#146 NephMadness: Pain Meds in Chronic Kidney Disease

April 1, 2019 | By Justin Berk

In kidney disease, choosing an analgesic can be a real pain

The use of pain meds in CKD (chronic kidney disease) often goes something like this: NSAIDs are evil, acetaminophen hardly works, opioids are dangerous, and all the rest (tramadol, gabapentinoids, antidepressants) are messy. But, we tackle the complexities of pain management in patients with chronic kidney disease in this special @NephMadness 2019 episode that, on a scale of 1-10, will leave you feeling very relieved in addressing pain.

Full show notes available at http://thecurbsiders.com/episode-list. Join our mailing list and receive a PDF copy of our show notes every Monday. Rate us on iTunes, recommend a guest or topic and give feedback at thecurbsiders@gmail.com.

Earn CME and read about each region in NephMadness 2019 at AJKD blog.

Credits

Written and produced by: Justin Berk MD, Samantha Gelfand MD

NephMadness Pun Contest produced by: Hannah R Abrams MS3

Cover art by: Kate Grant MBChB, Dip GUMed

Hosts: Matthew Watto MD, Paul Williams MD, Stuart Brigham MD

Edited by: Matthew Watto MD, Emi Okamoto MD

Guests:  Samantha Gelfand MD, Matthew Sparks MD, David Juurlink MD

Pain Meds in CKD – Time Stamps

• 00:00 Kidney Pun
• 01:19 Disclaimer, intro and guest bios
• 06:30 Guest one-liners
• 10:42 Books recommendations, staff picks and a patient complaint
• 15:25 Clinical Case and Pain Management Disclaimer
• 16:33 Modalities for pain meds in ckd
• 18:20 Opioids for pain and their metabolites
• 20:44 Dave Juurlink reframes the question, “what is our real goal with pain management?”
• 24:42 Matt Sparks reiterates the dangers of morphine and codeine in patients with advanced CKD
• 27:44 Communicating meds that are contraindicated or relatively contraindicated in CKD
• 30:40 Buprenorphine
• 32:40 What about the WHO Pain Ladder for CKD?
• 33:32 Should we use more cannabinoids? Ketamine?
• 37:07 Dave Juurlink rants on Tramadol
• 44:20 How to pick winners in NephMadness
• 46:06 NSAIDS and CKD
• 57:07 Gabapentinoids (gabapentin and pregabalin) for neuropathic pain and driving?!
• 65:57 Estimating eGFR in CKD and AKI. Which equation is best?
• 70:38 How would each of our experts treat this patient with CKD and knee pain
• 75:20 NephMadness 2019 picks for the pain region
• 82:55 Outro

Pain Meds in CKD Pearls

Patients requiring dialysis on opioids have more falls, altered mental status, and fractures and may have higher mortality.

The metabolites of hydromorphone are inert while the metabolites of morphine can accumulate in CKD (even, in theory, after dialysis).

Tramadol is an SNRI that metabolizes to a mu-receptor agonist via CYP2D6 enzyme. The speed of the CYP2D6 enzyme has wide variability among populations and common drugs (e.g. bupropion, amiodarone, paroxetine) inhibit this enzyme.

Drug interactions are important to consider, as the average patients on dialysis takes 19 pills per day.

The mechanism of NSAIDs is inhibiting prostaglandin synthesis (via COX inhibition), which reduces the inflammation causing pain. Renal blood flow is often prostaglandin-dependent and can decrease with NSAID use.

Pharmacokinetic data suggests that only a very modest amount of topical NSAIDs get absorbed,

Co-administration of GABAnergics with opioids is linked to increased mortality

Pain Meds in CKD Show Notes

When approaching patients with chronic kidney disease and pain, consider the benefits and the risks. We aim to provide pain relief and improve quality of life and function. The potential harms are often more occult. Also, consider the type of pain syndrome and to which medications it may respond. Close follow up is important, and consider other non-pharmacologic options.

Opioids

Risks

• Dr Juurlink notes: Prolonged use of opiates leads to physical dependence. This creates a situation where patients feel ill (increased pain, insomnia, nausea) when they stop opiods and the primary benefit of continuing therapy becomes the avoidance of withdrawal.
• Patients on hemodialysis who take opioids have more falls, altered mental status, and fractures and may have higher mortality (though perhaps pain itself is a poor prognostic factor).

Consider Metabolites

• One of the key steps in prescribing opioids safely is knowing the metabolites.
• Morphine and codeine should be avoided in chronic kidney disease. They are metabolized to morphine-3-glucuronide and morphine-6-glucuronide (M6G). M6G is very potent and crosses the blood-brain barrier. These metabolites are cleared by the kidney, but in CKD metabolites will build up and continue to exert an effect and possible toxicity. The longer it stays around, the longer it can accumulate in central nervous system.
• When you dialyze patients on morphine, the M6G can re-accumulate and potentially continue to cause altered mental status
• Oxycodone may be used with caution.
• The hydromorphone (Dilaudid) metabolite (H6G) is cleared by the kidney and is metabolically inert. So while it may build up, it does not cause a toxicity syndrome.

Tramadol aka Tramadont

Metabolism

• Tramadol is a serotonin norepinephrine reuptake inhibitor (SNRI) which interferes with pain pathways in the dorsal horn.
• It is metabolized to O-desmethyltramadol (ODT), a mu-1 agonist like opioids. The conversion from the SNRI to ODT is done by CYP2D6 and there is a wide variation function of this enzyme. This makes it difficult to to assess how a patient will respond.
• The population from Ethiopia and Saudi Arabia seems to consist of more rapid metabolizers via CYP2D6 (causing increased ODT and mu agonism) while those in Scandinavia appear to have slower metabolism (causing more SNRI effect, less ODT).
• Note that ODT should not be confused with Wu-Tang Clan’s ODB, who died with tramadol in his system!

Medication Interactions with Tramadol

• Multiple common medications (e.g. bupropion, paroxetine, amiodarone, cinacalcet) can block CYP2D6 and can even precipitate opioid withdrawal in patients taking tramadol.
• Tramadol can cause serotonin syndrome when taken with other serotonergic medications.
• Other risks include increased seizures and hypoglycemia.
• In patients with CKD, the drug interactions are particularly important as patients on dialysis take an average of 19 pills per day.

Kashlak Pearl: Treat yourself to this delightful post on Tox & Hound by Dr Juurlink that eviscerates tramadol. Here’s a quote:

“I like to think of tramadol as what would happen if codeine and Prozac had a baby, and that baby grew into a sullen, unpredictable teenager who wore only black and sometimes kicked puppies and set fires.” –Dr Juurlink

NSAIDs in CKD

Mechanism

• NSAIDs work by inhibiting cyclooxygenase (COX) and thus decreasing prostaglandin synthesis. This reduces the inflammation causing pain.
• Renal blood flow, particularly in CKD, often depends on prostaglandins and can decrease with NSAID use.
• Heart failure, cirrhosis, nephrotic syndrome have low effective renal blood flow which relies on prostaglandins. In these patients, NSAIDs may decrease the eGFR.
• When close to ESRD, you run the risk that a transient decrease in blood flow may still cause an issue…possibly knocking patients onto dialysis.
• If a patient is already on dialysis and anuric, the adverse effects of NSAIDs are less significant. For those patients still making urine, there are still renal risks.

Chronic NSAIDs

• In less severe renal disease, chronic NSAIDS may have low risk of worsening CKD and may be okay in small doses (read more in Curbsiders episode #69).
• Consider other side effects as well (e.g. increased blood pressure, gastrointestinal toxicity, sodium retention, hyperkalemia).

Topical NSAIDs

• Example: diclofenac gel
• There is a possibility of systemic absorption and they have been linked to kidney toxicity in case reports.
• However, these are rare (i.e., case reports) and pharmacokinetic data suggests that only a very modest amount gets absorbed,

GABAnergics

• Gamma-amino buytric acid (GABA) reduces glutamate-mediated pain signaling and is renally cleared. Therefore, the dose of GABAnergic medications needs to be decreased as eGFR decreases.
• These can be helpful for neuropathic pain, e.g. diabetic neuropathy, but may not improve other pain syndromes.
• Initial doses are low, for example gabapentin 100 mg or pregabalin 25 mg daily in CKD or three times weekly after dialysis in hemodialysis patients (expert opinion).
• Can cause significant altered mental status. Counsel on: Don’t Gabanergic and drive!
• Well described withdrawal syndrome which looks similar to alcohol withdrawal.
• Co-administration with opioids is linked to increased mortality.

Other Considerations for Pain Meds in CKD

Cannabinoids

• Consider oral cannabinoids (expert opinion). Although the benefit is not clear, there are less harms than other options.

Baclofen

• Baclofen should be avoided in patients with severe chronic kidney disease or dialysis.

Estimating eGFR in CKD and AKI

• CKD-epi or MDRD equation are both acceptable and more accurate than Cockcroft-Gault (expert opinion). Cockcroft-Gault is used by the FDA as a “historical remnant”.
• Significant acute kidney injury (ie Cr rising 1 to 2 within a day) is a dynamic situation. Assume an eGFR of 0, aka no clearance, because of the unclear trajectory.
• In one great trial in a pediatric hospital, very proactive dose adjustments for eGFR changes, positively affected outcomes. See NephJC coverage.

For more, check out the NephMadness Pain Bracket!

Goals and Learning Objectives

Goal

Listeners will have the ability to list the benefits and risks of various pain meds in CKD (chronic kidney disease)

Learning objectives

After listening to this episode listeners will…

1. Acknowledge the difficulty of pain management in patients with chronic kidney disease
2. Describe the metabolism of different opiates and how they are affected by kidney disease
3. Explain the mechanism of tramadol metabolism and how it creates unpredictability in dosing regimens
4. Identify the mechanism of NSAIDs and how they affect renal blood flow.
5. Describe the role of topical NSAIDs in patients with CKD and pain
6. Describe the adverse effects of GABAnergic medications

Disclosures

The authors report no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.

Links from the show

1. NephMadness 2019
2. Sam’s Pick: Hemingway’s A Moveable Feast
3. Dave’s Epic Misinterpretation: 2nd Debut product line
4. Matt Spark’s Recommendation: Zotero reference manager
5. CJASN: Opioid Analgesics and Adverse Outcomes among Hemodialysis Patients
6. Opioid prescriptions associated with increased mortality
7. Opioid metabolites discussion
8. Buprenorphine transdermal patch for chronic pain
9. Tox and Hound: Tramadont (written by David Juurlink)
10. Patients on dialysis have an average of 19 prescriptions
11. NSAIDS may have low risk of worsening CKD: Episode #69
12. Patients on dialysis take 19 pills per day, on average
13. A Defense of NSAIDs in CKD
14. Case study of kidney toxicity in topical NSAIDS
15. Very modest amount of topical NSAID gets absorbed
16. Description of gabapentin withdrawal syndrome
17. Co-administration of gabapentin with opioids is linked to increased mortality
18. Cochrane review: Cannabinoids for chronic pain
19. Baclofen should be avoided in severe CKD.
20. NephJC discussion of NINJAs: Using technology to dose-adjust medications in acute kidney injury
21. Yo Gabba Gabba

Other resource to check out: Pain Management in CKD: A Guide for Nephrology Providers

Citation

Samantha Gelfand, Matt Sparks and David Juurlink. Guest experts. “#146 NephMadness: Pain Meds in Chronic Kidney Disease”. The Curbsiders Internal Medicine Podcast http://thecurbsiders.com. April 1, 2019.