Jeffrey Fudin

Consensus Recommendations on Initiating Prescription Therapies for Opioid-Induced Constipation

Abstract 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.

Medication Pain Management in the Elderly: Unique and Underutilized Analgesic Treatment Options

BACKGROUND By 2030, the US population of adults aged ≥65 years will increase by >80%, and these adults will account for nearly 20% of the US population. In this population, the decline of multiple physiologic processes and diseases collectively influence treatment options. Physiologic changes, drug-drug interactions resulting from polypharmacy, and drug-disease interactions combine to make elderly patients more sensitive to the adverse events (AEs) associated with medications, all of which must be considered in drug selection. OBJECTIVE This article focuses on select underutilized medication options for analgesia that may provide significant advantages in the elderly population above and beyond commonly prescribed conventional choices. METHODS We performed a complete review of the literature using the search terms pain management, elderly, opioids, NSAIDs, topical NSAIDs, levorphanol, buprenorphine transdermal, and tapentadol. Databases searched included PubMed, Google Scholar, Ovid, and Athens. Package inserts were utilized for approval dates, indications, and formulations available. We looked at reviews of agents to identify important studies for consideration that searches may have missed. Pharmacology and pharmacokinetic data were taken from randomized trials focusing in this area. Pivotal Phase III trials were utilized for discussion of clinical trial experience and to summarize efficacy and AEs. For purposes of validity, only peer-reviewed literature was included. RESULTS There were limited data that specifically outlined analgesic drug selection and highlighted safer alternatives for the elderly patient based on polypharmacy risks, end-organ deterioration, and/or drug choices that presented less risk. We focused on unique opioid alternatives: levorphanol, which offers several therapeutic advantages similar to methadone but without the pharmacokinetic and drug-interaction pitfalls associated with methadone; tapentadol, associated with significantly less gastrointestinal distress and constipation; and transdermal buprenorphine, an agonist/antagonist with less risk for the toxicities associated with conventional opioids and with compliance benefits. Topical NSAIDs are discussed as a viable therapeutic option. Specific attention to a more desirable tolerability profile, including avoidance of drug interactions, end-organ dysfunction, and gastrointestinal bleed with topical NSAID agents versus their oral counterparts is discussed, including the ability to achieve superior tissue levels for appropriately selected inflammatory conditions. CONCLUSION It is incumbent that providers consider these options as part of an analgesic armamentarium in an effort to maximize therapeutic benefit and minimize risks in the increasing elderly patient population.

The damage done by the war on opioids: the pendulum has swung too far

In the United States, patterns of opioid use for the management of pain have drastically changed over the past 30 years. In the 1980s, the American pain medicine landscape was characterized by opiophobia, the fear to prescribe opioids. Around the turn of the millennium, however, we witnessed a fairly rapid shift to opiophilia, or the “overprescribing” of opioids. The ubiquitous undertreatment of pain was the catalyst for clinicians and pain societies to successfully lobby for increased use of opioids for all pain types, including non-cancer pain. The approval of new standards for pain management incorporating pain as the “fifth vital sign” by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO)1 seemingly fueled this increase in opioid prescription. From 1991–2009, prescriptions for opioid analgesics tripled, with emergency department visits related to non-medical use of prescription opioid overdoses doubling from 2005–2009.2 In 2010, accidental overdose deaths associated with opioids increased for the eleventh consecutive year, highlighting the drastic shift in opioid use.3 The figurative pendulum began to swing toward opiophobia following the publication of data that demonstrated that the risk of addiction associated with chronic opioid use was likely underestimated.4 Guidelines for the use of controlled substances released by the Federation of State Medical Boards of the US in 1998 reflected this change in attitude.5 At present, there is a general consensus that opioids are over-prescribed and education among health care providers is sorely lacking, with considerable debate on how to appropriately address the issue not yet resulting in a balance between treating legitimate pain patients, and mitigating abuse, overdoses, and related deaths. In this environment, physicians and non-physician prescribers, health systems, regulatory agencies, and insurers are seeking tangible targets for intervention.

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.

CYP2D6 Phenotype-Specific Codeine Population Pharmacokinetics

ABSTRACT Codeines metabolic fate in the body is complex, and detailed quantitative knowledge of it, and that of its metabolites is lacking among prescribers. We aimed to develop a codeine pharmacokinetic pathway model for codeine and its metabolites that incorporates the effects of genetic polymorphisms. We studied the phenotype-specific time courses of plasma codeine, codeine-6-glucoronide, morphine, morphine-3-glucoronide, and morphine-6-glucoronide. A codeine pharmacokinetic pathway model accurately fit the time courses of plasma codeine and its metabolites. We used this model to build a population pharmacokinetic codeine pathway model. The population model indicated that about 10% of a codeine dose was converted to morphine in poor-metabolizer phenotype subjects. The model also showed that about 40% of a codeine dose was converted to morphine in EM subjects, and about 51% was converted to morphine in ultrarapid-metabolizers. The population model further indicated that only about 4% of MO formed from codeine was converted to morphine-6-glucoronide in poor-metabolizer phenotype subjects. The model also showed that about 39% of the MO formed from codeine was converted to morphine-6-glucoronide in extensive-metabolizer phenotypes, and about 58% was converted in ultrarapid-metabolizers. We conclude, a population pharmacokinetic codeine pathway model can be useful because beyond helping to achieve a quantitative understanding the codeine and MO pathways, the model can be used for simulation to answer questions about codeines pharmacogenetic-based disposition in the body. Our study suggests that pharmacogenetics for personalized dosing might be most effectively advanced by studying the interplay between pharmacogenetics, population pharmacokinetics, and clinical pharmacokinetics.

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 Pearsons chi-squared and Fishers 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).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 Pearsons chi-squared and Fishers 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).

Potential P-glycoprotein Pharmacokinetic Interaction of Telaprevir With Morphine or Methadone

ABSTRACT Telaprevir (TVR) effects on P-glycloprotein and cytochrome P450 (CYP) may significantly elevate serum levels of morphine and methadone. Recent literature points to major interactions when combining TVR with warfarin or rifampin. Opioid interactions are especially dangerous in hepatitis C patients, as coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) occurs in 50–90% of HIV-infected drug users that are prescribed opioids for chronic pain and/or methadone for maintenance. TVR has been shown to significantly inhibit the active transport enzyme pGP and may therefore increase intestinal morphine absorption. TVR also inhibits hepatic CYP3A4 that are responsible for metabolizing methadone. Patients requiring opioid analgesics must be carefully monitored because of potential for elevated opioid levels and overdose risk. Current recommendations minimize potential drug interactions between telaprevir and opioids, especially methadone, based on a single 7-day trial. We outline the various pharmacokinetic mechanisms involved when combining TVR with methadone or morphine and recommend that current data are not sufficiently robust to minimize the potentially significant interaction with opioids, especially methadone. Clinicians must be mindful of these understated interactions, know that the opioid dose may need to be significantly increased or reduced, and use caution during upward titration of opioids affected by these enzyme systems.

Individualized Hydrocodone Therapy Based on Phenotype, Pharmacogenetics, and Pharmacokinetic Dosing.

Objectives:(1) To quantify hydrocodone (HC) and hydromorphone (HM) metabolite pharmacokinetics with pharmacogenetics in CYP2D6 ultra-rapid metabolizer (UM), extensive metabolizer (EM), and poor metabolizer (PM) metabolizer phenotypes. (2) To develop an HC phenotype-specific dosing strategy for HC that accounts for HM production using clinical pharmacokinetics integrated with pharmacogenetics for patient safety. Setting:In silico clinical trial simulation. Participants:Healthy white men and women without comorbidities or history of opioid, or any other drug or nutraceutical use, age 26.3±5.7 years (mean±SD; range, 19 to 36 y) and weight 71.9±16.8 kg (range, 50 to 108 kg). Main Outcome Measures:CYP2D6 phenotype-specific HC clinical pharmacokinetic parameter estimates and phenotype-specific percentages of HM formed from HC. Results:PMs had lower indices of HC disposition compared with UMs and EMs. Clearance was reduced by nearly 60% and the t1/2 was increased by about 68% compared with EMs. The canonical order for HC clearance was UM>EM>PM. HC elimination mainly by the liver, represented by ke, was reduced about 70% in PM. However, HC’s apparent Vd was not significantly different among UMs, EMs, and PM. The canonical order of predicted plasma HM concentrations was UM>EM>PM. For each of the CYP2D6 phenotypes, the mean predicted HM levels were within HM’s therapeutic range, which indicates HC has significant phenotype-dependent pro-drug effects. Conclusions:Our results demonstrate that pharmacogenetics afford clinicians an opportunity to individualize HC dosing, while adding enhanced opportunity to account for its conversion to HM in the body.

Rational dosing of gabapentin and pregabalin in chronic kidney disease

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Levorphanol use: past, present and future

Abstract Levorphanol is a potent opioid analgesic that was first approved for use in the United States in 1953. Levorphanol is approved for use in moderate to severe pain where an opioid analgesic is appropriate. Levorphanol has a wide range of activities including mu opioid agonism, delta agonism, kappa1 and kappa3 receptor agonism, N-methyl-d-aspartate receptor antagonism and reuptake inhibition of both norepinephrine and serotonin. This multimodal profile might prove effective for pain syndromes that are refractory to other opioid analgesics, such as central and neuropathic pain and opioid-induced hyperalgesia. Levorphanol is well suited as a first-line opioid and can also be used during opioid rotation. It has no known effect on the cardiac QT interval or drug–drug interactions involving hepatic cytochrome P450s enzymes. In these regards, levorphanol may offer a superior safety profile over methadone and other long-acting opioids. Despite its prospective value of multiple mechanisms of action and the potential for treating various types of pain, levorphanol use has been largely supplanted by other recently approved opioids. Its waning use over the years has caused it to be referred to as the “Forgotten Opioid” and resulted in what some consider its underutilization. In fact, levorphanol is relatively unfamiliar to most prescribers. The purpose of this review is to inform practitioners about the attributes of this opioid and reintroduce it to clinicians as an option for treating moderate to severe pain when alternative treatment options are inadequate, not indicated or contraindicated.