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.

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.

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.

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.

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.

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.

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.

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.

A Randomized, Crossover, Pharmacokinetic and Adhesion Performance Study of a Lidocaine Topical System 1.8% During Physical Activity and Heat Treatment in Healthy Subjects.

PURPOSE: This study compares the pharmacokinetic (PK) profile, adhesion, and safety of lidocaine topical system 1.8%, a novel lidocaine topical system approved to treat postherpetic neuralgia, under conditions of heat and exercise vs normal conditions. MATERIALS AND METHODS: This open-label, 3-period, 3-treatment crossover study randomized 12 healthy adults to receive three lidocaine topical systems 1.8% during each of three treatment periods, with 7-day washouts between treatments. The product was applied to the mid-lower back and was removed after 12 hours. During Treatment A, subjects exercised on a bicycle for 30 minutes at 0, 2.5, 5.5, and 8.5 hours. During Treatment B, heat (temperature set at 36.7-40.3°C) was applied at 0 and 8.5 hours. Treatment C was normal conditions. The PK profile of each subject under exercise and heat conditions was compared to normal conditions. Skin irritation, adhesion, and adverse events were assessed. RESULTS: Twelve subjects completed the study. Exposure to external heat resulted in increased peak plasma concentration of lidocaine with a mean Cmax of 160.3±100.1 ng/mL vs 97.6±36.9 ng/mL under normal conditions, with no effect on the extent of exposure (AUC). Concentrations returned to normal within 4 hours after the heat was removed. No clinically relevant differences in absorption were observed under exercise conditions with a mean Cmax of 90.5±25.4 ng/mL and no effect on the extent (AUC) of lidocaine exposure was observed relative to normal conditions. No systems detached during the study. Adverse events were mild, with none leading to discontinuation. CONCLUSION: Transient heat exposure resulted in increased lidocaine plasma concentrations compared to normal conditions, whereas exercise had no effect. The effects of heat appear to be immediate, reversible, and below systemic therapeutic threshold in antiarrhythmic treatment (1000-1500 ng/mL), and well below the safe systemic threshold of 5000 ng/mL. Lidocaine topical system 1.8% remained adhered to the skin and was well tolerated under all conditions. ClinicalTrials.gov: NCT04150536.

A Randomized, Open-Label, Bioequivalence Study of Lidocaine Topical System 1.8% and Lidocaine Patch 5% in Healthy Subjects.

PURPOSE: This study was designed to characterize drug delivery with lidocaine topical system 1.8% vs lidocaine patch 5% through 2 PK studies. PATIENTS AND METHODS: Two Phase 1, single-center, open-label, randomized PK studies were performed in healthy adults. In Study 1, 56 subjects received a single intravenous bolus of 0.7 mg/kg of lidocaine as a lead-in to allow for the accurate determination of apparent dose of both products. After a 7-day washout period, subjects were randomized to receive either lidocaine topical system 1.8% or lidocaine patch 5% for 12 hours followed by another 7-day washout period, after which subjects crossed over to receive the other treatment for 12 hours. In Study 2, 54 subjects were randomized to receive either lidocaine topical system 1.8% or lidocaine patch 5% for 12 hours. After a 7-day washout period, subjects crossed over to receive the other treatment. Adhesion and skin irritation assessments were performed after application of the products in Study 2. In both studies, serial blood samples were collected to measure the plasma concentration of lidocaine after product application. Safety assessments and adverse events were monitored in both studies. RESULTS: The comparative PK analysis demonstrated that the two products, despite their difference in drug load and strength, are bioequivalent. Both products were well tolerated. In Study 2, dermal response scores (skin tolerability after removal) were similar between lidocaine topical system 1.8% and lidocaine patch 5%, with a mean irritation score per patch <1 (barely perceptible erythema), which is not considered to be clinically significant. CONCLUSION: Bioequivalence was demonstrated between lidocaine topical system 1.8% and lidocaine patch 5%. A comparison of the single-time adhesion scores at 12 hours in Study 2 favored lidocaine topical system 1.8% over lidocaine patch 5%. Both products were well tolerated as a single application in healthy adult human subjects. CLINICALTRIALSGOV: NCT04144192, NCT04149938.

Pharmacotherapeutic Management of Neuropathic Pain in End-Stage Renal Disease.

BACKGROUND: Chronic noncancer pain is pervasive throughout the general patient population, transcending all chronic disease states. Patients with end-stage renal disease (ESRD) present a complicated population for which medication management requires careful consideration of the pathogenesis of ESRD and intimate knowledge of pharmacology. The origin of pain must also guide treatment options. As such, the presentation of neuropathic pain in ESRD can present a challenging case. The authors aim to provide a review of available classes of medications and considerations for the treatment of neuropathic pain in ESRD. SUMMARY: In this narrative review, the authors discuss important strategies and considerations for the treatment of neuropathic pain in ESRD, including the pathogenesis of neuropathic pain, physiological changes for consideration in ESRD patients, and disease-specific consideration for medication selection. Pharmacotherapeutic classes discussed include: anticonvulsants, antiarrhythmics, antidepressants, topicals, and opioids. KEY MESSAGE: Pain management in ESRD patients requires careful assessment of drug-specific properties, accumulation, metabolism (presence of active/toxic metabolites), extraction by dialysis, and presence of drug - drug interactions. In the absence of pharmacokinetic data in ESRD patients, therapeutic window and potential risks should be factored in the decision making along with continued monitoring throughout therapy.

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.

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.