities. It is recommended that patients initiate therapy on a minimal dose of an analgesic medication and up-titrated slowly based on response and tolerance with very close monitoring for side effects or adverse events. An opioid-sparing approach is recommended in most cases.
Non-pharmacologic Therapies
The non-pharmacologic approach is the first step in pain management. In particular, in patients where drugs are not free of risks, non-pharmacologic techniques should be encouraged. Non-pharmacologic interventions include biofeedback, CBT, massage, and physical therapy/exercise programs.
CBT has become a well-established and accepted treatment for chronic pain in the general population. Robust evidence from a meta-analysis of 35 trials (>4700 patients) supports its efficacy for improving chronic pain symptoms and pain related physical disability in the general population. However, the effect size may be small, and the long term effects are not durable. In the CKD/ESRD population, CBT is effective in improving depression, but its effect on pain has not been tested. CBT has been shown to be effective in the general non-cancer chronic pain population and is based on concepts surrounding poor self-management skills, self-efficacy, and coping skills, which typically exist in this patient population. There is a strong premise that CBT may be a successful non-pharmacologic pain management strategy.
The potential benefits of complementary and alternative medicine have not been adequately investigated in patients with CKD/ESRD. These interventions include relaxation techniques, mindfulness, and acupuncture. A systematic review of randomized control trials investigating the effect of relaxation techniques in >400 patients with chronic pain in the general population found no significant benefit in reducing pain. However, the studies were of low quality, and thus the data are not conclusive at this time. In HD patients, two small studies have shown that relaxation techniques may improve pain intensity and health-related quality of life. , Mindfulness-based techniques including meditation, which involves focusing the mind on experiences (e.g. sensations, emotions, thoughts) in the present moment, have shown some promise in improving pain in the non-ESRD population. Moreover, a recent pilot study demonstrated that a brief, individualized, chairside mindfulness meditation intervention was feasible and acceptable for HD patients. A recent Cochrane analysis evaluated 24 studies on various types of acupuncture in patients with CKD. There is a paucity of evidence on the efficacy of acupuncture for fatigue, depression, sleep disturbance, and uremic pruritus in HD patients. Moreover, data on possible acupuncture-related harm are lacking. Therefore no conclusions may be drawn on its safety.
In the multimodal approach to chronic pain, invasive interventional pain techniques may potentially play a role in treating pain refractory to conventional pharmacologic treatment or to reduce the dose of analgesics in patients with CKD/ESRD. There is a paucity of literature on this topic. However, spinal cord stimulation (SCS) could be useful in HD patients suffering from peripheral vascular disease, stump pain after amputation, and painful diabetic neuropathy (PDN), but current guidelines only support a weak recommendation.
Pharmacologic Therapies
The World Health Organization ladder for analgesic pain control, originally created for cancer pain treatment, has been validated for use in the CKD/ESRD population. The modified ladder uses a three-step approach for pain management. Mild pain is generally treated in step 1 using non-opioid analgesics, such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). Step 2 treats moderate pain with the addition of mild or weak opioids such as tramadol, low dose oxycodone, and low dose hydromorphone. Step 3 initiates higher-dose opioids, such as higher doses of oxycodone/hydromorphone, fentanyl, methadone, and buprenorphine to treat severe pain. Adjunctive medications, such as gabapentin, pregabalin, tricyclic anti-depressants (TCAs), and serotonin norepinephrine reuptake inhibitors (SNRIs), can be added at any step of the ladder.
When pharmacologic interventions for pain management in CKD/ESRD are being implemented, it is best to identify the level of current renal function. Moreover, special emphasis should be placed when choosing pharmacologic therapies to prevent further deterioration of renal function and protection of existing renal function in patients with moderate to severe impairment. Therefore, drug adjustments may be required for CKD/ESRD. Two methods of dosing regimen adjustment have been recommended: (1) extending the time between doses while maintaining the same dose size (reducing the number of daily doses) or (2) to reduce the size of the individual prescribed dose at the same dosing interval. Sometimes, a combination method can be needed when both these methods (interval extension and dose reduction) are used. The interval extension method is generally not indicated for drugs with a short half-life because of the risk of a prolonged period with a subtherapeutic drug concentration. However, it is recommended for drugs with a relatively long half-life.
Non-opioid Medications
Acetaminophen is the most commonly used non-opioid analgesic for ESRD. Notably, the National Kidney Foundation promotes acetaminophen as the non-narcotic analgesic of choice for mild to moderate pain in CKD/ESRD. The proposed adjustment in HD patients suggests dosing every 8 h. Clinical studies have shown the effective removal of acetaminophen and its metabolites by HD.
NSAIDs are commonly prescribed for their inflammatory and analgesic properties. However, they are known to have gastrointestinal, cardiovascular, and renal toxicity. Clinical investigations on NSAIDs in patients with CKD/ESRD are typically single-dose studies or trials conducted for short periods and were not designed to evaluate efficacy and safety. Limited information is currently available regarding the use of NSAIDs in patients undergoing HD. Considering the potential for nephrotoxicity, it is strongly recommended to avoid NSAIDs in patients with CKD/ESRD. Despite this, the literature suggests that they continue to be commonly prescribed in this population. In a cohort study of 972 subjects with CKD, 16.9% used NSAIDs every day or several times a week, which increased to 35% among those on HD. In 46.7% of these cases, the CKD/ESRD patients used NSAIDs without being advised to do so by a medical professional and were unaware of the potential side effects of the painkillers, and the remaining were prescribed by physicians or pharmacists. Over 40% of the exposed patients experienced renal function deterioration in this cohort, 37.6% experienced peptic ulcer disease, and 18.2% experienced altered blood pressure control. Thus if NSAID use is considered in patients with kidney disease, a full description of risks and benefits should be discussed with the patient, and ongoing monitoring of renal function throughout treatment should be performed. Topical NSAIDs, such as diclofenac gel, can be effectively used without significant systemic adverse effects.
Anti-convulsants, particularly gabapentinoids, are strongly recommended as first line treatment for the management of neuropathic pain conditions, which are common in CKD/ESRD patients. Gabapentin and pregabalin have been specifically evaluated in patients with CKD/ESRD. Dose adjustment is required in terms of dose reduction and interval extension with these medications. Gabapentin has a favorable pharmacokinetic profile. It is excreted unchanged by the kidneys in urine, and plasma concentrations and toxicity correlate with impaired renal function. Its half-life, 6 to 8 h in healthy subjects, decreases to 4 h after HD and increases to 132 h without HD in ESRD patients. The low protein binding makes gabapentin easy to dialyze (approximately 35%). The recommended dose in HD patients is up to 300 mg daily, with a supplemental 200 to 300 mg dose after each HD session.
Similarly, pregabalin is easily dialyzable because it has a low molecular weight, a low volume of distribution (0.5 L/kg), and is not bound to plasma protein. The maximum recommended dose of pregabalin in ESRD patients is reduced to 25 to 75 mg/day, with mental doses after HD. However, a recent prospective, open-label, single-arm study on pregabalin for neuropathic pain in patients undergoing HD evaluated 45 patients carefully titrated to 150 mg during a 12 week study period. The authors reported a 22.2% withdrawal rate because of side effects (mainly drowsiness and dizziness) without serious drug-related adverse events. Pregabalin has been shown to be effective in reducing pain scores and improving QoL. These medications are associated with an increased risk of falls, cognitive impairment, and altered mental status in a dose-dependent fashion. These effects may be more pronounced in the elderly population.
Alternative neuropathic analgesics such as SNRI and tricyclic anti-depressants (TCA) have been extensively studied and are reported to be efficacious in non-CKD/ESRD populations and are recommended as first or second line treatment in many neuropathic chronic pain conditions. However, data supporting the safety and efficacy of these medications in CKD/ESRD are not available. These medications are not removed by HD, and the anticholinergic and serotonergic effects of these medications may be intensified in patients with ESRD. A recent systematic review concluded that most studies on anti-depressants for depression in ESRD patients involved a small number of subjects and were observational, leading to possible bias. Dose reduction is currently recommended for duloxetine, amitriptyline, venlafaxine, desvenlafaxine, and milnacipran. In general, anti-depressants should be started at lower doses and carefully titrated to the effective dose to reduce the risk of side effects.
Opioid Medications
Opioids are widely used in chronic pain management and historically have been the mainstay of pharmacologic treatment for severe and refractory chronic pain. However, there is no high-quality clinical evidence for their long term use in chronic non-cancer pain, and systematic reviews have only reported a moderate benefit. The Centers for Disease Control and Prevention (CDC) current guidelines recommend a cautious opioid prescription for chronic pain in which non-opioid therapy is indicated as the preferred treatment for chronic pain and opioid use is suggested only when the benefits for pain and function are expected to outweigh the risks. Compared with the general population, patients with CKD and ESRD are likely to be undertreated with opioids because of provider concerns about decreased metabolism and clearance and the increased risk of adverse events. Should opioid use be initiated in CKD/ESRD patients, it is recommended that they be started with the lowest possible dose and using immediate release formulations (instead of extended release). If the pain does not respond with an improvement in pain using a low dose, the pain may not be opioid-responsive. If the pain responds slightly, for either a lower degree or a shorter period than desired, it may be reasonable to increase the dose or frequency. Prescribers should be cautious with opioids at a morphine milligram equivalent daily dose (MME) above 50 mg. Concurrent benzodiazepines and other sedatives should be avoided in line with the current CDC guidelines.
The therapeutic window for opioid medications is narrow, even in a generally healthy population. Individuals with CKD or ESRD have not been included in many trials of opioid use in chronic pain, so the specific analgesic impact of opioids is not known in this population. However, individuals with CKD and ESRD likely experience many known side effects of opioids, including sedation, confusion, and constipation. While the literature on these specific adverse effects is limited in populations with CKD/ESRD, they are well documented in the elderly, which represents a high proportion of individuals with CKD/ESRD. Even low dose opioids are associated with increased morbidity and mortality in the context of ESRD. ,
ESRD and HD lead to additional complications related to the metabolism and dialyzability of opioid medications. Most naturally occurring opioids have active metabolites, which may lead to increased toxicity in patients with CKD/ESRD. For example, morphine and codeine are metabolized in the liver to the active metabolites morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), respectively. , These metabolites are known to accumulate in patients with impaired kidney function, and their accumulation can lead to potential neurotoxicity and other adverse reactions, such as nausea, vomiting, and respiratory depression. The active metabolite of meperidine, normeperidine, is renally excreted and highly neurotoxic. , When it accumulates in patients with CKD and ESRD, it places them at a high risk of seizures. Morphine, codeine, and meperidine are generally avoided in patients with decreased kidney function, similar to a few other opioids ( Table 47.2 ).
TABLE 47.2
Opioid Medications to be Avoided in Chronic Kidney Disease/End Stage Renal Disease
| Medication | Pharmacokinetics in CKD and ESRD | Known observed toxicities |
| Morphine | Active metabolite morphine-6-glucuronide (M6G) is renally clearedM6G accumulates in renal insufficiencyM6G concentrations are 15 times higher in HD patients than those with normal renal function | Respiratory depressionCentral nervous system depressionSeizuresMyoclonusLethal overdose |
| Codeine | Hepatic metabolism into active metabolitesReduced clearance of parent drug and metabolites in renal insufficiencyRisk for drug accumulation in HD patients | Nausea and vomitingHypotensionRespiratory depression or arrestCNS depression |
| Hydrocodone | Limited data in renal disease and failure85% of an oral dose is excreted as parent drug or metabolite in the urine within 24 hRisks of adverse effects are increased with renal insufficiency and drug accumulation | |
| Tapentadol | Limited data on use in renal insufficiency and failureUndergoes first pass metabolism into inactive metabolites, 99% of which are excreted in the urineAUC of the metabolite is increased 5.5 times in severe renal insufficiency | |
| Meperidine | Hepatic metabolism into active metabolite normeperidine, which is renally excretedHalf-life of normeperidine is increased in renal insufficiencyHD has been reported in case of overdose, suggesting the drug can be dialyzed | Mental status changes, seizures |
| Tramadol (especially Extended Release) | Limited data - Has not been studied in renal disease | SeizuresSerotonin syndrome |
Semi-synthetic opioids such as hydromorphone, synthetic opioids (e.g. fentanyl and methadone), and the semi-synthetic opioid buprenorphine do not have active metabolites and are reported to have a higher safety profile in patients with CKD and ESRD. , Although oxycodone is metabolized by the liver into active metabolites that may accumulate in CKD/ESRD, it may be used cautiously in these patients. However, sustained-release formulations should be avoided because of the risk of accumulation and toxicity. , Buprenorphine has a lower risk profile and can be utilized with either split dosing or a continuous transdermal patch. Tramadol belongs to a class of medications with a dual mode of action, both as an agonist of the µ-opioid receptor and as an SNRI. Since its metabolism depends on an individual’s cytochrome P450 profile, its opioid metabolism and resultant potency are highly variable and unpredictable. It is generally considered safe in the general population and in CKD and ESRD in its immediate release formulation. , However, given the variability in effect, it should be used cautiously, starting with the smallest dose in patients with ESRD. Limited data exist for the safety of extended release tramadol in CKD and ESRD, and as such, its use in this population is not recommended. ,
As in any patient population, when prescribing opioids, providers should educate patients on the risks of opioid overdose and incorporate risk mitigation strategies into the treatment plan. This includes considering a prescription for naloxone, an opioid antagonist, when risk factors for opioid overdose, such as a history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/d), or concurrent benzodiazepine use, are present.
Liver Disease
Prevalence
Liver disease is a major public health problem, accounting for over 700,000 deaths annually. Pain is very common in patients with liver disease, and it is often difficult for practitioners to manage because of underlying medical comorbidities. Pain has been reported in up to 82% of patients with liver cirrhosis and is chronic in over half of the patients with liver it. Despite the high prevalence of pain in this population and its potential for adverse consequences, there is limited research, knowledge, and guidance on the management of pain in liver disease and cirrhosis, with most available literature focusing on pain assessment and treatment in cirrhotic disease.
Assessment of Pain in Liver Disease and Cirrhosis
An evaluation of pain in patients with liver disease or cirrhosis can be accomplished via standard screening assessments, such as numeric or visual analog rating scales. As with the general population, as discussed in detail in the previous section on renal disease, once pain has been identified as being present, the next step is to determine the nature and likely mechanism of the pain, including location, quality, and duration, and perform a physical examination to assess underlying etiology.
Special Considerations in Patients With Liver Disease and Cirrhosis
Most patients with liver disease and cirrhosis reporting pain describe abdominal pain as their primary pain area. However, a large proportion of patients also report pain in the lower back, large joints, and diffusely. As non-alcoholic fatty liver disease increases in prevalence, it may overlap with other common non-hepatic painful conditions, such as osteoarthritis, which is a common etiologic factor of obesity. As with renal disease, specific considerations should be noted that are intrinsic and related to the disease process itself. The high prevalence of abdominal pain in patients with liver disease and cirrhosis is likely related to several factors, including liver capsular distension, ascites, peritonitis, and splenomegaly. , Notably, cirrhosis is a pro-inflammatory state, and the same cytokines associated with cirrhosis are also associated with pain. Fibromyalgia-like syndrome has been found in both hepatitis C virus (HCV) and non-HCV-related liver disease, which may be related to this systemic inflammation.
Pain Management Approach in Patients With Liver Disease
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