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Written by - Archana Vajjala, MBBS; Shweta S. Shah, MD
Infographics: Salar Bani-Hani, MD; Archana Vajjala, MBBS
INTRODUCTION
Pain is a common symptom experienced by patients with chronic kidney disease (CKD), including children, and is often undertreated. Limited data exist regarding pain management in pediatric CKD.
The mean prevalence of pain is 47%, with a range of 8–82% in end-stage kidney disease (ESKD) patients. It can have a negative impact on health-related quality of life (HRQoL), dialysis adherence, healthcare utilization, and mortality. Chronic pain may also contribute to other physical and psychosocial symptoms such as depression, anxiety, and fatigue. In patients with CKD and kidney failure, pain is related to many factors like uremia, bone mineral disease (osteitis fibrosa cystica, amyloidosis, osteomalacia), and uremic neuropathy. Comorbid conditions such as ischemic peripheral artery disease, diabetic neuropathy, osteoarthritis, and osteopenia/ osteoporosis (in adults) add to this.
The art of prescribing analgesics requires careful consideration due to the following reasons:
The use of analgesics can have adverse effects on kidney function due to altered pharmacokinetics.
Decreased renal clearance can affect the safe dosing of analgesics.
Pain management in patients on kidney replacement therapy (KRT) requires understanding the clearance of the drug/ or its metabolites (active and inactive) via dialysis.
To avoid inappropriate analgesic prescriptions.
NON-PHARMACOLOGICAL MANAGEMENT OF PAIN (Table 1):
Pain is most commonly managed pharmacologically in children, but in some instances, non-pharmacologic management like topical heat, cooling, and physical therapy can alleviate muscle pain. Distraction techniques and involvement of child-life specialists or meditation can help with chronic pain management. Acupuncture is under research for pain management in CKD patients.
Table 1. Nonpharmacological Pain Management
PHARMACOLOGICAL MANAGEMENT OF PAIN (Table 2):
Local agents (Lidocaine patches, Buprenorphine, and Fentanyl Patches)
Systemic agents
Acetaminophen is considered the first-line therapy for pain management in children with CKD. Opioids can be used for treating moderate to severe pain. Buprenorphine holds promise as a potentially helpful drug for treating pain in pediatric patients with CKD, but there is limited data available to support this. Despite all these options, pain often remains challenging to treat in children with CKD.
Table 2. Pharmacological pain management
Table 2 Legend: COX: Cyclooxygenase; M3G: morphine-3-glucuronide; M6G: morphine-6-glucuronide; BBB: Blood Brain Barrier; HD:hemodialysis; H3G: hydromorphone-3-glucuronide; M1: O-desmethyl tramadol; RLS: Restless leg syndrome; CB1 & CB2 : Cannabinoid receptors 1 and 2.
1) ACETAMINOPHEN
Acetaminophen is primarily used as the non-narcotic agent of choice for mild to moderate pain in patients with CKD. The National Kidney Foundation (NKF) recommends acetaminophen as the drug of choice for pain control in patients with kidney disease.
The findings of the PATH-BP trial suggest that regular intake of acetaminophen (4gm) increases systolic BP in individuals with hypertension (HTN) by approximately 5mmHg compared with placebo. Caution should be used when prescribing acetaminophen to patients with HTN and those at risk of ischemic heart disease & stroke.
Caution: Acute and long-term acetaminophen overdose may cause nephrotoxicity, increasing the risk of kidney failure, especially in patients with comorbidities or concomitant use of nephrotoxic drugs.We could rephrase it as, though no dose adjustment is needed in CKD, a few observational studies have shown higher odds of decline in eGFR in acetaminophen users (Lifetime cumulative dose > 100 g). Therefore, intermittent short-term use of an appropriate dose is recommended.
Ingestion of toxic amounts (>2000 mg/kg) of acetaminophen can cause acute kidney injury (AKI) due to direct nephrotoxicity by N-acetyl-p-benzoquinone imine (NAPQI), leading to acute proximal tubular necrosis, and chronic use may result in CKD and kidney failure from chronic interstitial fibrosis or papillary necrosis.
2) NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs):
NSAIDs are a class of drugs that have analgesic and anti-inflammatory benefits. They have long been regarded as dangerous for use in patients with CKD because of their risk for nephrotoxicity and clinically significant reduction in GFR through renal afferent arteriole constriction mediated via renal prostaglandin inhibition.
Caution: Usage of NSAIDs is associated with AKI, progressive loss of glomerular filtration rate in CKD, electrolyte derangements, acute interstitial nephritis, papillary necrosis, HTN, and hypervolemia in patients with pre-existing heart failure. Cautious use of NSAIDs is recommended in patients with CKD after carefully considering these risk factors individually.
Avoid long-acting NSAIDs with a half-life >12h. Adequate fluid intake and concurrent use of contrast dyes, nephrotoxic, or drugs causing hemodynamic instability should be avoided.
A chronic renal insufficiency cohort (CRIC) study recently compared the usage of opioids with NSAIDs in patients with CKD and observed that opioids had more adverse effects in CKD, with a significant increase in the risk of death and poor kidney outcomes compared to NSAIDs.
3) OPIOIDS:
Opioids are commonly used in pain control in the perioperative period in those with kidney disease. However, long-term trends show an increase in overdose-related deaths or hospitalizations in the general population due to its abuse potential.
Most opioids and their metabolites are excreted via kidneys, and the accumulation of metabolites can lead to toxicity. Patients on hemodialysis who take opioids have a high risk of falls, fractures, and confusion, thus higher mortality. Long-term use can lead to physical dependence and can cause withdrawal when abruptly tapered.
Figure 1: Metabolism and excretion of different types of opioid analgesics. All metabolites and some parent compounds are renally excreted. Some are excreted via the GI tract.
A) MORPHINE:
Morphine sulfate is one of the most frequently used opioids for post-operative pain and cancer-related pain management in children and adults.
NOTE: Morphine clearance is reduced and its effect is prolonged in neonates compared with older children and adults because of the immature glucuronidation pathway.
Caution: In patients with kidney disease because of the risk of developing opioid resistance or toxicity. Avoid morphine in CKD (CrCl <30 mL/min) and kidney failure (on dialysis) due to the accumulation of active metabolites and difficulty in managing their adverse effects.
B) HYDROMORPHONE:
Hydromorphone is a morphine analog that binds to several opioid receptors and is better tolerated in patients with renal insufficiency. It is more potent than morphine hence less drug is needed to provide similar analgesic response. Due to the need for a lesser amount of medicine, the production of hydromorphone-3-glucuronide (H3G) is lower. Thus, neurotoxic effects may be comparatively less than that of M3G (morphine metabolite) in the general population. However, the accumulation of H3G in patients with kidney disease is up to 100 times the parent drug level and can cause opioid neurotoxicity. Thus further low doses are required in CKD patients. Some studies suggest that hydromorphone is removed with dialysis; hence dose adjustment is needed between treatments and when patients come off dialysis. Unlike morphine, hydromorphone does not have an active 6-glucuronide metabolite, thus lowering the risk of developing respiratory depression.
C) OXYCODONE:
Oxycodone is a semi-synthetic opioid used to treat moderate to severe pain. It has a higher volume of distribution and is 50% protein bound. The half-life of oxycodone is increased in uremic patients despite its 8% to 14% elimination rate as the parent compound. A 25-50% dose reduction is warranted in mild to moderate renal failure and avoid use in advanced CKD. Although there is not sufficient data, oxycodone metabolite is removed by hemodialysis and could be used in HD.
D) BUPRENORPHINE:
Buprenorphine is a synthetic opioid used to treat pain and opioid use syndrome. It is an effective and well-tolerated analgesic for moderate to severe pain in patients with CKD with good efficacy, tolerability, and drug delivery systems.
Interestingly, transdermal drug delivery is as effective as sublingual buprenorphine in managing pain, providing sustained analgesia over 3 to 7 days.
Caution: In patients with respiratory depression, gastrointestinal obstruction and hypersensitivity to any of its components. It is not recommended in patients on full opioid agonists (e.g., morphine, heroin) because of the risk of precipitating acute opioid withdrawal. BuprenorPhin is not dialyzable.
E) TRAMADOL
Tramadol is an acceptable analgesic for treating moderate pain in patients with CKD as it lacks direct nephrotoxic effects. However, it's important to note that its systemic elimination is reduced with advanced CKD (GFR <30 ml/min/1.73 m2).
Caution: Higher blood levels of the compound may induce respiratory depression and reduce the seizure threshold in uremic patients. It may precipitate the serotonin syndrome in patients taking selective serotonin reuptake inhibitors like fluoxetine, sertraline, and paroxetine. The maximum dose of tramadol prescribed to advanced CKD patients has been suggested not to exceed 50 mg orally twice daily.
The FDA warns against using tramadol for pain in all children aged <12 years because of the high risk of respiratory depression.
F) OTHER OPIOIDS:
Fentanyl and methadone may be used for severe pain in CKD patients.
Fentanyl is a potent synthetic opioid most commonly used for severe pain in patients with kidney failure due to its primary hepatic elimination. Its metabolites are inactive and non-toxic. It is also available in the form of a patch/ transdermal delivery.
Patients on hemodialysis can be successfully treated with transdermal fentanyl patches for moderate to severe chronic pain while being cautious about its long elimination half-life and potential for serious complications.
Caution: Life-threatening or severe breathing difficulties and diarrhea are seen, mainly during the first 72 h of a patient's treatment initiation and any time the drug’s dose is increased.
The liver metabolizes methadone & its primary metabolite is excreted via the gastrointestinal system and kidneys. Interestingly compensatory fecal excretion of methadone metabolites occurs in patients with renal impairment. Hence, methadone and its metabolites usually do not accumulate significantly in patients with renal insufficiency.
4) GABAPENTINOIDS
Gabapentinoids are often used in patients with kidney disease to treat neuropathic pain, pruritus & restless leg syndrome (RLS). Careful dosing should be done in dialysis patients. With normal renal function, the maximum dose of gabapentin that can be used is 3600 mg/day in divided doses. However, in patients with reduced clearance, side effects like falls and fractures due to sedation and low bone mineral density can be seen with doses >300 mg/day.
Caution: Symptoms similar to alcohol withdrawal can occur after stopping the medication. Co-administration with opioids is associated with increased mortality.
Table 3: Summary of analgesic dose adjustment recommended in CKD
5) CANNABINOIDS:
Cannabinoids produce more than 100 naturally occurring chemicals, the most abundant of which are Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These bind to cannabinoid receptors (CB1 and CB2) (Figure 2), which are present in various organs in the body. Medical marijuana has been linked to helping alleviate several side effects associated with CKD and dialysis, such as chronic pain, nausea and vomiting, anorexia, pruritus, RLS, and inflammation.
Both CB1 and CB2 receptors are found throughout the kidney. CB1 receptor activation can cause proximal tubule dysfunction and proteinuria. CB2 receptor activation promotes tissue repair and alleviates kidney injury (Fig.2). The bioavailability of inhaled and ingested THC is only 10% and 6%, respectively. The plasma half-life of THC is 1 to 3 days in occasional users and 5 to 13 days in chronic users.
Caution: Most adverse effect profiles are extrapolated from recreational marijuana, and data is scarce on medical marijuana. Renal function should be closely monitored in these patients & the lowest effective dose should be used.
Figure 2: Infographic showing the effect of cannabis on the kidney learned from animal models. CB1 receptor activation can cause proximal tubule dysfunction and proteinuria. CB2 receptor activation promotes tissue repair and alleviates kidney injury.
5) BACLOFEN
Baclofen (beta-[4-chlorophenyl]-GABA) is a commonly prescribed muscle relaxant and is primarily excreted by the kidneys (65-85%) with potentially serious side effects on patients with decreased kidney function.
Adverse effects: CNS depression and decreased level of consciousness are seen in patients with CKD and encephalopathy in patients with kidney failure. Other side effects are hypotonia, respiratory depression, bradycardia, HTN, and hypotension. Patients with CKD might require clearance of the drug by dialysis.
Recommended dose: decrease the amount in patients who have moderately reduced kidney function (estimated GFR 30-60 mL/min/1.73 m2) and avoid use in patients with severely reduced kidney function (estimated GFR < 30 mL/min/1.73 m2) or on KRT.
Table 4: Medications to be considered for acute pain relief in children with renal impairment
Table 5: Considerations for analgesics use in advanced CKD.
PEARLS:
Pain in pediatric CKD is under-recognized, and data on using safe analgesia and optimum management in this population is scarce.
Alteration in drug metabolism, accumulation of active metabolite, changes in the volume of distribution, absorption, and drug clearance by different kidney replacement therapies need to be considered for safe analgesia in CKD/ESKD patients.
Acetaminophen is a safe analgesic for mild to moderate pain. NSAIDs are to be cautiously used, weighing their risks and benefits. Opioids are reserved for moderate to severe pain. Due to the accumulation of active metabolites and potential for adverse effects, careful dosing and selection of opioids are warranted. Though medical marijuana shows some promise, further studies are needed.
Reviewed bySai Sudha Mannemuddhu, MD; Roshan P. George, MD; Swasti Chaturvedi, MBBS; Abdul Qader, MD; Andrew M. South, MD, MS; Monica Rairikar, MD, Sophia Ambruso, DO.