Integrating pharmacogenomics into precision pain management.

Studies suggest wide heterogeneity in pain management response. Improved methods of pain pharmacotherapy are urgently needed to improve clinical response and safety profile of analgesics. The study or application of how genetics influence response to medications is called pharmacogenomics (PGx). PGx testing is a tool that may support more precise selection and dosing of pain medicines. PGx guidelines exist for drug-gene interactions with high levels of evidence and can be applied in clinical practice for more precise care in patients with cancer. The Clinical Pharmacogenetics Implementation Consortium (CPIC) is a publicly funded international consortium of experts who curate published PGx data and create peer-reviewed guidelines on how to translate PGx results into actionable prescribing decisions. Given the immense need to improve pain management, it is important to increase awareness and consider application of CPIC guidelines to pain management strategies. This commentary concisely describes how PGx can be used to aid in more precise applications of pain pharmacotherapy based on the CPIC guidelines.

Application and Clinical Value of Definitive Drug Monitoring in Pain Management and Addiction Medicine.

OBJECTIVE: To assess routine application and clinical value of definitive urine drug monitoring (UDM) for drug detection, inconsistent drug use, and prescription adherence, along with a comparison to immunoassay screening (IAS). METHODS: Direct-to-definitive UDM performance was analyzed retrospectively in 5000 patient specimens. Drug findings, medication inconsistencies, and detection sensitivity were assessed, and definitive UDM versus IAS monitoring was studied. RESULTS: Definitive testing resulted in 18,793 drug findings with 28,403 positive drug and metabolite tests. Definitive testing expanded monitoring with 11,396 drug findings that would not be tested by IAS. The opioids accounted for the highest frequency of inconsistent positive drug-use findings, at 12%. Conversely, inconsistent negative drug findings, used as an index of prescription non-adherence, were determined in 1,751 of 15,409 monitored medications and included a high frequency of antidepressants and antipsychotics inconsistencies. Direct comparison of definitive UDM and IAS showed false-positives by IAS as well as a high rate of false-negatives that would be missed using current confirmation protocols. CONCLUSIONS: Results from routine application of direct-to-definitive UDM demonstrate the clinical value of drug-use identification and the objective evaluation of inconsistencies in drug misuse and medication adherence in pain management and addiction medicine practice. Without conversion to direct-to-definitive UDM, continuing use of IAS will limit the scope of drugs being tested, will result in an indeterminate rate of false negatives and will require confirmation testing to eliminate the reporting of false-positive IAS tests. The findings in this study provide evidence-based support for recommended use of a direct-to-definitive drug testing protocol.

Opioids and pituitary function: expert opinion.

PURPOSE: Opioids are highly addictive potent analgesics and anti-allodynics whose use has dramatically increased in recent decades. The precipitous rise in opioid dependency and opioid use disorder is an important public health challenge given the risks for severely adverse health outcomes. The long-term opioid impact on hypothalamic-pituitary axes is particularly underappreciated among both endocrinologists and primary care physicians. We review the effects of opioids on hypothalamic-pituitary-target gland function and their implications for clinical practice. METHODS: Experts in hypothalamic-pituitary disorders and opioid pharmacology reviewed recently published literature and considered strategies for diagnosing and managing these opioid-induced endocrine effects. RESULTS: Opioid suppression of hypothalamic-pituitary axes can lead to hypogonadotropic hypogonadism, central adrenal insufficiency, and hyperprolactinemia. These important clinical manifestations are often under-estimated, poorly evaluated, and typically either untreated or not optimally managed. Data on biochemical testing for diagnosis and on the effect of hormone replacement in these patients is limited and prospective randomized controlled studies for guiding clinical practice are lacking. CONCLUSIONS: Patients should be informed about risks for hypogonadism, adrenal insufficiency, and hyperprolactinemia, and encouraged to report associated symptoms. Based on currently available evidence, we recommend clinical and biochemical evaluation for potential central adrenal insufficiency, central hypogonadism, and/or hyperprolactinemia in patients chronically treated with opioids as well as the use of current expert guidelines for the diagnosis and treatment of these conditions.

Gaps in the Use of Long-Acting Opioids Within Intervals of Consecutive Days Among Cancer Outpatients Using Electronic Pill Caps.

OBJECTIVE: This study describes individual cancer patients' nonuse of extended-release or long-acting (ER/LA) opioids, including periods of gap between opioid doses taken. DESIGN: Secondary analysis of a three-month observational study of prescribed ER/LA opioids monitored using electronic pill caps. SETTING: Two outpatient oncology clinics of a large health system in the Mid-Atlantic region. PARTICIPANTS: Inclusion was based on self-identified African Americans and whites, at least 18 years old, diagnosed with solid tumors or multiple myeloma. For the current analysis, the additional inclusion criterion was prescription of an oral ER/LA opioid for cancer pain to be taken around the clock. METHODS: The electronic monitoring period for each study participant was partitioned into intervals of days between days with one or more openings (using medication event monitoring systems) representing rates of ER/LA opioid nonuse over consecutive days and over time. RESULTS: Of the sample (N = 109), two-thirds of the cancer patients had some nonuse of prescribed ER/LA opioids, with one in four having nonuse during 31.5-87.5% of their electronic-monitoring periods. Nonuse over periods of five or more, six or more, and seven or more consecutive days occurred for 37.6%, 34.9%, and 30.3% of the participants, respectively. CONCLUSIONS: About one in three ambulatory cancer patients in this study had substantial gaps between days of ER/LA opioid use, potentially resulting in risk of overdose depending upon the prescribed ER/LA opioid type, dose, and length of the time the opioid was stopped and resumed at the previous dose. This phenomenon has received little to no attention in the opioid safety discourse.

Initiation of Transdermal Fentanyl Among US Commercially Insured Patients Between 2007 and 2015.

INTRODUCTION: This study examined patterns of initial transdermal fentanyl (TDF) claims among US commercially insured patients and explored the risk of 30-day hospitalization among patients with and without prior opioid exposure necessary to produce tolerance. DESIGN: A retrospective cohort study of initial outpatient TDF prescriptions. SETTING: A 10% random sample of commercially insured enrollees within the IQVIA Health Plan Claims Database (formerly known as PharMetrics Plus). SUBJECTS: Individuals with a claim for TDF between 2007 and 2015. METHODS: The primary exposure was a new transdermal fentanyl claim, and the primary outcome was guideline concordance based on time and dose exposure. RESULTS: Among the 24,770 patients in the cohort, 4,848 (20%) patients had sufficient time exposure to opioids before TDF. Among those with sufficient time exposure, 3,971 (82%) had adequate opioid exposure based on the US Food and Drug Administration (FDA) package insert dosing guidance. Overall, 3,971 of the 24,770 (16%) patients received guideline-consistent TDF. An exploratory analysis of 30-day hospitalization after a TDF claim did not detect a difference in odds between guideline-consistent or -inconsistent groups when adjusted for variables known to influence the risk of opioid-induced respiratory depression. CONCLUSIONS: A majority of patients met FDA opioid dose thresholds for TDF but had insufficient time exposure based on package insert recommendations for tolerance. Exploratory analysis did not detect a difference in odds for all-cause hospitalization or respiratory-related 30-day hospitalization between guideline-consistent or -inconsistent TDF claims. Prescribers should continue to adhere to FDA TDF labeling, although certain aspects of the labeling should be reevaluated or clarified.

Understanding Buprenorphine for Use in Chronic Pain: Expert Opinion.

OBJECTIVE: An expert panel convened to reach a consensus on common misconceptions surrounding buprenorphine, a Schedule III partial µ-opioid receptor agonist indicated for chronic pain. The panel also provided clinical recommendations on the appropriate use of buprenorphine and conversion strategies for switching to buprenorphine from a full µ-opioid receptor agonist for chronic pain management. METHODS: The consensus panel met on March 25, 2019, to discuss relevant literature and provide recommendations on interpreting buprenorphine as a partial µ-opioid receptor agonist, prescribing buprenorphine before some Schedule II, III, or IV options, perioperative/trauma management of patients taking buprenorphine, and converting patients from a full µ-opioid receptor agonist to buprenorphine. RESULTS: The panel recommended that buprenorphine's classification as a partial µ-opioid receptor agonist not be clinically translated to mean partial analgesic efficacy. The panel also recommended that buprenorphine be considered before some Schedule II, III, or IV opioids in patients with a favorable risk/benefit profile on the basis of metabolic factors, abuse potential, and tolerability and that buprenorphine be continued during the perioperative/trauma period. In addition, switching patients from a full µ-opioid receptor agonist to buprenorphine should be considered with no weaning period at starting doses that are based on the previous opioid dose. CONCLUSIONS: These recommendations provide a framework for clinicians to address most clinical scenarios regarding buprenorphine use. The overall consensus of the panel was that buprenorphine is a unique Schedule III opioid with favorable pharmacologic properties and a safety profile that may be desirable for chronic pain management.

Rational Urine Drug Monitoring in Patients Receiving Opioids for Chronic Pain: Consensus Recommendations.

Objective: To develop consensus recommendations on urine drug monitoring (UDM) in patients with chronic pain who are prescribed opioids. Methods: An interdisciplinary group of clinicians with expertise in pain, substance use disorders, and primary care conducted virtual meetings to review relevant literature and existing guidelines and share their clinical experience in UDM before reaching consensus recommendations. Results: Definitive (e.g., chromatography-based) testing is recommended as most clinically appropriate for UDM because of its accuracy; however, institutional or payer policies may require initial use of presumptive testing (i.e., immunoassay). The rational choice of substances to analyze for UDM involves considerations that are specific to each patient and related to illicit drug availability. Appropriate opioid risk stratification is based on patient history (especially psychiatric conditions or history of opioid or substance use disorder), prescription drug monitoring program data, results from validated risk assessment tools, and previous UDM. Urine drug monitoring is suggested to be performed at baseline for most patients prescribed opioids for chronic pain and at least annually for those at low risk, two or more times per year for those at moderate risk, and three or more times per year for those at high risk. Additional UDM should be performed as needed on the basis of clinical judgment. Conclusions: Although evidence on the efficacy of UDM in preventing opioid use disorder, overdose, and diversion is limited, UDM is recommended by the panel as part of ongoing comprehensive risk monitoring in patients prescribed opioids for chronic pain.

Variability in Opioid Equivalence Calculations.

OBJECTIVE: Equianalgesic conversion methods are commonly used to switch patients from one opioid to another due to suboptimal pain relief or adverse events. There is no universally accepted opioid conversion method, however, and there is often significant variability between conversion resources. As a result, patients are at risk for undertreated pain and serious adverse events. The purpose of this survey was to compare the equianalgesic conversion estimates between nurse practitioners, pharmacists, and physicians for commonly prescribed opioids. METHODS: A survey form was developed using Survey Monkey. Participation was solicited by providing a link to the survey via social media (e.g., Facebook, Twitter, LinkedIn, etc.) and emailing professional organizations for sharing with their members and followers. Data collected included demographics and estimated morphine equivalents (MEQs) of hydrocodone 80 mg, fentanyl transdermal patches 1,800 mcg (as 75 mcg/hour), methadone 40 mg, oxycodone 120 mg, and hydromorphone 48 mg. Participants were also asked to provide their choice of reference utilized to complete the conversions, including personal knowledge. Descriptive analyses were performed using measures of central tendency. Hypothesis testing was performed using Pearson's chi-squared and Fisher's Exact Test for categorical data and the Kruskal-Wallis equality of populations rank test for continuous data to assess differences between median opioid doses by professional groups. RESULTS: The total number of respondents included in the analysis was 319. Physicians, pharmacists, and nurse practitioners/physician assistants comprised 25.4%, 56.7%, and 16.3%, respectively, of respondents. The overall mean (± standard deviation) MEQ doses for fentanyl, hydrocodone, hydromorphone, methadone, and oxycodone were: 176 (±117) mg, 88 (±42) mg, 192 (±55) mg, 193 (±201) mg, and 173 (±39) mg, respectively. For fentanyl, the mean (±standard deviation) MEQ doses were 180 (±122) mg, 178 (±128) mg, and 157 (±68) mg, for physicians, pharmacists, and nurse practitioners/physician assistants, respectively. For all three groups of clinicians, the median MEQ dose for fentanyl was 150 mg. The mean (±standard deviation) MEQ doses of methadone for physicians, pharmacists, and nurse practitioners/physician assistants were: 214 (±142) mg, 171 (±107) mg, and 185 (±129) mg, respectively. The median MEQ dose for methadone was 160 mg for each of the clinician groups. CONCLUSIONS: As evidenced by large standard deviations, there was significant variation in mean opioid conversions to MEQ doses within each profession type, particularly for fentanyl and methadone. The median MEQ doses provided for opioid conversions were the same among each profession. No universal method exists that allows each of the five studied opioids to be accurately and consistently converted to another opioid (i.e., morphine).

Is levorphanol a better option than methadone?

BACKGROUND: Methadone has been a stalwart pharmacologic option for the management of opioid drug dependence for many years. It substitutes for opioid agonists and possesses certain pharmacokinetic properties that confer characteristics preferable to those of other opioids for this application. Methadone is likewise used as an option for the treatment of pain, particularly chronic pain. It has a spectrum of pharmacodynamic activity, including contributions from non-opioid components, that translates to its specific clinical attributes as an analgesic. Unfortunately, basic science studies and accumulated clinical experience with methadone have revealed some undesirable, and even worrisome, features, including issues of safety. The benefit/risk ratio of methadone might be acceptable if there was no better alternative, but neither its pharmacokinetic nor pharmacodynamic properties are unique to methadone. OBJECTIVE: We review the basic and clinical pharmacology of methadone and suggest that levorphanol should receive attention as a possible alternative. CONCLUSION: Unlike methadone, levorphanol is a more potent NMDA antagonist, possesses a higher affinity for DOR and KOR, has a shorter plasma half-life yet longer duration of action, has no CYP450 interactions or QTc prolongation risk, can be a viable option in the elderly, palliative care, and SCI patients, requires little to no need for co-administration of adjuvant analgesics, and has potentially a lower risk of drug-related Emergency Department visits compared to other opioids.

Consensus Recommendations on Initiating Prescription Therapies for Opioid-Induced Constipation.

OBJECTIVE: Aims of this consensus panel were to determine (1) an optimal symptom-based method for assessing opioid-induced constipation in clinical practice and (2) a threshold of symptom severity to prompt consideration of prescription therapy. METHODS: A multidisciplinary panel of 10 experts with extensive knowledge/experience with opioid-associated adverse events convened to discuss the literature on assessment methods used for opioid-induced constipation and reach consensus on each objective using the nominal group technique. RESULTS: Five validated assessment tools were evaluated: the Patient Assessment of Constipation-Symptoms (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL), Stool Symptom Screener (SSS), Bowel Function Index (BFI), and Bowel Function Diary (BF-Diary). The 3-item BFI and 4-item SSS, both clinician administered, are the shortest tools. In published trials, the BFI and 12-item PAC-SYM are most commonly used. The 11-item BF-Diary is highly relevant in opioid-induced constipation and was developed and validated in accordance with US Food and Drug Administration guidelines. However, the panel believes that the complex scoring for this tool and the SSS, PAC-SYM, and 28-item PAC-QOL may be unfeasible for clinical practice. The BFI is psychometrically validated and responsive to changes in symptom severity; scores range from 0 to 100, with higher scores indicating greater severity and scores >28.8 points indicating constipation. CONCLUSIONS: The BFI is a simple assessment tool with a validated threshold of clinically significant constipation. Prescription treatments for opioid-induced constipation should be considered for patients who have a BFI score of ≥30 points and an inadequate response to first-line interventions.

What's new in NSAID pharmacotherapy: oral agents to injectables.

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) represent a critically important class of medications useful in numerous musculoskeletal and inflammatory diseases. The focus of NSAID use has recently centered on gastrointestinal (GI) side effects and potential cardiovascular toxicity. Innovative new oral and intra-articular pharmaceutically engineered dosage forms are examined. We review recently developed intravenous NSAIDs and their potential advantages over oral products in the perioperative setting. DESIGN: Databases searched included PubMed, Google Scholar, Ovid, and Athens. We contacted key U.S. and Japanese manufactures who are developing new and innovative NSAID technologies for inclusion in this overview. Early attempts at mitigating GI toxicity with oral agents combined with gastroprotective additives are outlined. RESULTS: Contemporary technologies coupled with uniquely advanced pharmaceutical manipulations to improve safety and efficacy are discussed including combined vasodilating agent naproxcinod as the prototypical cyclooxygenase-inhibiting nitric oxide (NO) donor; hydrogen sulfide-releasing compounds to protect GI mucosa; glycoscience technologies combining the intra-articular hyaluronic acid SI-613 combined with NSAIDs; and nano-formulated SoluMatrix submicron technologies that include diclofenac, indomethacin, naproxen, and meloxicam. CONCLUSIONS: New NSAIDs under development are intended to address GI and cardiovascular pitfalls inherent to current therapy options across the entire NSAID drug class. NO or hydrogen sulfide donating drugs, new reliable injectables for perioperative and inpatient use, novel intra-articular extended-release NSAIDs combined with IAHA, and nano-formulations of submicron NSAIDs featuring delivery of decreased doses without diminished efficacy promise to afford innovative technologies that likely will be the future of NSAID therapy.

Application Site Reactions from the Buprenorphine Transdermal Patch: A Case Series.

Buprenorphine is a partial mu-opioid agonist available as a transdermal patch for use in patients with chronic pain. Transdermal products can be associated with application site reactions (ASRs). The incidence of ASRs to the buprenorphine transdermal patch (BTP) have been described as low and seldom requiring patch discontinuation. In this case series, we describe four patients who developed an erythematous, rash-like ASR to the BTP leading to treatment discontinuation or rotation to buprenorphine buccal films (BBF). All subjects had demonstrated tolerability to lower patch strengths before developing an ASR with titration to a BTP of a higher strength. The strength at which an ASR emerged varied among subjects; however, all ASRs developed with BTP strengths 10 mcg/hr or higher. The dose-response relationship and prolonged onset to ASR emergence may be suggestive of an allergic delayed hypersensitivity reaction. However, in this case series three subjects demonstrated tolerability to BBF either before or after developing a skin reaction to BTP.

Open-Label Adhesion Performance Study of a Prescription Lidocaine Topical System 1.8% versus Three Lidocaine-Containing Over-the-Counter Patches in Healthy Subjects.

Purpose: This study evaluates and compares the clinical adhesion performance of a prescription lidocaine topical system 1.8% versus two different over-the-counter (OTC) lidocaine patches 4% and an OTC combination menthol and lidocaine patch 1%/4% in human subjects. Patients and Methods: This study was an open-label, randomized, four-treatment, four-sequence, Phase 1 adhesion performance study in healthy adult volunteers (N = 24). Lidocaine topical system 1.8% (R) and the three OTC patch products (T1, T2, and T3) were separately applied for 12 hours. Adhesion of all products was scored at 0, 3, 6, 8, and 12 hours post-application. Results: There were no issues with the conduct of the study. Overall, the majority (≥59.1%) of subjects treated ("patched") with the lidocaine topical system 1.8% (R) demonstrated ≥90% adhesion (FDA adhesion score 0) throughout the 12-hour administration period versus 27.3% of subjects treated with OTC lidocaine patch 4% (T1), 22.7% of subjects treated with OTC lidocaine patch 4% (T2), and 18.2% of subjects treated with OTC menthol/lidocaine patch 1%/4%. Only one subject (4.5%) treated with lidocaine topical system 1.8% was observed with <75% adhesion (FDA adhesion score <2) versus 11 (50.0%) and 10 (45.5%) for the two OTC lidocaine patches 4% (T1 and T2), respectively, and 13 (59.1%) subjects for the OTC menthol/lidocaine patch 1%/4%. There were no complete detachments observed for lidocaine topical system 1.8%, whereas 50.0% and 31.8% complete detachments were observed for the two OTC lidocaine patches 4% (T1 and T2), and 27.3% complete detachments were observed for the OTC menthol/lidocaine patch 1%/4%. No adverse events were observed for any of the treatments. Conclusion: Lidocaine topical system 1.8% demonstrated superior adhesion relative to the three lidocaine-containing OTC products over the 12-hour treatment period.

Evolving Roles of Palliative Care Pharmacists.

In this article, we provide an overview of pharmacists' involvement with palliative care, starting with recent history, up to present day. The aim of this review is to highlight advances in the field of palliative care pharmacy and the integral role pharmacists have on the palliative care team. We conclude that despite participating on multidisciplinary palliative care teams for over 20 years, pharmacy still lacks a board certification in palliative care.

History of Respiratory Stimulants.

The interest in substances that stimulate respiration has waxed and waned throughout the years, intensifying following the introduction of a new class of drugs that causes respiratory depression, and diminishing when antidotes or better drug alternatives are found. Examples include the opioids--deaths increasing during overprescribing, diminishing with wider availability of the opioid receptor antagonist naloxone, increasing again during COVID-19; the barbiturates--until largely supplanted by the benzodiazepines; propofol; and other central nervous system depressants. Unfortunately, two new troubling phenomena force a reconsideration of the status-quo: (1) overdoses due to highly potent opioids such as fentanyl, and even more-potent licit and illicit fentanyl analogs, and (2) overdose due to polysubstance use (the combination of an opioid plus one or more non-opioid drug, such as a benzodiazepine, sedating antidepressant, skeletal muscle relaxant, or various other agents). Since these now represent the majority of cases, new solutions are again needed. An interest in respiratory stimulants has been revived. This interest can be informed by a short review of the history of this interesting class of medications. We present a short history of the trajectory of advances toward more selective and safer respiratory stimulants.

Opioid Taper Practices Among Clinicians.

INTRODUCTION: Opioid dose tapers are used frequently when cross-titrating from one or more opioids to another or when discontinuing therapy. Currently, there is no universally accepted evidence-based standard of care for this procedure which can leave patients at risk for withdrawal symptoms, inadequate pain control, or elevated suicide risk. OBJECTIVE: The objective of this study was to examine practices and rationale among clinicians, to determine if there is a difference among respondents in their comfort level, method and rationale for tapering opioids at various morphine milligram equivalents (MME) and to assess the need for the development of a standard of care. METHODS: Data were derived from an electronic survey developed using SurveyMonkey®. The survey was disseminated via e-mail listservs, social media, and professional organizations. Data were collected regarding profession, confidence tapering opioids at varying total MME, method and rationale for tapering, and pharmacologic management of withdrawal symptoms. Pearson's Chi squared and Fisher's exact tests were used to assess statistical significance of results. RESULTS: A total of 149 clinicians completed the survey, physicians, NPs, pharmacists, and PAs accounted for 51%, 20%, 19%, and 10% of participants, respectively. Overall, 55% of the respondents self-identified as pain specialists. There were no statistically significant differences in reported comfort level among the different types of providers. Nearly 50% of participants indicated their rationale for tapering or discontinuing opioids was the 2016 CDC guidelines. CONCLUSION: Despite that the majority of providers surveyed self-identified as pain specialists, over 50% were not comfortable tapering opioids at doses greater than 120 MME/day. This observation suggests a need for further education and establishment of consensus guidelines on method and rationale for opioid tapering. Provider motivation for tapering was largely influenced by CDC guidelines based on low quality evidence. This strengthens the argument for the creation of guidelines based on high quality evidence.

Nonsteroidal Antiinflammatory Drugs for Acute and Chronic Pain.

Understanding nonsteroidal antiinflammatory drug (NSAID) use and impact on common rheumatic and arthritic conditions is critical to reconciling their appropriate use with their potentially serious adverse effects. NSAIDs have a profound impact on the treatment of connective tissue disorders because of their ability to address the underlying cause with specific benefits of decreasing stiffness and inflammation, and improving mobility. NSAID use is twice as common as opioid use, and inappropriate use of NSAIDs is widespread. NSAID use should be monitored and the impact understood to mitigate the risks. NSAID discontinuation should be evidence based and individualized to specific requirements.

Peripheral Opioid Receptor Antagonists for Opioid-Induced Constipation: A Primer on Pharmacokinetic Variabilities with a Focus on Drug Interactions.

Opioid analgesics remain a treatment option for refractory acute and chronic pain, despite their potential risk for abuse and adverse events (AEs). Opioids are associated with several common AEs, but the most bothersome is opioid-induced constipation (OIC). OIC is often overlooked but has the potential to affect patient quality of life, increase associated symptom burden, and impede long-term opioid compliance. The peripherally acting µ-receptor antagonists (PAMORAs) are a class of drugs that include methylnaltrexone, naloxegol, and naldemedine. Collectively, each is approved for the treatment of OIC. PAMORAs work peripherally in the gastrointestinal tract, without impacting the central analgesic effects of opioids. However, each has unique pharmacokinetic properties that may be impacted by coadministered drugs or food. This review focuses on important metabolic and pharmacokinetic principals that are pertinent to drug interactions involving µ-opioid receptor antagonists prescribed for OIC. It highlights subtle differences among the PAMORAs that may have clinical significance. For example, unlike naloxegol or naldemedine, methylnaltrexone is not a substrate for CYP3A4 or p-glycoprotein; therefore, its plasma concentration is not altered when coadministered with concomitant medications that are CYP3A4 or p-glycoprotein inducers or inhibitors. With a better understanding of pharmacokinetic nuances of each PAMORA, clinicians will be better equipped to identify potential safety and efficacy considerations that may arise when PAMORAs are coadministered with other medications.