Pain medicine training resources: Module 4

Download fact sheets that cover changes in the new edition, updated disorders, and general information about the DSM–5.

Abstract
An overreliance on opioids has impacted all types of pain management, making it undoubtedly a root cause of the "epidemic" of prescription opioid abuse in the United States. Yet, an examination of the statistics that led the US Centers for Disease Control and Prevention to declare that prescription opioid abuse had reached epidemic levels shows that the abuse occurrences and deaths are arising outside the hospital or hospice setting, which strongly implicates the outpatient use of opioids to treat chronic pain. Such abuse and related deaths are occurring in chronic pain patients themselves and also through diversion. Overprescribing to outpatients has afforded distressed and vulnerable individuals access to these highly addictive drugs. The focus of this article is on what we have learned since opioid treatment of chronic pain was first popularized at the end of the 20th century and how this new information can guide chronic pain management in the future.

In the last ten years, gabapentin and pregabalin have been becoming dispensed broadly and sold on black markets, thereby, exposing millions to potential side-effects. Meanwhile, several pharmacovigilance-databases have warned for potential abuse liabilities and overdose fatalities in association with both gabapentinoids. To evaluate their addiction risk in more detail, we conducted a systematic review on PubMed/Scopus and included 106 studies. We did not find convincing evidence of a vigorous addictive power of gabapentinoids which is primarily suggested from their limited rewarding properties, marginal notes on relapses, and the very few cases with gabapentinoid-related behavioral dependence symptoms (ICD-10) in patients without a prior abuse history (N=4). In support, there was no publication about people who sought treatment for the use of gabapentinoids. Pregabalin appeared to be somewhat more addictive than gabapentin regarding the magnitude of behavioral dependence symptoms, transitions from prescription to self-administration, and the durability of the self-administrations. The principal population at risk for addiction of gabapentinoids consists of patients with other current or past substance use disorders (SUD), mostly opioid and multi-drug users, who preferred pregabalin. Pure overdoses of gabapentinoids appeared to be relative safe but can become lethal (pregabalin > gabapentin) in mixture with other psychoactive drugs, especially opioids again and sedatives. Based upon these results, we compared the addiction risks of gabapentin and pregabalin with those of traditional psychoactive substances and recommend that in patients with a history of SUD, gabapentinoids should be avoided or if indispensable, administered with caution by using a strict therapeutic and prescription monitoring.

Abstract
Patients with acute lumbar disc prolapse with sciatica who are not considered candidates for surgery are usually treated with physiotherapy and non-steroidal anti-inflammatory agents. Moreover, the treatment with benzodiazepines is common practice in the absence of class I or II level of evidence. Here we assessed the role of benzodiazepines in the conservative management of acute lumbar disc prolapse. Using a placebo-controlled, double-blinded design, 60 patients were randomized to receive placebo or diazepam in addition to mechanical physiotherapy and analgesics for the first 7 days of conservative treatment of clinically and radiologically confirmed lumbar disc prolapse. The primary objective was to evaluate if physiotherapy plus analgesics, but without benzodiazepines, is equivalent to the same therapy plus benzodiazepines. The primary endpoint was centralization of referred pain at day 7. Twenty-six female and 34 male patients were enrolled. The median age was 42 years (range 22-68 years). Analysis of the primary endpoint demonstrated equivalence between placebo and diazepam (median 60% vs. 50% reduction of distance of referred pain at day 7) within the predefined equivalence tolerance of 20% at a significance level of p<0.05. Regarding the secondary endpoints, the median duration of the stay in hospital was shorter in the placebo arm (8 vs. 10 days, p=0.008), and the probability of pain reduction on a visual analog scale by more than 50% was twice as high in placebo patients (p<0.0015). Benzodiazepines should not be used routinely in patients treated with mechanical physiotherapy for lumbar disc prolapse.

Abstract
The International Classification of Diseases (ICD) and the Diagnostic and Statistical Manual (DSM) are routinely used in diagnosing illicit substance use disorders, but for people taking prescribed opioids they remain controversial. In pain medicine, the concept of "Addiction" is preferred with reduced emphasis on tolerance and withdrawal. This article examines the prevalence and characteristics of pharmaceutical opioid dependence/disorder according to ICD, DSM, and the pain medicine concept of "Addiction," among chronic noncancer pain (CNCP) patients prescribed opioids. In the current study, we used data from a national sample of 1134 people prescribed opioids for CNCP. Past 12-month "Addiction" (based on Pain Medicine definition), DSM, and ICD dependence definitions were assessed using the Composite International Diagnostic Interview. Twenty-four percent of the cohort met the criteria for "Addiction," 18% for DSM-5 use disorder and 19% for ICD-11 dependence. There was "substantial" concordance between "Addiction" and both DSM-5 use disorder and ICD-11 dependence, although concordance was much greater with ICD-11 dependence (kappa = 0.63 and 0.79, respectively). Participants meeting the criteria for "Addiction" only were older, less likely to engage in nonadherent behaviours, self-reported fewer problems or concerns with their medication, and had lower rates of psychological distress than those who also met the DSM-5 and ICD-11 criteria. The definition of "Addiction" captures a larger group of patients than other classification systems and includes people with fewer "risk" behaviours. Despite removal of tolerance and withdrawal for prescribed opioid use for DSM-5, we found that "Addiction" was more closely related to an ICD-11 diagnosis of pharmaceutical opioid dependence.

Optimal methods to predict risk of aberrant drug-related behaviors before initiation of opioids for chronic noncancer pain and to identify aberrant behaviors after therapy is initiated are uncertain. We systematically reviewed published literature identified through searches of Ovid MEDLINE and the Cochrane databases through July 2008. Diagnostic test characteristics and accompanying confidence intervals were calculated with data extracted from the studies. Four prospective studies evaluated diagnostic accuracy of risk prediction instruments. Two higher-quality derivation studies found that high scores on the Screener and Opioid Assessment for Patients with Pain (SOAPP) Version 1 and the Revised SOAPP (SOAPP-R) instruments weakly increased the likelihood for future aberrant drug-related behaviors (positive likelihood ratios [PLR], 2.90 [95% CI, 1.91 to 4.39] and 2.50 [95% CI, 1.93 to 3.24], respectively). Low scores on the SOAPP Version 1 moderately decreased the likelihood for aberrant drug-related behaviors (negative likelihood ratio [NLR], 0.13 [95% CI, 0.05 to 0.34]) and low scores on the SOAPP-R weakly decreased the likelihood (NLR, 0.29 [95% CI, 0.18 to 0.46]), but estimates are too imprecise to determine if there is a difference between these instruments. One lower-quality study found that categorization as high risk using the Opioid Risk Tool strongly increased the likelihood for future aberrant drug-related behaviors (PLR, 14.3 [95% CI, 5.35 to 38.4]) and classification as low risk strongly decreased the likelihood (PLR, 0.08 [95% CI, 0.01 to 0.62]). Nine studies evaluated monitoring instruments for identification of aberrant drug-related behaviors in patients on opioid therapy. One higher-quality derivation study found higher scores on the Current Opioid Misuse Measure (COMM) weakly increased the likelihood of current aberrant drug-related behaviors (PLR, 2.77 [95% CI, 2.06 to 3.72]) and lower scores weakly decreased the likelihood (NLR, 0.35 [95% CI, 0.24 to 0.52]). In 8 studies of other monitoring instruments, diagnostic accuracy was poor, results were difficult to interpret due to methodological shortcomings, or standard diagnostic test characteristics were not reported. Definitions for aberrant drug-related behaviors were not standardized across studies and did not account for seriousness of identified behaviors. No reliable evidence exists on accuracy of urine drug screening, pill counts, or prescription drug monitoring programs; or clinical outcomes associated with different assessment or monitoring strategies.

Perspective: Evidence on prediction and identification of aberrant drug-related behaviors is limited. Although several screening instruments may be useful, evidence is sparse and primarily based on derivation studies, and methodological shortcomings exist in all studies. Research that performs external validation, uses standardized definitions for clinically relevant aberrant drug-related behaviors, and evaluates clinical outcomes associated with different assessment and monitoring strategies is needed.

Abstract
We summarise the evidence for medicinal uses of opioids, harms related to the extramedical use of, and dependence on, these drugs, and a wide range of interventions used to address these harms. The Global Burden of Diseases, Injuries, and Risk Factors Study estimated that in 2017, 40·5 million people were dependent on opioids (95% uncertainty interval 34·3-47·9 million) and 109 500 people (105 800-113 600) died from opioid overdose. Opioid agonist treatment (OAT) can be highly effective in reducing illicit opioid use and improving multiple health and social outcomes-eg, by reducing overall mortality and key causes of death, including overdose, suicide, HIV, hepatitis C virus, and other injuries. Mathematical modelling suggests that scaling up the use of OAT and retaining people in treatment, including in prison, could avert a median of 7·7% of deaths in Kentucky, 10·7% in Kiev, and 25·9% in Tehran over 20 years (compared with no OAT), with the greater effects in Tehran and Kiev being due to reductions in HIV mortality, given the higher prevalence of HIV among people who inject drugs in those settings. Other interventions have varied evidence for effectiveness and patient acceptability, and typically affect a narrower set of outcomes than OAT does. Other effective interventions focus on preventing harm related to opioids. Despite strong evidence for the effectiveness of a range of interventions to improve the health and wellbeing of people who are dependent on opioids, coverage is low, even in high-income countries. Treatment quality might be less than desirable, and considerable harm might be caused to individuals, society, and the economy by the criminalisation of extramedical opioid use and dependence. Alternative policy frameworks are recommended that adopt an approach based on human rights and public health, do not make drug use a criminal behaviour, and seek to reduce drug-related harm at the population level.

Abstract
Background: Gabapentinoid (pregabalin and gabapentin) abuse is increasingly being reported.

Objective: To assess the extent of gabapentinoid abuse, characteristics of typical abusers, patterns of abuse, and potential harms in order to bring this trend to providers' attention.

Methods: A systematic review of MEDLINE, Cochrane Library, ClinicalTrials.gov, and US FDA data, indexed through 28 July 2016, utilizing the following searches: pregabalin OR gabapentin OR gabapentinoid AND one of the following: abuse, misuse, overdose, or substance-related disorders[MESH], was conducted. Additional studies were identified through review of references. English-language epidemiological studies, clinical studies, and case reports/series of gabapentinoid abuse/misuse/overdose were included. The authors reached consensus regarding study inclusion after full-text review. The body of literature was assessed for bias qualitatively.

Results: Fifty-nine studies were included in this systematic review (24 epidemiological, three clinical abuse liability, 16 abuse/misuse/dependence case reports/series, 17 acute overdose case reports/series-one included both an epidemiological study and case series and was included in both counts). Analysis of these studies indicates increasing numbers of patients are self-administering higher than recommended doses to achieve euphoric highs. In the general population, a 1.6% prevalence of gabapentinoid abuse was observed, whereas prevalence ranged from 3% to 68% among opioid abusers. An international adverse event database identified 11,940 reports of gabapentinoid abuse from 2004-2015, with >75% reported since 2012. Risk factors include a history of substance abuse, particularly opioids, and psychiatric co-morbidities. While effects of excessively high doses are generally non-lethal, gabapentinoids are increasingly being identified in post-mortem toxicology analyses.

Conclusion: Evidence suggests gabapentinoids possess potential for abuse, particularly in individuals with a history of opioid abuse, and reports of such abuse are increasingly being documented. Prescribers should be aware of high-risk populations and monitor for signs of abuse.

Moderate-to-severe pain represents a heavy burden in patients' quality of life, and ultimately in the society and in healthcare costs. The aim of this review was to summarize data on tramadol and tapentadol adverse effects, toxicity, potential advantages and limitations according to the context of clinical use. We compared data on the pharmacological and toxicological profiles of tramadol and tapentadol, after an extensive literature search in the US National Library of Medicine (PubMed). Tramadol is a prodrug that acts through noradrenaline and serotonin reuptake inhibition, with a weak opioid component added by its metabolite O-desmethyltramadol. Tapentadol does not require metabolic activation and acts mainly through noradrenaline reuptake inhibition and has a strong opioid activity. Such features confer tapentadol potential advantages, namely lower serotonergic, dependence and abuse potential, more linear pharmacokinetics, greater gastrointestinal tolerability and applicability in the treatment of chronic and neuropathic pain. Although more studies are needed to provide clear guidance on the opioid of choice, tapentadol shows some advantages, as it does not require CYP450 system activation and has minimal serotonergic effects. In addition, it leads to less side effects and lower abuse liability. However, in vivo and in vitro studies have shown that tramadol and tapentadol cause similar toxicological damage. In this context, it is important to underline that the choice of opioid should be individually balanced and a tailored decision, based on previous experience and on the patient's profile, type of pain and context of treatment.

Significance: This review underlines the need for a careful prescription of tramadol and tapentadol. Although both are widely prescribed synthetic opioid analgesics, their toxic effects and potential dependence are not completely understood yet. In particular, concerning tapentadol, further research is needed to better assess its toxic effects.

Aims: A number of screening instruments are routinely used in Emergency Department (ED) situations to identify alcohol-use disorders (AUD). We wished to study the psychometric features, particularly concerning optimal thresholds scores (TSs), of four assessment scales frequently used to screen for abuse and/or dependence, the cut-down annoyed guilty eye-opener (CAGE), Rapid Alcohol Problem Screen 4 (RAPS4), RAPS4-quantity-frequency and AUD Identification Test (AUDIT) questionnaires, particularly in the sub-group of people admitted for acute alcohol intoxication (AAI).

Methods: All included patients [AAI admitted to ED (blood alcohol level ≥0.8 g/l)] were assessed by the four scales, and with a gold standard (alcohol dependence/abuse section of the Mini International Neuropsychiatric Interview), to determine AUD status. To investigate the TSs of the scales, we used Youden's index, efficiency, receiver operating characteristic (ROC) curve techniques and quality ROC curve technique for optimized TS (indices of quality).

Results: A total of 164 persons (122 males, 42 females) were included in the study. Nineteen (11.60%) were identified as alcohol abusers alone and 128 (78.1%) as alcohol dependents (DSM-IV). Results suggest a statistically significant difference between men and women (P < 0.05) in performance of the screening tests RAPS4 (≥1) and CAGE (≥2) for detecting abuse. Also, in this population, we show an increase in TSs of RAPS4 (≥2) and CAGE (≥3) for detecting dependence compared with those typically accepted in non-intoxicated individuals. The AUDIT test demonstrates good performance for detecting alcohol abuse and/or alcohol-dependent patients (≥7 for women and ≥12 for men) and for distinguishing alcohol dependence (≥11 for women and ≥14 for men) from other conditions.

Conclusion: Our study underscores for the first time the need to adapt, taking into account gender, the thresholds of tests typically used for detection of abuse and dependence in this population.

Abstract
Misuse of prescription opioids is a leading cause of premature death in the United States. We use state government administrative data and machine learning methods to examine whether the risk of future opioid dependence, abuse, or poisoning can be predicted in advance of an initial opioid prescription. Our models accurately predict these outcomes and identify particular prior nonopioid prescriptions, medical history, incarceration, and demographics as strong predictors. Using our estimates, we simulate a hypothetical policy which restricts new opioid prescriptions to only those with low predicted risk. The policy's potential benefits likely outweigh costs across demographic subgroups, even for lenient definitions of "high risk." Our findings suggest new avenues for prevention using state administrative data, which could aid providers in making better, data-informed decisions when weighing the medical benefits of opioid therapy against the risks.

Abstract
Introduction: Many psychopharmacologic agents are used as primary or adjuncts in pain management. Atypical antipsychotics (AAs) have also been used as adjuncts in pain management regimens in a variety of manners; however, their efficacy in this capacity is unclear.

Methods: A systematic review of all studies examining AA use for pain was conducted. Three literature databases were utilized to search for word combinations of "pain" and a variety of commonly prescribed AAs ie, (olanzapine, quetiapine, risperidone, aripiprazole, ziprasidone, clozapine, paliperidone, iloperidone, lurasidone). Articles chosen for review included retrospective analyses, randomized control trials, and case series/reports. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram illustrates the study selection process.

Results: Olanzapine, quetiapine, risperidone, aripiprazole, and ziprasidone are the only AAs with published studies in pain management. Among these, olanzapine and quetiapine have the most studies (11 and 6, respectively). Olanzapine shows preliminary and consistent efficacy in fibromyalgia and headache/migraine, although only 1 study was a randomized controlled trial with level I evidence of efficacy. Other AAs eg, (quetiapine) fail to demonstrate efficacy in pain syndromes and/or lack robust study designs.

Conclusions: Few studies have been conducted to evaluate the analgesic effects of AAs. The collective findings of multiple studies evaluating olanzapine in pain syndromes suggest a high, yet preliminary level of evidence of efficacy, warranting prospective studies in various pain syndrome contexts. Pharmacological mechanisms of AA action are elaborated, and the findings of this review are discussed. Risk and benefits of using AAs in chronic pain are described, and investigational implications and future directions are explored.

Abstract
Chronic pain and prescription opioid abuse are extremely prevalent both in this country and worldwide. Consequences of opioid misuse can be life-threatening with significant morbidity and mortality, exacting a heavy toll on patients, physicians, and society. Individuals with chronic pain and co-occurring substance use disorders and/or mental health disorders, are at a higher risk for misuse of prescribed opioids. Opioid abuse and misuse occurs for a variety of reasons, including self-medication, use for reward, compulsive use because of addiction, and diversion for profit. There is a significant need for treatment approaches that balance treating chronic pain; while minimizing risks for opioid abuse, misuse, and diversion. The use of chronic opioid therapy for chronic non-cancer pain has increased dramatically in the past 2 decades in conjunction with associated increases in the abuse of prescribed opioids and accidental opioid overdoses. Consequently, a validated screening instrument which provides an effective and rational method of selecting patients for opioid therapy, predicting risk, and identifying problems once they arise could be of enormous benefit in clinical practice. Such an instrument could potentially curb the risk of iatrogenic addiction. Although several screening instruments and strategies have been introduced in recent years, there is no single test or instrument which can reliably and accurately predict those patients not suitable for opioid therapy or identify those who need increased vigilance or monitoring during therapy. At present, screening for opioid abuse includes assessment of premorbid and comorbid substance abuse; assessment of aberrant drug-related behaviors; risk factor stratification; and utilization of opioid assessment screening tools. Multiple opioid assessment screening tools and instruments have been developed by various authors. In addition, urine drug testing, monitoring of prescribing practices, prescription monitoring programs, opioid treatment agreements, and utilization of universal precautions are essential. Presently, a combination of strategies is recommended to stratify risk, to identify and understand aberrant drug related behaviors, and to tailor treatments accordingly. This manuscript builds on the 2012 opioid guidelines published in Pain Physician and the 2016 guidelines released by the Centers for Disease Control and Prevention. It reviews the current state of knowledge regarding the growing problem of opioid abuse and misuse; known risk factors; and methods of predicting, assessing, monitoring, and addressing opioid abuse and misuse in patients with chronic non-cancer pain.

Abstract
Background: Early identification of problems is essential in minimising the unintended consequences of opioid therapy. This study aimed to develop a brief scale that identifies and quantifies recent aberrant behaviour among diverse patient populations receiving long-term opioid treatment.

Method: 40 scale items were generated via literature review and expert panel (N=19) and tested in surveys of: (i) N=41 key experts, and (ii) N=426 patients prescribed opioids >3 months (222 pain patients and 204 opioid substitution therapy (OST) patients). We employed item and scale psychometrics (exploratory factor analyses, confirmatory factor analyses and item-response theory statistics) to refine items to a brief scale.

Results: Following removal of problematic items (poor retest-reliability or wording, semantic redundancy, differential item functioning, collinearity or rarity) iterative factor analytic procedures identified a 10-item unifactorial scale with good model fit in the total sample (N=426; CFI=0.981, TLI=0.975, RMSEA=0.057), and among pain (CFI=0.969, TLI=0.960, RMSEA=0.062) and OST subgroups (CFI=0.989, TFI=0.986, RMSEA=0.051). The 10 items provided good discrimination between groups, demonstrated acceptable test-retest reliability (ICC 0.80, 95% CI 0.60-0.89; Cronbach's alpha=0.89), were moderately correlated with related constructs, including opioid dependence (SDS), depression and stress (DASS subscales) and Social Relationships and Environment domains of the WHO-QoL, and had strong face validity among advising clinicians.

Conclusions: The Opioid-Related Behaviours In Treatment (ORBIT) scale is brief, reliable and validated for use in diverse patient groups receiving opioids. The ORBIT has potential applications as a checklist to prompt clinical discussions and as a tool to quantify aberrant behaviour and assess change over time.

Abstract
Aims: This paper (i) reviews the language used to describe and manage those patient practices that fall outside standard medical models of opioid treatment (for pain and opioid dependence), and (ii) proposes a consistent terminology that can be applied across multiple healthcare settings.

Method: Peer-reviewed and grey literature documenting empirical studies of (non-)adherence with opioid treatment, proposed definitions or other potentially important aspects of terminology were included in this review.

Results: There are international inconsistencies in the terminology used to describe the unintended consequences of opioid treatment, and the terms used often lack specificity. The terms 'hazardous use', 'extramedical use', 'opioid dependence', 'diversion', 'non-adherence' and 'aberrant behaviours' are defined. We advocate for consistent application of these terms in the context of opioid treatment, and propose that care is taken to describe individual practices and intentions.

Conclusions: The increasing global attention on the use and diversion of pharmaceutical opioids warrants a discussion of current terms and definitions. Exaggerated concerns regarding 'addiction potential' may result in restrictions in the supply of opioids and the under-treatment of legitimate medical conditions. Researchers, clinicians, policy-makers and patients need to ensure greater care is given to terminology, including detailed descriptions of patient practices, the context in which they occur and severity of associated harm.

Abstract
Background: Misuse of prescription opioids, and other drugs prescribed for chronic pain, has increased, with major concerns about harm. This review was undertaken to identify validated measurement tools for risk assessment and monitoring of chronic non-cancer pain patients being considered for, or currently prescribed, analgesic drugs with abuse potential.

Methods: Selected databases (Embase, Medline, Cochrane library/CENTRAL, PsycINFO, PubMed, CINAHL) were systematically searched for studies evaluating tools for risk of analgesic misuse, either before, or during, analgesic therapy for chronic pain, using predetermined inclusion/exclusion criteria. Two independent reviewers assessed abstracts, selected full texts, extracted data and assessed quality.

Results: 30 studies from 1844 met inclusion criteria, including three systematic reviews, with an additional four studies from bibliography review. The studies covered 14 tools pertaining to opioid use, with none for non-opioid analgesics.

Conclusions: For predicting prescription opioid misuse, the pain medication questionnaire (PMQ) and the screener and opioid assessment for patients with pain (SOAPP) had the best evidence; both developed and validated in five separate studies (four each of acceptable quality). The current opioid misuse measure (COMM) performed best screening for current misuse, developed and validated in three studies of acceptable quality. A small number of tools may accurately predict, or identify, opioid misuse. There are none for non-opioid analgesics, where there is a potential need.

Abstract
We have previously observed that the non-opioid morphine metabolite, morphine-3-glucuronide, enhances pain via a toll-like receptor 4 (TLR4) dependent mechanism. The present studies were undertaken to determine whether TLR4-dependent pain enhancement generalizes to other classes of glucuronide metabolites. In silico modeling predicted that glucuronic acid alone and ethyl glucuronide, a minor but long-lasting ethanol metabolite, would dock to the same MD-2 portion of the TLR4 receptor complex previously characterized as the docking site for morphine-3-glucuronide. Glucuronic acid, ethyl glucuronide and ethanol all caused an increase in TLR4-dependent reporter protein expression in a cell line transfected with TLR4 and associated co-signaling molecules. Glucuronic acid-, ethyl glucuronide-, and ethanol-induced increases in TLR4 signaling were blocked by the TLR4 antagonists LPS-RS and (+)-naloxone. Glucuronic acid and ethyl glucuronide both caused allodynia following intrathecal injection in rats, which was blocked by intrathecal co-administration of the TLR4 antagonist LPS-RS. The finding that ethyl glucuronide can cause TLR4-dependent pain could have implications for human conditions such as hangover headache and alcohol withdrawal hyperalgesia, as well as suggesting that other classes of glucuronide metabolites could have similar effects.

Abstract
Objectives: This study evaluated the prevalence and correlates of aberrant drug-taking behaviours in two populations: patients with HIV-related pain and a history of substance abuse (n = 73) and patients with cancer pain and no history of substance abuse (n = 100).

Methods: All patients completed a Drug-Taking Behaviors Interview, the Brief Symptom Inventory (BSI), Brief Pain Inventory (BPI), Memorial Symptom Assessment Scale (MSAS), and the Marlowe Crowne Social Desirability Scale (MCSDS). The Pain Management Index was calculated to assess the adequacy of opioid prescribing.

Results: The cancer sample comprised 38 men and 62 women, and the AIDS sample comprised 63 men and 10 women. Patients with AIDS-related pain had higher global distress on the MSAS (F1, 170 = 20.05, P < 0.001), greater pain-related interference in their daily functioning on the BPI (F1, 161 = 22.87, P < 0.001), and a lower percentage of relief from their current medications (F1, 156 = 76.14, P < 0.001). AIDS patients also reported more than twice as many examples of aberrant drug-related behaviors per patient (mean = 6.14, SD = 4.60) as the cancer patients (mean = 1.42, SD = 1.91).

Conclusion: These data suggest that AIDS patients with histories of substance abuse receiving opioid therapy are more symptomatic, have more distress, experience more interference from residual pain, and engage in more problematic drug-related behaviors than patients with no history of drug abuse receiving opioids for cancer pain. Treatment of substance abusers with pain requires skills that complement best practices in opioid prescribing. Better approaches to the long-term treatment of these populations are needed.

Physician burnout is a universal dilemma that is seen in healthcare professionals, particularly physicians, and is characterized by emotional exhaustion, depersonalization, and a feeling of low personal accomplishment. In this review, we discuss the contributing factors leading to physician burnout and its consequences for the physician's health, patient outcomes, and the healthcare system. Physicians face daily challenges in providing care to their patients, and burnout may be from increased stress levels in overworked physicians. Additionally, the healthcare system mandates physicians to keep a meticulous record of their physician-patient encounters along with clerical responsibilities. Physicians are not well-trained in managing clerical duties, and this might shift their focus from solely caring for their patients. This can be addressed by the systematic application of evidence-based interventions, including but not limited to group interventions, mindfulness training, assertiveness training, facilitated discussion groups, and promoting a healthy work environment.

Abstract
Objectives: Driving under the influence of prescription and over-the-counter medication is a growing public health concern. A systematic review of the literature was performed to investigate which specific medications were associated with increased risk of motor vehicle collision (MVC).

Methods: The a priori inclusion criteria were: (1) studies published from English-language sources on or after January 1, 1960, (2) licensed drivers 15 years of age and older, (3) peer-reviewed publications, master's theses, doctoral dissertations, and conference papers, (4) studies limited to randomized control trials, cohort studies, case-control studies, or case-control type studies (5) outcome measure reported for at least one specific medication, (6) outcome measure reported as the odds or risk of a motor vehicle collision. Fourteen databases were examined along with hand-searching. Independent, dual selection of studies and data abstraction was performed.

Results: Fifty-three medications were investigated by 27 studies included in the review. Fifteen (28.3%) were associated with an increased risk of MVC. These included Buprenorphine, Codeine, Dihydrocodeine, Methadone, Tramadol, Levocitirizine, Diazepam, Flunitrazepam, Flurazepam, Lorazepam, Temazepam, Triazolam, Carisoprodol, Zolpidem, and Zopiclone.

Conclusions: Several medications were associated with an increased risk of MVC and decreased driving ability. The associations between specific medication use and the increased risk of MVC and/or affected driving ability are complex. Future research opportunities are plentiful and worthy of such investigation.

Abstract
Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their pharmacology, interactions, safety profiles, and how pharmacology is being manipulated to misuse these common medications, with the aim to expand on the subject outlined by the authors focusing on abuse prevention and prevalence rates. The reviewed literature was identified in several online databases through searches conducted with phrases created by combining the international non-proprietary names of the drugs with terms related to drug misuse. The results show that OTC opioids are misused as an alternative for illicit narcotics, or prescription-only opioids. The potency of codeine and loperamide is strongly dependent on the individual enzymatic activity of CYP2D6 and CYP3A4, as well as P-glycoprotein function. Codeine can also be utilized as a substrate for clandestine syntheses of more potent drugs of abuse, namely desomorphine ("Krokodil"), and morphine. The dangerous methods used to prepare these substances can result in poisoning from toxic chemicals and impurities originating from the synthesis procedure. OTC opioids are generally safe when consumed in accordance with medical guidelines. However, the intake of supratherapeutic amounts of these substances may reveal surprising traits of common medications.

Abstract
Objective: The crisis of prescription opioid (PO) related harms has focused attention toward identifying and treating high-risk populations. This review aims to synthesize systematic reviews on the epidemiology and clinical management of comorbid chronic pain and PO or other substance misuse.

Methods: A systematic database search was conducted to identify systematic reviews published between 2000 and 2016. Eligible studies were systematic reviews related to chronic non-cancer pain and PO or other substance misuse. Evidence from the included reviews was synthesized according to epidemiology and clinical management themes.

Results: Of 1908 identified articles, 18 systematic reviews were eligible for final inclusion. Two meta-analyses estimated the prevalence of chronic non-cancer pain in individuals using POs non-medically to be approximately 48% to 60%, which is substantially higher than the prevalence of chronic non-cancer pain in general population samples (11% to 19%). Five systematic reviews estimated the rates of PO or other opioid use in chronic pain populations with substantial variation in results (0.05% to 81%), likely due to widely varying definitions of dependence, substance use disorder, misuse, addiction, and abuse. Several clinical assessment and treatment approaches were identified, including: standardized assessment instruments; urine drug testing; medication counts; prescription drug monitoring programs; blood level monitoring; treatment agreements; opioid selection; dosing and dispensing strategies; and opioid agonist treatment. However, the reviews commonly noted serious limitations, inconsistencies, and imprecision of studies, and a lack of evidence on effectiveness or clinical utility for the majority of these strategies.

Conclusion: Overall, current systematic reviews have found a lack of high-quality evidence or consistent findings on the prevalence, risk factors, and optimal clinical assessment and treatment approaches related to concurrent chronic pain and substance misuse. Given the role of systematic reviews in guiding evidence-based medicine and health policy, there is an urgent need for high-quality primary research to guide future systematic reviews to address the escalating epidemic of harms related to chronic pain and substance misuse.