Safe Use of Opioids in Chronic Kidney Disease and Hemodialysis Patients: Tips and Tricks for Non-Pain Specialists

Figures & data

Figure 1 Mechanism of action of opioids on central sensitization. The dorsal root ganglion (DRG) is a group of cell bodies responsible for pain transmission from the primary afferent fibers (PAF), also known as nociceptors, and the central nervous system (CNS). Presynaptic neurons release glutamate, substance P, and calcitonin gene-related protein (CGRP) in the synaptic cleft. On the post-synaptic neurons, also named second order neurons, glutamate activate two main receptors: the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) and N-methyl-D-aspartate (NMDA) receptor. The flow of positive charged ions, calcium (Ca²⁺) and sodium (Na⁺), through the NMDA and the AMPA receptors respectively, automatically leads pain signal to increase. Substance P, on the other hand, binds to the neurokinin-1 (NK-1) receptors, which leads to intracellular signaling that activate protein kinase C (PKC). This action removes the magnesium ion (Mg²⁺) that physiologically blocks NMDA receptors; therefore, substance P indirectly activates NMDA receptors and increases Ca²⁺ influx in the neurons, leading to increased neurotransmitter release. CGRP binds specific CGRP receptors on the second order neurons, leading to a change in receptor expression and function. All these mechanisms potentially contribute to central sensitization in chronic pain. Endogenous opioids and exogenous opioid agonists bind μ opioid receptors (MOR) in the pre- and post-synaptic neurons. Opioids close the voltage-gated calcium channels on the PAF and stop Ca²⁺ influx in the pre-synaptic neurons, where they reduce the release of glutamate, substance P, and CGRP. In addition to that, binding of MOR on the post-synaptic neurons activate and open potassium channels, leading to an outflow of potassium ions (K⁺) and cellular hyperpolarization. Hyperpolarized second order neurons become less sensitive to excitatory inputs.

Table 1 Pharmacology of Opioids for Chronic Pain Management^39,40

Opioid	Physico-Chemical Properties ^Citation40			Metabolism ^Citation39	Elimination ^Citation39
	Vd (L/kg)	PPB (%)	MW (g/mol)
Buprenorphine	8.3	96	467.6	Extensive first-pass hepatic metabolism. Phase 1 metabolism via CYP3A4 and CYP3A5 to norbuprenorphine. Phase 2 metabolism via glucuronidation to the inactive compounds B3G and N3G	Metabolites are primarily eliminated via feces. Only 10–30% of the dose is excreted in urine.
Fentanyl citrate	4	80–85	336.5	Extensive hepatic metabolism into inactive metabolites. Phase 1 metabolism via CYP3A4 to norfentanyl (99%)	<7% excreted unchanged in the urine. <1% excreted unchanged in the feces.
Hydromorphone hydrochloride	1.22	7.1	321.8	Extensive first-pass hepatic metabolism (62%) Phase 2 metabolism: Glucuronidation via UGT2B7 to H3G with no analgesic activity (possibly causes neuroexcitation, agitation, and confusion) Minor Phase 1 metabolism via CYP3A4 and CYP2C9 to norhydromorphone	Mainly eliminated through the urine as H3G. 7% excreted unchanged in the urine. 1% excreted unchanged in the feces.
Oxycodone hydrochloride	2.6	45	405.9	Phase 1 metabolism: -via CYP3A4 and CYP3A5 (N-demethylation) to noroxycodone, and then via CYP2D6 to noroxymorphone -via CYP2D6 (O-demethylation) to oxymorphone, and then via CYP3A4 to noroxymorphone	Mainly eliminated through the urine: 23% unbound noroxycodone 10% conjugated oxymorphone 9% free and conjugated oxycodone <1% oxymorphone
Tramadol	3	20	299.8	Extensive first-pass hepatic metabolism Phase 1 metabolism: -via CYP3A4 and CYP2B6 (N-demethylation) to N-desmethyl-tramadol (M2) -via CYP2D6 (O-demethylation) to O-desmethyltramadol (M1)	90% excreted in the urine (30% as unchanged drug) 10% excreted in the feces
Tapentadol hydrochloride	6.7	20	221.3	Phase 2 metabolism via glucuronidation (97%). Minor contribution of Phase 1 metabolism via CYP2C9 (13%) to N-desmethyl tapentadol and CYP2D6 (2%) to hydroxyl tapentadol. All metabolites are inactive.	99% renal excretion of tapentadol and its metabolites. 3% excreted in urine as unchanged drug.
Methadone	2–6	60–90	309.5	Extensive first-pass hepatic metabolism into inactive metabolites. N-demethylation Metabolism by different CYP450 enzymes: CYP2C19, CYP3A7, and CYP2C8 preferentially metabolize (R)-methadone; CYP2B6, CYP2D6, and CYP2C18 preferentially metabolize (S)-methadone; CYP3A4 does not have an enantiomer preference	Excreted in the feces and urine after extensive biotransformation. 20% excreted unchanged in the urine.
Morphine sulphate	3.2	35	758.8	Phase 2 metabolism via glucuronidation by UGT2B7 (90%) to: -M3G without analgesic activity, but possibly neurotoxic -M6G with analgesic activity. Minor conversion to normorphine.	70–80% excreted in the urine 10% excreted in the feces <10% excreted in urine as unchanged drug.
Codeine	2.6	7	406.4	Phase 2 metabolism via glucuronidation by UGT2B7 and UGT2B4 (80%) to C6G Phase 1 metabolism: -via CYP3A4 (N-demethylation) to norcodeine (10%) without analgesic properties -via CYP2D6 (O-demethylation) to morphine (5–10%)	90% excreted by kidneys 10% excreted in urine as unchanged drug.

Abbreviations: Vd, volume of distribution; PPB, plasma protein binding; WS, water solubility; MW, molecular weight; B3G, buprenorphine-3-glucuronide; N3G, norbuprenorphine-3-glucuronide; H3G, hydromorphone-3-glucuronide; H6G, hydromorphone-6-glucuronide; C6G, codeine-6-glucuronide.

Notes: Green: safe use in CKD; Yellow: use with caution in CKD; Orange: not recommended in CKD

Table 2 Clinical Use of Opioids for Chronic Pain Management in CKD and HD Patients^28,30,39

Opioid	Route of Administration	Starting Dosage	Indications	Clinical Use in CKD^30	Dializability and Clinical Use in HD^28, 39
Buprenorphine	Transdermal patch 7 days 4 days	5–20 mcg/h ≥ 35 mcg/h	Severe chronic pain	Safer profile. No dosage adjustment required at any stage of CKD.	Not removed by HD. No dosage adjustment required.
Fentanyl citrate	Transdermal patch 3 days	≥12 mcg/h	Severe chronic pain	Safer profile. No clinically significant accumulation in CKD.	PK characteristics do not favor removal by HD. Clearance depends on filter, flow rate and type of dialysis. It could be absorbed by CT190 dialysis membranes.
Hydromorphone hydrochloride	Oral	≥4 mg OD	Severe chronic pain (second line treatment)	Use with caution, with close monitoring. Dose adjustment required in renal failure*: Mild: 100% normal dose Moderate: 50% normal dose Severe: 25% normal dose Increase dosing intervals as needed.	H3G accumulates between dialysis treatments. Easily dialyzed: 60% removed by HD. Sudden decreases in opioid concentrations may result in withdrawal symptoms. Post-dialysis supplemental dosing could be required, but no clinical data are available.
Oxycodone hydrochloride	Oral	≥5 mg BID	Severe chronic pain (second line treatment)	Use with caution, with close monitoring. Dose adjustment required in renal failure: Mild: 50% normal dose Moderate: 25–50% normal dose Severe: contraindicated Increase dosing intervals as needed.	Oxycodone and its active metabolite, noroxycodone, are removed by HD. Oxycodone has been used in dialysis-dependent patients, and it is well-tolerated, without need for opioid compensation.
Tramadol	Oral	≥50 mg BID	Severe chronic pain (second line treatment)	Use with caution, with close monitoring. Dose adjustment required in renal failure: Mild: 100% normal dose Moderate: 50% normal dose Severe: 50% normal dose Increase dosing intervals as needed.	Significantly removed by hemodialysis. Re-dosing after a HD session may be necessary.
Tapentadol hydrochloride	Oral	≥25 mg BID	Severe chronic pain (second line treatment)	No dose adjustment required for mild to moderate renal failure. No data available for severe CKD.	Data not available in HD. It is likely to be dialyzed to some extent, because of its low protein binding, low molecular weight, and average water solubility.
Methadone	Oral	1–2 mg BID	Severe chronic pain Mainly for MMT	Use only when other opioids are contraindicated. Dose reduction may be required in ESRD because its half-life is very long and unpredictable, therefore toxicity may be delayed	Methadone and its metabolites are not removed by HD. No supplemental doses are required after a HD session. Check Q-T interval. Arrhythmias may be exacerbated by potassium and magnesium reduction after HD.
Morphine sulphate	Not recommended due to metabolites accumulation. To be avoided in CKD and HD patients.
Codeine	Not recommended due to metabolites accumulation. To be avoided in CKD and HD patients.

Notes: *Mild: Creatinine Clearance 60 to < 90 mL/min; Moderate: Creatinine Clearance 30 to < 60 mL/min; Severe: Creatinine Clearance 15 to < 30 mL/min. Green: safe use in CKD; Yellow: use with caution in CKD; Orange: not recommended in CKD.

Abbreviation: MMT, methadone maintenance treatment.

Table 3 Safe and Appropriate Use of Opioids in Chronic Pain Management⁸⁷

1	Patient should be selected and regularly assessed
2	Non-pain specialists need access to expert advice
3	Opioids should be prescribed by competent doctors
4	The correct dose is the lowest possible dose
5	Clear treatment goals should be agreed with the patients
6	Close on-going patient supervision is recommended to reassess the benefits and risks of continued therapy
7	Opioids should be tapered down or discontinued, if benefits do not outweigh risks
8	Patients and their families should be educated on safe opioid use and storage
9	Patients should be made aware of the potential for misuse, abuse and addiction
10	Signs of addictive behavior should be monitored and addressed
11	Opioids should be dispensed by competent pharmacists

Table 4 Peripherally Acting μ-Opioid Receptor Antagonist (PAMORAs) in Patients with CKD

	Route of Administration	Absorption Tmax (Hours)	Distribution	Metabolism	Elimination T1/2 (Hours)	Standard Dose in General Population	Use in CKD Patients	Use in HD Patients
Methylnaltrexone	Oral; Subcutaneous	Oral: 1.5 hrs (delayed by 2 hrs with high-fat meals). Subcutaneous: 30 min.	Vss: 1.1L/Kg	- Sulfation (Phase II) to methylnaltrexone-3-sulfate - Carbonyl reduction (Phase I) to methyl-6-naltrexol and methyl-6β-naltrexol	8	8 mg (0.4 mL for body weight 38–61 kg) 12 mg (0.6 mL for body weight 62–114 kg)	Dose reduction required in patients with moderate to severe CKD: - 4 mg for body weight ≤ 61 kg - 8 mg for body weight 62–114 kg	Not recommended (no data)
Naloxegol	Oral	< 2hrs in most of subjects a secondary Cmax occurs approx 0.4–3 hrs after the first Cmax	Vz/F: 968–2.140 L	CYP3A (Phase I) N-dealkylation O-demethylation Oxidation Partial loss of the PEG chain	6–11	25 mg daily	Dose reduction required in patients with moderate to severe CKD: 12.5 mg as starting dose	NA
Naldemedine	Oral	0.75 hr; 2.5 hr (with food)	Vz/F: 155 L	- CYP3A4 (Phase I) to nor-naldemedine - Glucuronidation (Phase II) to naldemedine-3-glucuronide	11	200 mcg daily	No dose adjustment is required at any stage of CKD, including ESRD	No dose adjustment is required for HD patients. Not removed by HD.

Abbreviations: C_max, peak plasma drug concentration; V_z/F, apparent volume of distribution during terminal phase after non-intravenous administration; Vss, apparent volume of distribution at steady-state; t_1/2, elimination half-life; T_max, time to reach maximum (peak) plasma concentration following drug administration at steady state.

Note: Data from Raffa RB, Taylor R Jr, Pergolizzi JV Jr. Treating opioid-induced constipation in patients taking other medications: avoiding CYP450 drug interactions. J Clin Pharm Ther. 2019;44(3):361–371. doi:10.1111/jcpt.12812.¹⁰³

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