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13 Articles in Volume 18, Issue #6
Authorities’ Use of Big Data May Harm—or Help—Your Chances of Investigation
Gaps in the Pharmacist’s Pain Management Role
How can cyproheptadine manage complicated chronic pain cases?
Letters to the Editor: Trackable Pills; Buprenorphine; CRPS Diagnosis
Managing a New High-Dose Opioid Patient
Managing Opioid Use Disorder
Medication Selection for Comorbid Pain Management (Part 2)
Mobile Trackers and Digital Therapeutics
New Insights in Understanding Chronic, Central Pain
Nocebo Effects: How to Prevent them in Patients
Polarizing Topics in Chronic Pain
The Fight to End Peripheral Neuropathy
Urine Drug Monitoring

Medication Selection for Comorbid Pain Management (Part 2)

In Part 2 of this series, this case examines treatment options for managing a patient with chronic OA pain, complicated by COPD.

Many factors are taken into account when determining optimal treatment of a patient’s pain. One aspect to consider is a patient’s comorbidities. In this case, a patient on chronic opioid therapy with a long-acting/extended release (ER/LA) morphine formulation for osteoarthritic pain also has chronic obstructive pulmonary disease (COPD). The COPD diagnosis increases his risk for opioid adverse effects. The case will explore a potential alternative opioid that has a better safety profile in regard to respiratory complications.

This case is the second 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; Case 3 examined treatment options for managing a patient with diabetic peripheral neuropathy, kidney disease, and substance use disorder; and Case 4 focused on the use of opioids in those with chronic kidney disease and diabetic peripheral neuropathy.

The Patient

A 63-year-old male with bilateral osteoarthritic knee pain. The patient is not a surgical candidate at this time. He is currently prescribed morphine SR 15 mg PO TID, in addition to diclofenac 1% gel topically TID. The patient has on file a signed informed consent, urine drug monitoring (UDM) from 3 months ago that is still appropriate, and a prescription drug monitoring program (PDMP) check from 3 months ago with no significant findings. The morphine SR helps to reduce his pain and allows him to continue working full-time. No aberrant behavior is identified, and he denies any adverse drug effects. He has trialed acetaminophen, duloxetine, and tramadol in the past with no significant improvement in pain, function, or quality-of-life. He currently does yoga and sees a psychologist for cognitive behavior therapy for chronic pain. The patient has controlled COPD with tiotropium and budesonide/formoterol. The patient quit smoking 1 year ago. His primary care provider expresses concern about the use of morphine SR with COPD and asks for an alternative opioid.

Background & Guidelines

Respiratory depression is a known adverse effect of opioids. Analgesia and side effects are the result of interaction with opioid receptors, primarily the mu-opioid receptors as well as the delta-opioid receptors.1 Both central (medulla within the brainstem) and peripheral (chemoreceptors) mechanisms are involved in respiration and opioids interfere with both.2,3 In opioid-induced respiratory depression, respiration slows and is irregular, subsequently contributing to hypercapnia and hypoxia.2,3

Several guidelines address COPD in the setting of chronic opioid therapy. The Veterans Affairs (VA)/Department of Defense Clinical Practice Guideline for Opioid Therapy for Chronic Pain lists severe respiratory instability including COPD, asthma, pneumonia, and neuromuscular conditions as well as sleep disordered breathing as a significant risk factor for adverse outcomes for opioid therapy.4 Similarly the Washington State Agency Medical Directors’ Group (AMDG) interagency Guideline on Prescribing Opioids for Pain, recommends clinicians use “extreme caution” and “consider consultation” in patients with medical comorbidities, such as COPD, that could make the patient more sensitive to the adverse effects of opioids.5

The Risk Index for Overdose or Serious Opioid-Induced Respiratory Depression (RIOSORD) is an available screening tool to assess a patient’s risk for opioid-induced respiratory depression. It has been validated in both the VA setting and with commercial insurance users.6 The tool assigns points for specific characteristics related to the patient’s health conditions, opioid medication, and other factors in the 6 months prior. The characteristics, scores, and average predicted probabilities are different in the VA population and commercially insured population. In both the VA study and commercial insurance users, COPD was listed as a risk factor and assigned a value of five points.6,7 Points are totaled to determine the patient’s average predicted probability for an overdose or serious opioid-induced respiratory depression within 6 months of calculating the score.6,7 See Table I.

One potential use of this tool is to determine the baseline risk of respiratory depression or overdose of the patient prior to initiating opioids. Alternatively, the tool may be used while the patient is on chronic opioid therapy.6 Some providers have also used RIOSORD to determine candidates for at-home naloxone.

Buprenorphine as an Alternative Option

Unfortunately, all currently available opioid medications impact respiration. However, there are differences in the degree of respiratory depression based on their classification, which is determined by how the medication interacts with the opioid receptor.1 Buprenorphine, a partial mu-receptor agonist, has a ceiling on respiratory depression making it a safer option compared to full opioid agonists.2,8,9 Buprenorphine does not have an analgesic ceiling.8 Therefore, if opioids are to be used, the potentially safest option in those with chronic respiratory disease is buprenorphine. On the other hand, a provider may deem an individual as too high-risk for the use of opioids and instead choose to taper the patient off opioids with continued pain management using non-opioid and non-pharmacologic approaches. The respiratory safety advantage with buprenorphine is negated when used concomitantly with benzodiazepines.8,10,11

Pharmacodynamics & Pharmacokinetics

Buprenorphine has interesting pharmacodynamic properties. In addition to its mechanism of action as a partial mu-receptor agonist, buprenorphine interacts with kappa-opioid receptors as an antagonist, which may lead to anti-hyperalgesic effects and lack of immunosuppressant effects.8,9,11 It binds very strongly (high affinity) to both of these receptors.10,11 The strength of the bond to mu-opioid receptors is strong — so in overdose or when reversal is needed, the onset of effect of naloxone may be delayed and incomplete requiring repeated doses or a continuous infusion.10,11 With mu-receptors, it slowly dissociates contributing to its slow onset of activity and long duration of action.8,11 A slow dissociation may also be beneficial with lessening withdrawal symptoms.11 The role of activation of nociception or opioid receptor-like 1 (ORL1) is still being researched but may be implicated with anti-hyperalgesic effects.8

With regard to the relevant pharmacokinetics of buprenorphine, most of this medication is eliminated unchanged, while about one-third undergoes transformation by glucuronidation to buprenorphine 3-glucuronide (inactive) and N-dealkylation via cytochrome P450 3A4 (CYP3A4) to norbuprenorphine (active but 40 times less potent than parent).11 Thus those with chronic hepatic disease or dysfunction may have reduced activity of CYP3A4 and reduced clearance of the medication. Despite limited effects of CYP3A4 inhibitors on the kinetics of buprenorphine, caution is still advised with the combination.8,11 The primary route of elimination of buprenorphine is extensively through the biliary system.11 Renal dysfunction does not impact the clearance of buprenorphine, so no dosage adjustments are needed with kidney dysfunction.11

Available Formulations

There are two formulations of buprenorphine, three if you count buprenorphine IV or IM (Buprenex), FDA-approved for the treatment of pain – as well as buprenorphine transdermal (Butrans) and buprenorphine buccal films (Belbuca).8,12,13 Typically, non-injectable routes are preferred in the treatment of chronic pain due to the pain associated with administration and their pharmacokinetics. so buprenorphine IM/IV will not be discussed further. Certainly, other formulations of buprenorphine may be used off-label for the treatment of pain; however, this discussion will focus on the formulation specifically approved for managing pain.

Patients taking more than 30 MME/day need to be tapered to no more than 30 MME/day for 1 week before they can be converted to buprenorphine. Depending on the formulation, patients exceeding 80 MED (buprenorphine transdermal) or 160 MME/day (buprenorphine buccal) may not achieve adequate analgesia with buprenorphine. In the presented case, the patient will need to be reduced to morphine SR 15 mg PO BID for 1 week. The starting dose of buprenorphine should then be determined based on the patient’s previous dose of opioids. Specific formulation selection should be based on patient preference, insurance coverage, cost, previous opioid dose, or dosing frequency preferences. The patient would then start buprenorphine transdermal 10 mcg/hr week or buprenorphine buccal 150 mcg q12h. Doses can be titrated q3 days (buprenorphine transdermal) or q4 days (buprenorphine buccal). See Table II for additional dosing information and Table III for overall advantages and disadvantages of buprenorphine. Doses exceeding the recommended maximum doses have been associated with QTc prolongation.12,13


Chronic respiratory conditions such as chronic obstructive pulmonary disease are a listed risk factor for negative outcomes with opioids. The RIOSORD tool may help to assess a patient’s risk for opioid-induced respiratory depression prior to establishing or during opioid therapy. Depending on the individual patient and circumstance, opioids may or may not be appropriate. If opioids are deemed necessary and benefits thought to outweigh risks, buprenorphine, a partial mu-receptor agonist, offers less risk for respiratory depression compared to full mu-opioid receptor agonists and may be a safer option.

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