Timothy J. Atkinson

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.

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).

Rational dosing of gabapentin and pregabalin in chronic kidney disease

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Opioid Prescribing Levels Off, but Is Less Really More?

A nations opioid consumption was once seen as a sign of civility. The higher the per capita rate of morphine consumption, as calculated by the World Health Organization, the more advanced and caring a nations health care system was seen to be—this suggested better care of the elderly, the sick, the suffering, and the dying [1]. So it is of interest that when numbers from IMS Health were released earlier this year (and reported in a feature article in the Milwaukee Journal Sentinel) showed that opioid prescribing has experienced a slight decrease from 243 million prescriptions in 2011 to 241 million in 2012, this change was hailed as a sign of good things to come for Americans [2]. While a reduction in “pill mill” activity and inappropriate prescribing should be lauded, there is unfortunately much to be concerned about for both the majority of people with pain and the well-intentioned prescribers alike. Moreover, the sensationalization by mainstream media and by politicians has served to fuel a fire that creates negative outcomes for legitimate pain patients [3,4]. There is no question that at one time it was suggested that more opioids were better, while to some extent minimizing the risks to individual patients and to society at large. There is still some debate over the reasons for the rapid growth of opioid use. We argue that this growth was largely due to well-intentioned physicians and thought leaders who had positive experiences treating pain in the advanced cancer patient population. Expanded opioid prescribing in that arena led to dramatic improvements in quality of life, and as a result, many were hopeful that similar improvements would be seen in the much larger and more diverse chronic noncancer pain population [5–7]. When reports of OxyContin abuse first surfaced over a …

Combined fentanyl and methadone induced serotonin syndrome is called into question.

Hillman and colleagues in their recent article titled “Serotonin Syndrome Caused by Fentanyl and Methadone in a Burn Injury” provide an excellent overview of serotonin syndrome. They present an interesting case of a patient that was severely burned from manufacturing methamphetamine, who presumably developed serotonin syndrome during a lengthy hospital stay. The case report and title reflect confidence that fentanyl and methadone combined were indeed the direct cause of serotonin syndrome. This caught our attention and despite limited information available, we have concerns that it is published as evidence. The authors’ reasons for concluding that combined fentanyl and methadone resulted in serotonin syndrome are understandable, but the evidence presented does not definitely support causation. Fentanyl is an opioid in the phenylpiperidine class with l-opioid and 5-HT1A agonist properties. However, the clinical relevance of 5-HT1A agonism and extent to which 5-HT concentrations are affected is unclear in humans with the only available data coming from a few case reports riddled with confounding factors. While the evidence from animal studies doesn’t always translate to humans, receptor studies and neurotransmitter concentrations are routinely studied in animal models where the evidence is much more robust. Receptor studies in rats, for example, show that increases in 5-HT concentrations are dose-dependent and relatively shortlived overall. Concentrations are measured in the dorsal raphe nucleus (DRN) where low doses result in no measurable effect on 5-HT, medium doses (10 lg/kg) increased 5-HT for 1.5 hours, and high doses (100 lg/kg) increased 5-HT for 3 hours. This time-limited increase in 5-HT may partially explain why the incidence of serotonin syndrome is so low despite widespread and routine concomitant use of fentanyl and serotonergic agents. Fentanyl dosing from this case report never approached these levels. To further confound the issue, 5-HT1A auto-receptors inhibit additional efflux of 5-HT at higher doses through a negative feedback mechanism requiring utilization of citalopram, or another selective serotonin reuptake inhibitor (SSRI), to increase extracellular concentrations for accumulation and accurate measurement. 4 The majority of available case reports involved multiple serotonergic medications or medical conditions that increased risk. The ICU is a dynamic environment with numerous perplexing influences that must be considered before anyone can say with confidence that fentanyl and methadone combined precipitated serotonin syndrome. Our examination of these factors is limited by the small This is the sole work of the authors and stated opinions/ assertions do not reflect the opinion of employers, or employee affiliates. It was not prepared as part of Drs. Atkinson, Fudin, or Pham’s official government duties in their various roles as government employees.

Emerging Trends in Pain Medication Management: Back to the Future: A Focus on Ketamine

Providers face many challenges when faced with pain management. Pain is complex, difficult to understand and diagnose, and especially enigmatic to manage. The discovery of nonopioid agents for pain management has become particularly important considering the ongoing opioid epidemic. This review is focused on revisiting ketamine, an agent that has historically been used for anesthesia, in new ways to manage pain. Ketamine has unique pharmacologic properties that may prevent the development of pain as well as reduce chronic pain. This has led to the use of ketamine for perioperative analgesia as well as chronic pain syndromes. In select patients with pain refractory to other treatment modalities, ketamine may provide much needed relief.

Opioids and Related Medications

Specialty physicians and collaborating providers sometimes place themselves in awkward patient situations when prescribing opioids. Rather than performing risk assessments and monitoring individual patients, standardized prescriptions for procedures or symptom flares are thought to be sufficient to mitigate risk. A keen understanding of the issues surrounding opioid therapy will aid the specialty provider to recognize risk in the treatment of severe pain unresponsive to standard protocols yet respond appropriately and compassionately to legitimate pain complaints.

From Rare to Reality: The Challenge of Controlling Pain in Patients onBuprenorphine in the Acute Care Setting

Prescription opioid use has increased dramatically in the past 20 years with prescriptions for opioids and overdoses both increasing by 400% in what is now being called an opioid epidemic. The CDC’s Guidelines for Prescribing Opioids for Chronic Pain were released in March 2016 and the result has been increasing scrutiny of opioid prescriptions. For pain patients, this means minimizing opioid use and decreasing reliance, while others are being tapered off opioids altogether. Opioid tapers are predictably revealing unanticipated levels of opioid use disorder and unsupportable demand for enrollment in opioid assisted treatment (OAT) via buprenorphine/naloxone (Suboxone®) or methadone treatment programs. In July 2016, the Department of Health and Human Services released a final rule increasing prescribing limits of buprenorphine/naloxone (Suboxone®) to allow qualifying providers to treat up to 275 patients rather than capping panel size at 100. In addition to increased use in the treatment of opioid use disorder, there are new formulations of buprenorphine approved for chronic pain management. Therefore, while opioid use overall is decreasing, use of buprenorphine itself is dramatically increasing and introducing new challenges to treatment in trauma and acute pain settings based on its unique pharmacology. In recent years, case reports highlighting the challenge of managing pain when patients are treated with buprenorphine were published but until now were rarely seen in practice. It is, therefore, incumbent on all providers in these settings to become intimately familiar with buprenorphine and prepare to safely and effectively manage pain in these challenging patients.