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

Abstract

In patients suffering from moderate-to-severe chronic kidney disease (CKD) or end-stage renal disease (ESRD), subjected to hemodialysis (HD), pain is very common, but often underestimated. Opioids are still the mainstay of severe chronic pain management; however, their prescription in CKD and HD patients is still significantly low and pain is often under-treated. Altered pharmacokinetics and the lack of clinical trials on the use of opioids in patients with renal impairment increase physicians' concerns in this specific population. This narrative review focused on the correct and safe use of opioids in patients with CKD and HD. Morphine and codeine are not recommended, because the accumulation of their metabolites may cause neurotoxic symptoms. Oxycodone and hydromorphone can be safely used, but adequate dosage adjustments are required in CKD. In dialyzed patients, these opioids should be considered as second-line agents and patients should be carefully monitored. According to different studies, buprenorphine and fentanyl could be considered first-line opioids in the management of pain in CKD; however, fentanyl is not appropriate in patients undergoing HD. Tapentadol does not need dosage adjustment in mild-to-moderate renal impairment conditions; however, no data are available on its use in ESRD. Opioid-related side effects may be exacerbated by common comorbidities in CKD patients. Opioid-induced constipation can be managed with peripherally-acting-μ-opioid-receptor-antagonists (PAMORA). Unlike the other PAMORA, naldemedine does not require any dose adjustment in CKD and HD patients. Accurate pain diagnosis, opioid titration and tailoring are mandatory to minimize the risks and to improve the outcome of the analgesic therapy.

Keywords: PAMORA; chronic kidney disease; hemodialysis; neuropathic pain; opioids; pain.

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.