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.
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.
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.
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
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
Tramadol vs Gabapentinoids
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.
“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.
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.
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.
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.
Comments
April 2, 2019, 12:08am Anantha Ananthakrishnan writes:
Fantastic review with great pearls! Strongly recommend this one!!
Really enjoyed the podcast as per usual! One thing stood out to me though after looking at the show notes. Kind of a dorky point but I believe the primary metabolite for hydromorphone is actually hydromorphone 3 glucuronide (Not H6G as it says in the show notes). I was always taught that it is not metabolically inert, but that it is neuroexcitatory and can cause agitation, myoclonus or seizures if it accumulates? (although most of this data is from animal studies) https://www.jpsmjournal.com/article/S0885-3924(05)00033-3/fulltext#sec4
Thanks for bringing this to our attention...we'll have to take a closer look!
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Comments
Fantastic review with great pearls! Strongly recommend this one!!
Thanks for the great feedback!
Really enjoyed the podcast as per usual! One thing stood out to me though after looking at the show notes. Kind of a dorky point but I believe the primary metabolite for hydromorphone is actually hydromorphone 3 glucuronide (Not H6G as it says in the show notes). I was always taught that it is not metabolically inert, but that it is neuroexcitatory and can cause agitation, myoclonus or seizures if it accumulates? (although most of this data is from animal studies) https://www.jpsmjournal.com/article/S0885-3924(05)00033-3/fulltext#sec4
Thanks for bringing this to our attention...we'll have to take a closer look!