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17 Articles in Volume 19, Issue #4
Analgesics of the Future: Inside the Potential of Nerve Growth Factor Antagonists
Best Practices Are Still Largely Undefined in Task Force Report
Brief Behavioral Interventions for Chronic Pain
Cervicogenic Headache: Diagnosis and Management
Chronic Headache and Central Pain Conditions
Considering Comorbidities When Selecting Medications for Pain (Part 4)
For APPs: How to Contribute to Clinical Research
Gabapentin and Suicidal Ideation: Is There a Link?
Intranasal Ketamine for the Relief of Cluster Headache
Letters: Slipping Rib Syndrome; Burning Leg Pain; CGRP Complications
Pain Assessment Tools for Malingering in Patients with Chronic Pain
Refractory Chronic Migraine: Mild, Moderate, or Severe
Should Probuphine be considered for MAT?
Special Report: The Abuse Potential of Gabapentin & Pregabalin
Tension-Type Headache: Evidence for Trigger Points
Treatment Alternatives for Migraine
Trigeminal Neuralgia: Current Diagnosis and Treatment Options

Considering Comorbidities When Selecting Medications for Pain (Part 4)

A case presentation on the use of opioids in those with chronic kidney disease and diabetic peripheral neuropathy.
Pages 60-65

Many factors are assessed when determining appropriate treatment options for patients with pain. These may include the patient’s pain complaint, medications the patient is prescribed, and other diagnoses. An important comorbidity to look for is the patient’s renal function. This case explores the use of opioid medications in a patient with chronic kidney disease and diabetic peripheral neuropathy (DPN).

This case is the fourth in a four-part series examining how comorbidities play a role in the selection of medications for pain management. Case 1 reviewed non-opioid options for a patient with chronic pain complicated by hypertension and post-traumatic stress disorder;1 Case 2 focused on the use of buprenorphine in a patient with osteoarthritic pain, complicated by chronic obstructive pulmonary disease;2 and Case 3 examined treatment options for managing a patient with diabetic peripheral neuropathy, kidney disease, and substance use disorder.3

The Patient

The patient is a 55-year-old female with DPN and chronic kidney disease (stage 3). Her creatinine clearance is 45 mL/min. Currently, she is prescribed gabapentin 600 mg by mouth twice a day and venlafaxine sustained action (SA) 112.5 mg by mouth daily. In the past, she completed cognitive behavioral therapy (CBT) for chronic pain and continues to utilize self-management techniques and relaxation. The patient’s pain had been controlled until recently, but is now impacting her ability to work full-time as a secretary and babysit her grandkids. She trialed tramadol but had nausea and vomiting. A previous trial of nortriptyline led to intolerable dry mouth. Her primary care provider (PCP) is considering initiating opioids and wants to know what the best option may be to treat the patient’s neuropathic pain in the setting of chronic kidney disease (CKD). A recent electrocardiogram (ECG) taken within the past 3 months showed QTc = 465. Urine drug monitoring (UDM) was appropriately negative. A prescription drug monitoring program (PDMP) check found no unexpected prescriptions (SOAPP-R score = 4).

Being aware of comorbidities is an important aspect of determining an appropriate treatment. (Source: 123RF)

Role of Opioids in Neuropathic Pain

The American Diabetes Association’s (ADA) position statement on diabetic neuropathy states that opioids, like tramadol and tapentadol, are not recommended as first- or second-line options because of the risks associated with opioids.4 The ADA instead recommends the use of gabapentinoids, serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs) first.4 Tramadol appears in multiple guidelines as a second-line option typically after the failure of gabapentinoids, SNRIs, and TCAs.5-7 The guidelines vary on the placement of strong opioids. For example, the Canadian Pain Society (CPS) considers morphine, oxycodone, fentanyl, and hydromorphone as second-line treatment while the Neuropathic Pain Specialist Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) considers oxycodone and morphine as third-line.5,6 The European Federation of Neurological Societies puts oxycodone as a third-line medication for diabetic neuropathy.7 The National Institute for Health and Care Excellence (NICE) guidelines place tramadol as a third-line option;8 in this guideline, morphine and long-term use of tramadol are recommended in a specialist setting.8 The CPS places tapentadol and methadone as fourth-line alternatives.5

Renal Considerations

The pharmacodynamics and pharmacokinetics of medications are important to review in patients with CKD. Issues to consider include the medication’s metabolism and metabolites, route of elimination, and potential for accumulation.9 Factors that contribute to the ability of drugs to be dialyzed include molecular weight, protein binding, volume of distribution, and water solubility.9 Medications that have low molecular weight, low protein binding, low volume of distribution, and high water solubility are more likely to be removed during dialysis.9 If dialysis is started on someone on an opioid that is readily dialyzed, withdrawal may occur.9 Another consideration in dialysis is drug monitoring. Dialysis patients may not make adequate urine for UDM. In these situations, serum drug monitoring may be used, although it is less preferred compared to urine screening.9

The World Health Organization’s (WHO) 3-step analgesic ladder for cancer pain has been adapted for patients with CKD and end-stage renal disease (ESRD). One reference places tramadol, hydrocodone, and oxycodone at Step 2; and moderate pain and methadone, hydromorphone, and oxycodone at Step 3 with severe pain in patients with ESRD.10 Similarly, the Coalition for Supportive Care of Kidney Patients (CSCKP) adapted the WHO analgesic ladder for ESRD, ultimately recommending hydrocodone, oxycodone, or tramadol for Step 2, moderate pain and hydromorphone as Step 3 with severe pain.11

The CSCKP also lists hydromorphone (except in stage 4 or 5 CKD or if dialysis is stopped due to accumulation of hydromorphone-3-glucuronide), fentanyl, and methadone as recommended medications in CKD and/or ESRD.11 For patients with CKD and/or ESRD, tramadol, hydrocodone, and oxycodone are to be used with caution.11 Morphine, codeine, and meperidine are listed as “do not use” in CKD and/or ESRD by the CSCKP.11 Furthermore, buprenorphine is also recommended in patients with CKD and/or ESRD.12,13 Table I offers a brief overview of these options.

Discussion of Options


Buprenorphine is a semi-synthetic, partial mu-receptor opioid agonist that is classified as a phenanthrene opioid.14,15 It binds with high affinity to the mu-opioid receptor leading to the displacement of other opioids from the mu-receptor, posing issues if its effects need to be reversed quickly.14 Buprenorphine has low intrinsic activity at the mu-opioid receptor,14 which leads to a ceiling for respiratory depression.14 Also, buprenorphine dissociates slowly from the mu-opioid receptor, contributing to slow onset, long half-life, and less risk for withdrawal symptoms.15,16 In addition to the mu-receptor activity, buprenorphine is a kappa-opioid receptor antagonist and agonist at opioid-receptor-like (ORL-1) receptors, which are thought to contribute to its antihyperalgesic effects and role in the treatment of neuropathic pain.14,17

There is extensive first-pass metabolism of buprenorphine, so oral bioavailability is limited to around 10%.16 Buprenorphine is highly lipophilic and highly bound to plasma proteins.16 Buprenorphine is metabolized via glucuronidation to the inactive metabolite buprenorphine-3-glucuronide and by N-dealkylation by CYP3A4 to active norbuprenorphine.15 Most of buprenorphine is excreted in the feces (70%).16 Pharmacokinetics of buprenorphine remain intact with kidney dysfunction.13,15 Although accumulation of norbuprenorphine may occur with renal dysfunction, it is thought to be insignificant due to its lower potency compared to the parent drug.13

Two noninjectable buprenorphine products have been approved for the treatment of pain, including buprenorphine transdermal (Butrans) and buprenorphine buccal films (Belbuca). Prior to initiation of these products, patients needed to be tapered to 30 mg or less of morphine equivalent doses (MED) to avoid the precipitation of withdrawal. Both of these formulations may not achieve adequate analgesia if the patient is already on a certain dose of opioids (eg, 80 MED with buprenorphine transdermal and 160 MED with buprenorphine buccal). The dose of buprenorphine may be titrated every 3 days (buprenorphine transdermal) or 4 days (buprenorphine buccal films). Opioid-naïve doses are buprenorphine 5 mcg patch q7 days or buprenorphine buccal film 75 mcg q12h. Following taper of prior opioid doses to < 30 MED, the patient may be started on buprenorphine 10 mcg patch q7 days, buprenorphine buccal film 150 mcg q12h if previously on 30 to 89 MED, or buprenorphine buccal film 300 mcg q12h if previously on 90 to 160 MED.18,19


Many clinicians may not be familiar with levorphanol, earning its moniker as the “forgotten opioid.” Levorphanol falls into the same structural class as morphine: the phenanthrene group.20 The medication is considered to be about 4 to 8 times as potent as morphine.20 It binds to mu-, delta-, and kappa-opioid receptors to a greater degree than morphine, and inhibits serotonin and norepinephrine reuptake.21 Additionally, levorphanol inhibits N-methyl-D-aspartate (NMDA) receptors and does so more powerfully than methadone.20 The NMDA antagonism and inhibition of norepinephrine reuptake make levorphanol advantageous for neuropathic pain.20,21 Unlike methadone, levorphanol does not lead to QTc prolongation.20-23

Upon oral administration, levorphanol is well-absorbed.20 It is highly bound to plasma proteins and has a large volume of distribution.20 Levorphanol is not a substrate for CYP P450 or p-glycoprotein, avoiding drug-drug interactions from these pathways; there are medications that may interfere with glucuronidation, making drug-drug interactions still possible.20,21 Phase II metabolism via glucuronidation is primarily responsible for metabolism of levorphanol to the 3-glucuronide metabolite.21 Levorphanol-3-glucuronide is eliminated renally and may accumulate in renal dysfunction.23 Therefore, caution is advised with the use of levorphanol in kidney dysfunction.23 The half-life of levorphanol is 11 to 16 hours and there is accumulation of the drug with repeated dosing.21

For those that are opioid-naïve, levorphanol should be started at 1 to 2 mg by mouth three or four times a day with increases of 25% weekly.20-22 To convert from other opioids, 1/15 to 1/12 of the morphine equivalent dose is used; this incorporates an adjustment for incomplete cross-tolerance.20-22 Dosage adjustments should occur no sooner than q72h.20-22


Methadone, a synthetic opioid, belongs to the diphenylheptane structural group. Methadone is indicated for the treatment of opioid use disorder (OUD) in specially-licensed facilities and for the treatment of pain by anyone with a DEA license (although methadone should be reserved for those with knowledge of and experience with its unique qualities).24 Methadone is not appropriate for “as needed” (PRN) use or for the treatment of acute pain.24 In addition to mu-opioid receptor activity that leads to methadone’s analgesic effects as well as some of its side effects (eg, sedation, respiratory depression), it is also a NMDA receptor antagonist.25,26 The NMDA receptor activity gives methadone potential benefit for the treatment of neuropathic pain and also protects against the development of tolerance.25,26 Methadone further inhibits serotonin and norepinephrine reuptake.21 Again, the combined NMDA antagonism and norepinephrine reuptake inhibition activity enhances methadone’s usefulness in neuropathic pain. The analgesic activity varies between 4 to 8 hours with single doses.27 Additionally, the respiratory depressant effects of methadone peak after the analgesic effects, which may set a patient up for disaster (ie, respiratory depression and death) if the dose is adjusted too quickly.27 Methadone is associated with QTc prolongation, placing patients at risk for life-threatening arrhythmias. This prolongation may occur due to methadone’s inhibition of human ether a go-go-related gene (hERG) cardiac channel.24

The medication does have some notable pharmacokinetics. It is well-absorbed, highly bound to plasma proteins (alpha-1-acid glycoprotein [85% to 90%]), and highly lipophilic.24 Several cytochrome p-450 (CYP) enzymes (ie, CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6) are responsible for metabolizing methadone to inactive metabolites including 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP).24 Moreover, methadone is a substrate for p-glycoprotein (p-gp) efflux pumps,24 which may lead to multiple drug-drug interactions. Metabolites are excreted renally, but no dosage adjustments are needed with renal insufficiency; methadone is not expected to be removed with hemodialysis.13,28 The half-life of methadone is quite variable, ranging from 8 to 59 hours, which differs from the duration of analgesic activity noted above.27

Methadone is not appropriate for every patient, however, and a careful assessment of the risks and benefits is essential. Data shows that methadone use for the treatment of chronic pain has led to a disproportionate number of accidental opioid overdoses compared to the amount prescribed.29 Similar to the need for experienced providers to prescribe methadone, the drug should be used in patients that are reliable and compliant with provider instructions.24 As noted, methadone is associated with QTc prolongation. Risk factors for QTc prolongation may include electrolyte abnormalities, impaired liver function, structural heart disease, genetic predisposition, and use of other medications associated with QTc prolongation including but not limited to tricyclic antidepressants, antipsychotics, and venlafaxine.24 Baseline ECGs are recommended before initiating methadone in those that have risk factors for QTc prolongation, a history of prolonged QTc, and a history of ventricular arrhythmias.24 An ECG within the previous 3 months is considered adequate.9 For QTc intervals between 450 to 500 msec, another opioid should be used.24 If the QTc interval exceeds 500 msec, methadone is contraindicated.24 Because of methadone’s interactions with multiple CYP enzymes and p-gp, a thorough review of potential drug-drug interactions is needed prior to initiation.24

Dosing of methadone depends on if the patient is opioid-naïve or opioid tolerant. If methadone is initiated in an opioid naïve patient, it is recommended to start at 2.5 mg by mouth q12h or q8h, although this dose may be reduced to daily in frail, elderly patients.24,30 The greater challenge may lie in switching a patient maintained on another opioid to methadone (a nonlinear conversion).30 This challenge has been discussed at length in previous articles in PPM (see McPherson, et al, “Practical Guide to the Safe Use of Methadone,” March 2015 issue) and led to the development of a new mathematical model incorporated into PPM’s online Opioid Conversion Calculator (see Fudin, et al, “Mathematical Model for Methadone Conversion Examined,” September 2012 issue).30,31

If a patient has a 7-day period without methadone, he or she should be considered opioid-naïve.24 Because of the discrepancy between analgesic and terminal half-lives, frequency of dose titration is crucial. Note that the package insert for methadone suggests dose titration as early as 3 to 5 days, which may be aggressive.27 The Methadone Safety Guidelines recommend that methadone should not be adjusted sooner than every 5 to 7 days. Dose adjustments should not exceed 5 mg/day until doses of 30 to 40 mg/day are reached, and adjustments can be made in 10 mg increments.24,30


Tapentadol is a synthetic phenylpropylamine opioid available in both immediate-release (IR) and extended-release (ER) formulations.32 The ER formulation is indicated for the treatment of severe pain that requires around-the-clock, long-term opioid treatment, and for neuropathic pain associated with DPN.33 Tapentadol has weak mu-receptor activity, and also inhibits the reuptake of norepinephrine.32 This mechanism contributes to tapentadol’s proposed role in the treatment of neuropathic pain. In animal studies, tapentadol has about 18 times less binding affinity for the mu-opioid receptor compared to morphine.34 The tapentadol:morphine equivalent is roughly 2.5:1.34 The half-life of tapentadol is around 5 hours.32 Special adverse effects include hypotension and increased risk for seizures.33

Due to first-pass metabolism, oral bioavailability of tapentadol is around 32%.33 There is low protein binding (20%).33 The primary route of metabolism of tapentadol is through Phase 2 glucuronidation (55%) with some sulfation (15%) to inactive metabolites.32 A small percentage (roughly 13%), is metabolized to N-desmethyltapentadol by CYP2C19 and CYP2C9, and a minor fraction (2%) is made into hydroxyl tapentadol.32 The majority of tapentadol and its metabolites are excreted in the urine (99%).32 According to the labeling information, tapentadol is not recommended with severe renal impairment with creatinine clearance (CrCl) < 30 mL/min, and no dosage adjustments are needed with mild-moderate renal impairment of CrCl 30 to 90 mL/min.33

Again, dosing should depend on the status of the patient and whether he or she is opioid naïve or opioid tolerant. For opioid naïve patients, initial doses of tapentadol start at 50 mg by mouth twice a day.33 The package insert also recommends this dose for patients who are opioid tolerant with judicious use of short-acting opioids for breakthrough pain.33 Another conversion calculator recommends the use of 1:3.3 morphine:tapentadol conversion ratio when switching from morphine or other opioids to tapentadol.35 Titration of tapentadol should not exceed 50 mg by mouth twice a day, no sooner than every 3 days.33

Case Revisited: Non-Opioid Options

Although this article is focused on the opioid aspects of pain management in a patient with chronic kidney disease and diabetic peripheral neuropathy, it is worth noting some points related to non-opioids in this patient. Gabapentinoids are renally excreted, and there are recommended dose adjustments based on CrCl beginning at < 60 mL/min.36,37 SNRIs have renal considerations as well. Duloxetine is not recommended with CrCl < 30 mL/min.38 Venlafaxine has recommended dose adjustments for renal insufficiency with 25% to 50% reduction in total daily dose with CrCl 30 to 89 mL/min and a reduction of 50% or more with CrCl < 30 mL/min.39 Therefore, the patient’s nonopioid medications may be optimized.

Since the patient has trialed nonopioid and nonpharmacologic options, opioids may be a reasonable next step if the benefits are thought to outweigh the risks. Risk mitigation strategies were employed and appropriate. The patient’s SOAPP-R score places her at a low risk.

What opioid, then, may be most appropriate for this patient with neuropathic pain and Stage 3 CKD? Fentanyl or hydromorphone would be reasonable because of the patient’s kidney dysfunction, although these opioids do not have unique mechanisms of action that have proposed roles in treating neuropathic pain. Given the patient’s prolonged QTc interval and PCP initiation of opioids, methadone is not the best option. Because of levorphanol’s cost, issues with availability, and limited provider experience, it is also not ideal.

This leaves buprenorphine and tapentadol. Proceeding here may include determining cost, insurance coverage, patient preference, and/or the route of administration. Buprenorphine would have the advantage of being appropriate at any level of kidney function, whereas tapentadol would become inappropriate if the CrCl fell to less then 30 mL/min. Ultimately, after discussing with the patient, tapentadol SA is chosen and will be initiated at the opioid naïve dosing of tapentadol SA 50 mg by mouth twice a day.

Recent guidelines recommend that short-acting opioids be used when initiating opioid therapy, due to increased risk for overdose during the initiation and titration phase of long-acting opioids.40 Therefore, the patient could be initiated on a low dose of hydrocodone/acetaminophen or oxycodone/acetaminophen with dose titration to establish opioid tolerance (60 mg of morphine, 30 mg of oxycodone, or 60 mg of hydrocodone), then switch to the long-acting formulation. In this case, the patient was also co-prescribed naloxone and signed an informed consent for treatment with chronic opioids. A follow-up was scheduled via telephone for 1 week later and in the office 4 weeks later.


Considering comorbidities is essential when determining appropriate treatment. This presented case highlighted opioids with mechanisms particularly beneficial in neuropathic pain—buprenorphine, levorphanol, methadone, and tapentadol—while also tackling the challenge of treating a patient with renal dysfunction. Opioids preferred in renal dysfunction include buprenorphine, hydromorphone, fentanyl, and methadone.

Last updated on: June 20, 2019
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Medication Selection for Comorbid Pain Management (Part 3)
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