**4. Pain in patients with CKD**

#### **4.1. Acute pain in patients with CKD**

The cause for acute pain is mainly acute injury such as surgery, procedures, and childbirth. It can be caused by acute inflammation or ischemia as well, for example, acute abdomen, colic, and ischemic heart diseases. Treatment should be directed to reduce the pain as soon as possible with multiple modalities; at the same time, the primary cause should be addressed.

Blocking the pain along different parts of pain pathway allows reducing the required doses and diminishing side effects. This approach has been defined as multimodal analgesia.

Multimodal analgesia can be achieved by combining systemic paracetamol, NSAID, opioids, and local anesthetics according to patient's condition. All these medications may require dose adjustment, and locoregional anesthesia may raise a concern of hematoma formation due to reduced platelet activity and anticoagulant use in patients receiving hemodialysis [9].

Choice and dosage of medications depend on the condition of the kidneys; here the staging can roughly guide physicians to correct regimen.

For example, in stages 1 and 2, kidney function is preserved well enough to excrete the medications and their metabolites. But still, kidney function tests should be frequently done so not to miss any deterioration due to trauma, dehydration, and surgical stress during perioperative period. In young patients who are not taking other nephrotoxic medications and in stage 1, acetaminophen plus short course of NSAIDs could be used. NSAIDs should not be used in stage 2 with GFR 60–89 mL/min/1.73 m2 . Locoregional anesthesia must be used when applicable, especially for postoperative pain and trauma patients. In cases of moderate to severe pain, opioids should be added including tramadol, with or without gabapentinoids (Gabapentin or Pregabalin) to supplement for neuropathic pain, especially in trauma [9].

Recommendations of the WHO for cancer pain and its three-step approach can be tailored to manage pharmacologic treatment of chronic pain in CKD patients [2, 15, 16]. In patients with mild pain, acetaminophen may suffice, and if NSAIDs are required, care should be taken to avoid other medications which worsen the hemodynamics (compounds that affect the renin-angiotensin-aldosterone system). NSAIDs should be avoided in patients with impaired

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For moderate pain, weak opioid tramadol may be added, but codeine and dihydrocodeine should not be prescribed. Tramadol dose is adjusted according to CKD stage, given in regular

Severe pain requires the use of strong opioids, preferably those without active metabolites such as methadone, fentanyl, and oxycodone. Although, oxycodone is mainly metabolized in the liver, around 20% is eliminated by kidneys. For that reason, it may be wise to reduce the dose according to CKD stage; in mild renal failure, up to 50% of normal dose should be given, and in advanced stages, 25% of normal dose and increase in dosing interval should be done.

In all steps of WHO ladder, adjuvant medications should be added and tailored to a particular type of pain. If patient is experiencing neuropathic pain, antidepressants and anticonvulsants should be added to pain regimen. Musculoskeletal pain may have spastic component; thus muscle relaxants are beneficial. Bisphosphonates are considered adjuvant for bone pain due to malignancy. There is at least one meta-analysis to support the effect of omega-3 polyunsaturated fatty acids as an effective adjunct for joint pain (rheumatoid arthritis, inflammatory

Pharmacologic treatment of chronic neuropathic pain for adults should be done in a stepwise approach. The first line is tricyclic antidepressants (TCAs), followed by selective serotonin

Topical lidocaine should be considered alone or in combination with one the first-line thera-

Opioid analgesics or tramadol could be used alone or in combination with one of the first-line

Acetaminophen, chemical name N-acetyl-p-aminophenol, is used as a first-line medication for mild and moderate pain. It is very well absorbed from the gastrointestinal tract, mainly in the small intestine, via passive transport, and its serum concentration peaks around 2 hours.

doses for stages 1 and 2, but is reduced by 50% in advanced stages of CKD.

In patients with consistent pain, fentanyl patch can be a good option [15, 16].

norepinephrine reuptake inhibitors (SSNRIs). Gabapentinoids are next to use.

In painful diabetic peripheral neuropathy, gabapentinoids are recommended.

**5. Medications used for pain and their pharmacologic properties in** 

cardiac output or with dehydration.

bowel disease) [17].

therapies.

**CKD patients**

**5.1. Acetaminophen**

pies for localized peripheral neuropathic pain.

In stages 3 and 4, kidney function significantly reduced (GFR between 15 and 59 mL/ min/1.73 m2 ) which mandate all the pain medications to be dose adjusted and NSAIDs to be avoided. Acetaminophen should be used in regular doses for mild pain, reduced dose tramadol may be added, and for stronger pain, opioid such as fentanyl or hydromorphone may be useful. Morphine and codeine are not recommended. Regional anesthesia proves to be a valuable modality to avoid opioids and their undesired properties, especially in this stage, but should be avoided in individuals with impaired platelet function and/or coagulation. Reduced doses of gabapentinoids are considered in neuropathic pain, and caution should be taken when patients receive concomitant opioids. A decrease in around 50% of the dose for each 50% decline in GFR or CCr and an increase in the time interval between the doses are recommended [9, 10].

Acute pain management in end-stage renal disease (ESRD) patients follows the same abovementioned principles; in addition to it, more than half of them may already have been experiencing chronic pain as well. Moreover, these patients are usually malnourished and have many other multiple concomitant diseases. If they are already undergoing dialysis, sudden drop in serum concentration of pain medications and exacerbation of pain is expected. Acetaminophen may be used in regular doses of 4 g/day, but general condition of patient and other organ system diseases may require dose reduction. NSAIDs should be avoided in ESRD; even if nephrotoxicity is not of a concern, they cause gastrointestinal damage, electrolyte disturbances, and hypertension. Cyclo-oxygenase-2 inhibitors are also considered unsafe as they contribute to already existent multiple risk factors for myocardial ischemia in this group of patients [11].

Morphine, codeine, and meperidine produce active metabolites, in which clearance depends on kidney function. In ESRD patients, the accumulation of active metabolites of opioids produces excessive somnolence, as well as more dangerous complications such as respiratory depression, seizures, myoclonus, and exacerbation of acidosis. Safe alternative to these longacting opioids are fentanyl, alfentanil, and adjusted dose of hydromorphone [12]. These can be best given as PCA in acute pain cases if strong opioids are required.

#### **4.2. Chronic pain in CKD patients**

Chronic pain is defined by Treede et al. as pain that persists past normal healing time [13] and hence lacks the acute warning function of physiological nociception [14]. It may be due to prolonged tissue injury with persistent activation of nociceptors or other undefined mechanisms [15].

Recommendations of the WHO for cancer pain and its three-step approach can be tailored to manage pharmacologic treatment of chronic pain in CKD patients [2, 15, 16]. In patients with mild pain, acetaminophen may suffice, and if NSAIDs are required, care should be taken to avoid other medications which worsen the hemodynamics (compounds that affect the renin-angiotensin-aldosterone system). NSAIDs should be avoided in patients with impaired cardiac output or with dehydration.

For moderate pain, weak opioid tramadol may be added, but codeine and dihydrocodeine should not be prescribed. Tramadol dose is adjusted according to CKD stage, given in regular doses for stages 1 and 2, but is reduced by 50% in advanced stages of CKD.

Severe pain requires the use of strong opioids, preferably those without active metabolites such as methadone, fentanyl, and oxycodone. Although, oxycodone is mainly metabolized in the liver, around 20% is eliminated by kidneys. For that reason, it may be wise to reduce the dose according to CKD stage; in mild renal failure, up to 50% of normal dose should be given, and in advanced stages, 25% of normal dose and increase in dosing interval should be done. In patients with consistent pain, fentanyl patch can be a good option [15, 16].

In all steps of WHO ladder, adjuvant medications should be added and tailored to a particular type of pain. If patient is experiencing neuropathic pain, antidepressants and anticonvulsants should be added to pain regimen. Musculoskeletal pain may have spastic component; thus muscle relaxants are beneficial. Bisphosphonates are considered adjuvant for bone pain due to malignancy. There is at least one meta-analysis to support the effect of omega-3 polyunsaturated fatty acids as an effective adjunct for joint pain (rheumatoid arthritis, inflammatory bowel disease) [17].

Pharmacologic treatment of chronic neuropathic pain for adults should be done in a stepwise approach. The first line is tricyclic antidepressants (TCAs), followed by selective serotonin norepinephrine reuptake inhibitors (SSNRIs). Gabapentinoids are next to use.

Topical lidocaine should be considered alone or in combination with one the first-line therapies for localized peripheral neuropathic pain.

Opioid analgesics or tramadol could be used alone or in combination with one of the first-line therapies.

In painful diabetic peripheral neuropathy, gabapentinoids are recommended.
