Quantifying drug overdose deaths: A troubled path from start to finish.

Between 1999 and 2019, according to the Centers for Disease Control and Prevention (CDC), nearly 450,000 people died from overdoses involving prescribed opioids. This review examines how drug overdose deaths are compiled by the CDC using the coding system of the International Classification of Diseases (ICD). When it comes to drug-involved deaths, the ICD may not tell the whole story or even the right story. To learn why, the authors examined the CDC's source data and the standard death certificate. In fatal drug overdose cases, death certificates are issued often before the results of post-mortem toxicology are known by the certifier. The CDC believes that this delay in the death investigation process may account for errors when, for example, certifiers list ambiguous terms such as "suspected acute drug intoxication" or "possible drug overdose" as a cause of death. When incomplete data are coded according to the ICD, the error is passed along while potentially useful information is lost. The result may reflect accurately the annual total of drug-involved overdose deaths while obscuring the lethality of individual substances, consumed alone or in combination, which contributed to, or caused, drug-involved deaths. The true cause of most fatal drug overdoses-polysubstance abuse-often is lost in this process. A key objective of this paper is to describe the process used by the CDC to report drug-involved mortality and how the current iteration of the ICD may be ill-suited for this important task.

Answering Big Questions in Pain Medicine.

The future of pain medicine is marked by many questions. What can other nations around the world learn from the opioid crisis that is still affecting the United States? The American opioid experience was mischaracterized and wrongly described, and its causes were misdiagnosed from the outset, leading to its mismanagement and the abandonment of many chronic pain patients to their suffering. There are a few new drugs in the analgesic armamentarium. What new targets do we have in pain medicine? There are many breakthroughs, discoveries, and potential new targets that could add to our analgesic prescribing choices. These include sigma receptors, d-amino acid oxidase, endoplasmic reticulum stress receptors, histone deacetylase, and others. Neuromodulation had been used with varying degrees of success for years, but with a simplistic approach based on the gate theory of pain. Despite our familiarity with neuromodulation and spinal cord stimulators, neuromodulation research indicates that the activation of glial cells may activate the immune system and enhance analgesia. Neuromodulation studies have concentrated on how electricity affects neuronal activity rather than how electrical activity could reduce pain. There are still more frontiers in our battle against pain and some promising avenues for treatments. This narrative review will try to summarize what can be done from the perspective of recent technological and pharmacological developments.

What Your Death Certificate Says About You May Be Wrong: A Narrative Review on CDC's Efforts to Quantify Prescription Opioid Overdose Deaths.

Mortality data in most countries are reported using the International Classification of Diseases (ICD), managed by the WHO. In this paper, we show how the ICD is ill-suited for classifying drug-involved deaths, many of which involve polysubstance abuse and/or illicitly manufactured fentanyl (IMF). Opioids identified in death certificates are categorized according to six ICD T-codes: opium (T40.0), heroin (T40.1), methadone (T40.3), other synthetic narcotics (T40.4), and other and unspecified narcotics (T40.6). Except for opium, heroin, and methadone, all other opioids except those that are unspecified are aggregated in two T-codes (T40.2 and T40.4), depending upon whether they are natural/semisynthetic or synthetic opioids other than methadone. The result is a system that obscures the actual cause of most drug overdose deaths and, instead, just tallies the number of times each drug is mentioned in an overdose situation. We examined the CDC's methodology for coding other controlled substances according to the ICD and found that, besides fentanyl, the ICD does not distinguish between other licit and illicitly manufactured controlled substances. Moreover, we discovered that the CDC codes all methadone-related deaths as resulting from the prescribed form of the drug. These and other anomalies in the CDC's mortality reporting are discussed in this report. We conclude that the CDC was at fault for failing to correct the miscoding of IMF. Finally, we briefly discuss some of the public policy consequences of this error, the misguided focus by public health and safety officials on pharmaceutical opioids, their prescribers and users, and the pressing necessity for the CDC to reassess how it measures and reports drug-involved mortality.

Influences of Gender on Intravenous Nalbuphine Actions After Major Abdominal Surgery: A Multicenter Study.

INTRODUCTION: Nalbuphine, a synthetic kappa-opioid receptor (KOR) agonist and a partial µ-opioid receptor (MOR) antagonist, has been used for years as an effective analgesic. It has been shown to have a better safety profile than morphine. Considering the long history of use of this drug, it is interesting that only a limited amount of information exists on how gender differences influence nalbuphine responses. In this randomized double-blind comparative trial after major abdominal surgery, the analgesic effects of two doses of continuous intravenous infusion of nalbuphine were evaluated based on gender. METHODS: Enrolled patients were divided into four groups (two females and two males with 32 patients in each group). Two of them (groups A1 and A2), one male and one female, received postoperative continuous intravenous infusions of nalbuphine at 2 mg/h via patient-controlled analgesia (PCA). Each patient had the potential of receiving a rescue bolus of 1 mg of nalbuphine with a lock out time of 15 min. The other two groups (groups B1 and B2) received half the infusion dose, 1 mg/h, and half the nalbuphine rescue dose with the PCA pump, 0.5 mg maximum every 15 min as needed. Patients' vital signs, numerical pain rating scores, rescue nalbuphine, and incidence of side effects were assessed immediately after the operation, and every 3 h during the first 12 h. RESULTS: Nalbuphine 2 mg/h dosing led to significantly lower pain scores amongst females compared to males at 6, 9, and 12 h; while the 1 mg/h infusion pain scores were only lower at the 9-h time period. Females receiving the nalbuphine 2 mg dose at 6 h, and the 1 mg dose at 6, 9, and 12-h measurements needed significantly lower doses of rescue nalbuphine. Females on the 1 mg dose experienced significantly more nausea, vomiting, and sedation at the 6-, 9-, and 12-h measurement times. In the multivariate analysis, female gender was a negative predictor at all measurement times. CONCLUSIONS: The current study supports the hypothesis that although nalbuphine was found to be an effective and well-tolerated analgesic after major abdominal surgery, females were statistically more responsive than males. TRIAL REGISTRATION: The study was registered at the Pan African Clinical trials Registry PACTR201304000486309, and approved for the Ethical aspects.

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.

Are opioid receptor antagonists adequate for "Opioid" overdose in a changing reality?

WHAT IS KNOWN AND OBJECTIVE: Deaths due to opioid-induced respiratory depression (OIRD) continue to rise despite intense regulatory and professional actions. COVID-19 has only worsened this situation.1 An opioid receptor antagonist (ORA) such as naloxone is the most common intervention for OIRD. However, with increasing overdose from highly potent illicit opioids and polysubstance abuse, appraisal of the adequacy of ORA seems warranted and timely. COMMENT: OIRD results from the binding of an excess number of agonist molecules to opioid receptors. Mechanistically, it makes sense to reverse this by displacing agonist molecules by administering an ORA. But realistically, the trend to higher-potency agonists and polysubstance abuse diminishes the effectiveness of this approach. We are left facing a crisis without a solution. WHAT IS NEW AND CONCLUSION: For the increasingly common OIRD from highly potent illicit agonists and polysubstance overdose, ORAs are correspondingly less effective. Alternatives are needed-soon.

CDC's Efforts to Quantify Prescription Opioid Overdose Deaths Fall Short.

In a 2018 report titled, Quantifying the Epidemic of Prescription Opioid Overdose Deaths, four senior analysts of the Centers for Disease Control and Prevention (CDC), including the head of the Epidemiology and Surveillance Branch, acknowledged for the first time that the number of prescription opioid overdose deaths reported by the CDC in 2016 was erroneous. The error, they said, was caused by miscoding deaths involving illicitly manufactured fentanyl (IMF) as deaths involving prescribed fentanyl. To understand what caused this error, the authors examined the CDC's methodology for compiling drug-related mortality data, beginning with the source data obtained from approximately 2.8 million death certificates received each year from state vital statistics registrars. Systemic problems often begin outside the CDC, with a surprisingly high rate of errors and omissions in the source data. Using the CDC's explanation for what caused the error, the authors show why an international program used by the CDC for reporting mortality is ill-suited for compiling and reporting drug overdose deaths. Except for heroin, methadone, and opium, each of which has an individual program code, all other opioids are separated in just two program codes according to whether they are synthetic or semisynthetic/opiates. Methadone-involved deaths pose a special problem for the CDC because methadone has dual indications for treating pain and for treating opioid use disorder (OUD). In 2019, more than seven times more methadone was administered or dispensed for OUD treatment than was prescribed for pain, yet all methadone-involved deaths are coded by the CDC as involving the prescribed form of the drug. The authors conclude that the CDC was at fault for failing to recognize and correct this problem before 2016. Public policy consequences of this failure are briefly mentioned.

The problem of postoperative respiratory depression.

WHAT IS KNOWN AND OBJECTIVE: Postsurgical recovery is influenced by multiple pre-, intra- and perioperative pharmacotherapeutic interventions, including the administration of medications that can induce respiratory depression postoperatively. We present a succinct overview of the topic, including the nature and magnitude of the problem, contributing factors, current limited options, and potential novel therapeutic approach. COMMENT: Pre-, intra- and perioperative medications are commonly administered for anxiety, anaesthesia, muscle relaxation and pain relief among other reasons. Several of the medications alone or in joint-action can be additive or synergistic producing respiratory depression. Given the large number of surgical procedures that are performed each year, even a small percentage of postoperative respiratory complications translates into a large number of affected patients. WHAT IS NEW AND CONCLUSION: Due to the large number of surgeries performed each year, and the variety of medications used before, during, and after surgery, the occurrence of postoperative respiratory depression is surprisingly common. It is a significant medical problem and burden on hospital resources. There is a need for new strategies to prevent and treat the acute and collateral problems associated with postoperative respiratory depression.

The complexity model: a novel approach to improve chronic pain care.

OBJECTIVE: More than 25% of the US population experiences chronic pain; yet few physicians specialize in the field of pain medicine. This article will review a theoretical model of care that stratifies treatment and patients by level and type of complexity and promotes communication between specialist and primary care providers. DISCUSSION: The undertreatment of pain was recently brought to national attention to encourage both clinicians and patients to advocate for improved pain care. The specialty of pain medicine and models of care, challenges of managing pain in a primary care setting, and the reliance on an opioid-focused approach are reviewed. An evolved model of pain care based on the complexity of pain and emphasizing a dynamic collaboration between the primary care provider and the pain specialist is discussed. CONCLUSIONS: From the perspective of the busy clinician, the treatment of chronic pain can be overwhelming. The scarcity of trained pain practitioners and the burgeoning number of patients with chronic pain necessitate a new approach that values the complex nature of chronic pain and offers a practical blueprint to meet these challenges.

Skin Matters: A Review of Topical Treatments for Chronic Pain. Part One: Skin Physiology and Delivery Systems.

Chronic pain is a complex disorder with multiple etiologies for which the pathologic mechanisms are still largely unknown, making effective treatment a difficult clinical task. Achieving pain relief along with improved function and quality of life is the primary goal of pain clinicians; however, most patients and healthcare professionals consider 30% pain improvement to be clinically significant-a success level that would be unacceptable in other areas of medicine. Furthermore, patients with chronic pain frequently have multiple comorbidities, including depression and sleep apnea, and most have seen several physicians prior to being seen by a pain specialist, have more than three specific pain generators, and are taking multiple medications. The addition of further oral medications to control pain increases the risk of drug-drug interactions and side effects. However, topical analgesics have the advantage of local application with limited systemic levels of drug. Topical therapies benefit from reduced side effects, lower risk of drug-drug interactions, better patient acceptability/compliance, and improved tolerability. This two-part paper is a review of topical analgesics and their potential role in the treatment of chronic pain.

Skin Matters: A Review of Topical Treatments for Chronic Pain. Part Two: Treatments and Applications.

In Part One of this two-part series, we discussed skin physiology and anatomy as well as generalities concerning topical analgesics. This modality of therapy has lesser side effects and drug-drug interactions, and patients tolerate this form of therapy better than many oral options. Unfortunately, this modality is not used as often as it could be in chronic pain states, such as that from neuropathic pain. Part Two discusses specific therapies, local anesthetics, and other drugs, as well as how a clinician might use specific aspects of a patient's neuropathic pain presentation to help guide them in the selection of a topical agent.

Toward a systematic approach to opioid rotation.

Patients requiring chronic opioid therapy may not respond to or tolerate the first opioid prescribed to them, necessitating rotation to another opioid. They may also require dose increases for a number of reasons, including worsening disease and increased pain. Dose escalation to restore analgesia using the primary opioid may lead to increased adverse events. In these patients, rotation to a different opioid at a lower-than-equivalent dose may be sufficient to maintain adequate tolerability and analgesia. In published trials and case series, opioid rotation is performed either using a predetermined substitute opioid with fixed conversion methods, or in a manner that appears to be no more systematic than trial and error. In clinical practice, opioid rotation must be performed with consideration of individual patient characteristics, comorbidities (eg, concurrent psychiatric, pulmonary, renal, or hepatic illness), and concurrent medications, using flexible dosing protocols that take into account incomplete opioid cross-tolerance. References cited in this review were identified via a search of PubMed covering all English language publications up to May 21, 2013 pertaining to opioid rotation, excluding narrative reviews, letters, and expert opinion. The search yielded a total of 129 articles, 92 of which were judged to provide relevant information and subsequently included in this review. Through a review of this literature and from the authors' empiric experience, this review provides practical information on performing opioid rotation in clinical practice.

Capsaicinoids in the treatment of neuropathic pain: a review.

The treatment of neuropathic pain is difficult. Oral pharmaceuticals have significant side effects, and treatment efficacy tends to be modest. The use of topical analgesics reduces the potential for systemic side effects and allows direct application of medications to the area of pain. The natural spicy substance, capsaicin, has historically been known for its topical use. Capsaicin, once applied to the skin, causes a brief initial sensitization followed by a prolonged desensitization of the local pain nerves. This occurs through stimulation of the transient receptor potential vanilloid-1 (TRPV1) expressing pain nerve fibers. While low-dose capsaicin has not resulted in good efficacy, the larger dose 8% topical capsaicin has had some of the best data currently available in the treatment of post-herpetic neuralgia (PHN) and other neuropathic conditions. This paper discusses the data currently existing for capsaicin 8% in the treatment of PHN. It further reviews data for the low-dose capsaicin products and the current status in the development of other capsaicinoids, e.g. resiniferotoxin, and high-concentration liquid capsaicin.

The chronic pain patient and functional assessment: use of the 6-Minute Walk Test in a multidisciplinary pain clinic.

OBJECTIVE: For chronic pain treatment, guidelines and regulatory agencies have defined functional improvement as a primary goal, especially when chronic opioid therapy is used. Functional improvement is frequently evaluated by qualitative questioning. This pilot study sought to establish a simple and inexpensive measure of functional change for a chronic pain population. METHODS: Using a multidisciplinary pain clinic standard physical therapy approach for all entering chronic pain patients, multiple functional tests were performed, including the 6-Minute Walk Test. Data was collected by retrospective chart review, at entry to the clinic and 3-6 months later and compared using simple t-test statistics on 45 patients. RESULTS: The average distance walked at center admission was 272.87 yards. At 3-6 month clinical retesting, the distance had improved significantly to 339.04 yards (p<0.0001). NRS scores at 3-6 months were also improved from baseline (p<0.001). CONCLUSIONS: While suggestive, this study has significant limitations. Not all patients entering into the clinic were included in this study, only those who had completed the necessary testing. Further, chart reviews are complicated by the accuracy with which data is recorded. This study is intriguing and presents positive data for a simple, inexpensive and reproducible test for physical functioning in a chronic pain population. Further study is warranted based on these descriptive results.

Recommendations for urine drug monitoring as a component of opioid therapy in the treatment of chronic pain.

OBJECTIVE: Several prominent guidelines recommend that patients on long-term opioid therapy have periodic urine drug monitoring (UDM) for appropriate use; however, none address the specific questions of which patients to test, which substances to test for, how often to test, and how to act on the results. DESIGN: In the absence of adequate scientific evidence in the literature, a panel of experts in the field of pain and addiction medicine was convened to develop consensus UDM recommendations. The panel met three times between March 2010 and April 2011, and reviewed several drafts of the recommendations document between meetings. RESULTS: The group was able to achieve consensus on a set of UDM recommendations addressing test selection, test frequency, interpretation of results, and how to handle discrepancies based on specific results. CONCLUSION: While the participating panel members recognize that there currently is a limited evidence base to support the expert panel's recommendations, primary care providers and pain specialists are largely acting today based on anecdote, intuition, and individual experience. The recommendations are meant to begin to provide a framework for standardizing practices for UDM in the treatment of chronic pain, and to serve as a catalyst to advance research that quantifies the effects of UDM on opioid therapy management and patient outcomes.

Development and implementation of a palliative care consultation tool.

OBJECTIVE: Palliative care services are becoming more commonplace in hospitals and have the potential to reduce hospital costs through length of stay reduction and remediation of symptoms. However, there has been little systematic attempt to identify when a palliative care consultation should be triggered in a hospital, and there is some evidence that these services are under-utilized and not fully understood. METHOD: In an initial attempt to address when a consultation might be appropriate, we attempted to pilot test a novel palliative care screening tool to help guide clinician judgment in this regard. A one-page, face-valid instrument was developed using expert opinion. RESULTS: The sample comprised 33 men (44.6%) and 41 women (55.4%) with an average age of 63.4 years (SD = 13.8) and an average length of stay of 22.7 days (SD = 10.1). The most significant symptom was pain, indicated as moderate-to-severe in 23 patients (31%). This was followed by fatigue (n = 10, 13.5%) and nausea (n = 6, 8.1%). At unit entry, 20 patients (33%) had moderate or severe pain. Upon discharge, this number had been reduced to 12/60 (20%). Chi-Square analysis showed a significant decrease in pain rankings overall (χ2 = 36.3, p < 0.0001). The average total tool score was 7.5 (SD = 3.1). Using an initial threshold of 12 to trigger a palliative care referral, 64 patients (86.5%) would not have received a referral and 10 (13.5%) would have. Of these 10 patients, 2 (20%) did not receive a palliative care consultation while they were hospitalized. SIGNIFICANCE OF RESULTS: The tool we developed increased consultations over the time period in which it was used, compared with the same time period 1 year prior. Although the threshold developed for triggering referrals seemed artificially high, the implementation of the screening tool did increase referrals.

Tolerability of NGX-4010, a capsaicin 8% patch, in conjunction with three topical anesthetic formulations for the treatment of neuropathic pain.

BACKGROUND: The objective of this study was to assess the safety, tolerability, and preliminary efficacy of NGX-4010, a capsaicin 8% patch, following pretreatment with three different topical anesthetics in patients with peripheral neuropathic pain. METHODS: This open-label, multicenter study enrolled 117 patients with post-herpetic neuralgia, HIV-associated distal sensory polyneuropathy, or painful diabetic neuropathy. Patients received pretreatment with one of three lidocaine 4%-based topical anesthetics (L.M.X.4(®) [Ferndale Laboratories Inc, Ferndale, MI], Topicaine(®) Gel [Estela Basso, Jupiter, FL], or Betacaine Enhanced Gel 4 [Tiberius Inc, Tampa, FL]) for 60 minutes followed by a single 60- or 90-minute NGX-4010 application, and were followed for 12 weeks. Tolerability and safety measures included "pain now" Numeric Pain Rating Scale (NPRS) scores, dermal assessments, medication use for treatment-related pain, adverse events (AEs), clinical laboratory parameters, physical examinations, and vital signs. The primary efficacy variable was the percentage change in mean NPRS scores for "average pain for the past 24 hours" from baseline to weeks 2 through 12. RESULTS: Treatment with NGX-4010 following pretreatment with any of the three topical anesthetics was generally safe and well tolerated. Nearly all patients completed ≥90% of the planned NGX-4010 application duration. The most common treatment-related AEs, application-site burning and application-site pain, were transient, mostly mild or moderate, and could be adequately managed by local cooling or short-acting oral opioid analgesics. Although slightly more patients used medication for treatment-related discomfort following pretreatment with Topicaine compared with L.M.X.4 or Betacaine, there were no statistical differences between the topical anesthetics. Neuropathic pain reduction from baseline to weeks 2 through 12 was approximately 30% and was similar among the topical anesthetics; the proportion of responders ranged from 45% to 50%. CONCLUSION: Treatment with NGX-4010 following pretreatment with any of the three topical anesthetics was generally safe and well tolerated; no significant differences in the parameters measured were noted between the pretreatment groups.