Spiritual Pain: A Symptom in Search of a Clinical Definition.

We conducted a literature search to identify and compare definitions of the experiential dimension of spiritual pain. Key databases were searched, up to the year 2021 inclusive, for papers with a definition of "spiritual" or "existential" pain/distress in a clinical setting. Of 144 hits, seven papers provided theoretical definitions/descriptions; none incorporated clinical observations or underlying pathophysiological constructs. Based on these findings, we propose a new definition for "spiritual pain" as a "self-identified experience of personal discomfort, or actual or potential harm, triggered by a threat to a person's relationship with God or a higher power." Our updated definition can inform future studies in pain assessment and management.

AAAPT Diagnostic Criteria for Acute Neuropathic Pain.

OBJECTIVE: Acute neuropathic pain is a significant diagnostic challenge, and it is closely related to our understanding of both acute pain and neuropathic pain. Diagnostic criteria for acute neuropathic pain should reflect our mechanistic understanding and provide a framework for research on and treatment of these complex pain conditions. METHODS: The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration (FDA), the American Pain Society (APS), and the American Academy of Pain Medicine (AAPM) collaborated to develop the ACTTION-APS-AAPM Pain Taxonomy (AAAPT) for acute pain. A working group of experts in research and clinical management of neuropathic pain was convened. Group members used literature review and expert opinion to develop diagnostic criteria for acute neuropathic pain, as well as three specific examples of acute neuropathic pain conditions, using the five dimensions of the AAAPT classification of acute pain. RESULTS: AAAPT diagnostic criteria for acute neuropathic pain are presented. Application of these criteria to three specific conditions (pain related to herpes zoster, chemotherapy, and limb amputation) illustrates the spectrum of acute neuropathic pain and highlights unique features of each condition. CONCLUSIONS: The proposed AAAPT diagnostic criteria for acute neuropathic pain can be applied to various acute neuropathic pain conditions. Both the general and condition-specific criteria may guide future research, assessment, and management of acute neuropathic pain.

Persistent Spinal Pain Syndrome: A Proposal for Failed Back Surgery Syndrome and ICD-11.

OBJECTIVE: For many medical professionals dealing with patients with persistent pain following spine surgery, the term Failed back surgery syndrome (FBSS) as a diagnostic label is inadequate, misleading, and potentially troublesome. It misrepresents causation. Alternative terms have been suggested, but none has replaced FBSS. The International Association for the Study of Pain (IASP) published a revised classification of chronic pain, as part of the new International Classification of Diseases (ICD-11), which has been accepted by the World Health Organization (WHO). This includes the term Chronic pain after spinal surgery (CPSS), which is suggested as a replacement for FBSS. METHODS: This article provides arguments and rationale for a replacement definition. In order to propose a broadly applicable yet more precise and clinically informative term, an international group of experts was established. RESULTS: 14 candidate replacement terms were considered and ranked. The application of agreed criteria reduced this to a shortlist of four. A preferred option-Persistent spinal pain syndrome-was selected by a structured workshop and Delphi process. We provide rationale for using Persistent spinal pain syndrome and a schema for its incorporation into ICD-11. We propose the adoption of this term would strengthen the new ICD-11 classification. CONCLUSIONS: This project is important to those in the fields of pain management, spine surgery, and neuromodulation, as well as patients labeled with FBSS. Through a shift in perspective, it could facilitate the application of the new ICD-11 classification and allow clearer discussion among medical professionals, industry, funding organizations, academia, and the legal profession.

Cannabis for the Treatment of Chronic Pain in the Era of an Opioid Epidemic: A Symposium-Based Review of Sociomedical Science.

OBJECTIVE: This manuscript reviews medical literature published pertaining to the management of chronic pain with medical marijuana therapy (MMJ), with an emphasis on the social, medical, and legal aspects of therapy. DESIGN: Narrative review of peer-reviewed literature. METHODS: The 3rd Symposium on Controlled Substances and Their Alternatives for the Treatment of Pain was held in Boston on February 27, 2016, with a focus on MMJ for the treatment of chronic pain. Invited speakers had diverse backgrounds, including pain management, addiction psychiatry, neurology, and legal authorities. The purpose of this conference and this subsequent narrative review is to provide a medical, legal, and logistical framework for physicians and other health care providers to refer to when considering the initiation of medical marijuana therapy. RESULTS: The invited speakers each covered a unique aspect of MMJ therapy for the treatment of chronic pain. These presentations highlighted the current data for and against the use of MMJ as a pain therapy. Optimal patient selection and screening, in addition to policy developments, were discussed. CONCLUSIONS: Increasing interest in MMJ for chronic pain underscores a need for primary care and pain physicians to better understand the indications and evidence for its use free from cultural bias. Given a lack of full conclusive clinical utility, continued research is needed to better understand how to best utilize MMJ therapy for the treatment of chronic pain. Policy initiatives, such as enumerated indications, should follow medical science in order to prevent another abused substance epidemic.

Systemic administration of local anesthetic agents to relieve neuropathic pain.

BACKGROUND: Lidocaine, mexiletine, tocainide, and flecainide are local anesthetics which give an analgesic effect when administered orally or parenterally. Early reports described the use of intravenous lidocaine or procaine to relieve cancer and postoperative pain. Interest reappeared decades later when patient series and clinical trials reported that parenteral lidocaine and its oral analogs tocainide, mexiletine, and flecainide relieved neuropathic pain in some patients. With the recent publication of clinical trials with high quality standards, we have reviewed the use of systemic lidocaine and its oral analogs in neuropathic pain to update our knowledge, to measure their benefit and harm, and to better define their role in therapy. OBJECTIVES: To evaluate pain relief and adverse effect rates between systemic local anesthetic-type drugs and other control interventions. SEARCH METHODS: We searched MEDLINE (1966 through 15 May 2004), EMBASE (January 1980 to December 2002), Cancer Lit (through 15 December 2002), Cochrane Central Register of Controlled Trials (2nd Quarter, 2004), System for Information on Grey Literature in Europe (SIGLE), and LILACS, from January 1966 through March 2001. We also hand searched conference proceedings, textbooks, original articles and reviews. SELECTION CRITERIA: We included trials with random allocation, that were double blinded, with a parallel or crossover design. The control intervention was a placebo or an analgesic drug for neuropathic pain from any cause. DATA COLLECTION AND ANALYSIS: We collected efficacy and safety data from all published and unpublished trials. We calculated combined effect sizes using continuous and binary data for pain relief and adverse effects as primary and secondary outcome measurements, respectively. MAIN RESULTS: Thirty-two controlled clinical trials met the selection criteria; two were duplicate articles. The treatment drugs were intravenous lidocaine (16 trials), mexiletine (12 trials), lidocaine plus mexiletine sequentially (one trial), and tocainide (one trial). Twenty-one trials were crossover studies, and nine were parallel. Lidocaine and mexiletine were superior to placebo [weighted mean difference (WMD) = -11; 95% CI: -15 to -7; P < 0.00001], and limited data showed no difference in efficacy (WMD = -0.6; 95% CI: -7 to 6), or adverse effects versus carbamazepine, amantadine, gabapentin or morphine. In these trials, systemic local anesthetics were safe, with no deaths or life-threatening toxicities. Sensitivity analysis identified data distribution in three trials as a probable source of heterogeneity. There was no publication bias. AUTHORS' CONCLUSIONS: Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Future trials should enroll specific diseases and test novel lidocaine analogs with better toxicity profiles. More emphasis is necessary on outcomes measuring patient satisfaction to assess if statistically significant pain relief is clinically meaningful.

CONTEXTE: La lidocaïne, le mexilétine, la tocainide et la flécainide sont des anesthésiques locaux qui apportent un effet analgésique lorsqu'ils sont administrés par voie orale ou parentérale. Des études anciennes décrivaient l'utilisation de lidocaïne ou de procaïne par voie intraveineuse pour soulager la douleur due au cancer ou la douleur postopératoire. Un regain d'intérêt a eu lieu quelques décennies plus tard lorsque des séries de patients et des essais cliniques ont rapporté que la lidocaïne par voie parentérale ou ses analogues oraux, tocainide, méxiléine et flécainide, soulageaient la douleur neuropathique chez certains patients. Avec la publication récente d'essais cliniques suivant des normes de qualité, nous avons révisé l'utilisation de lidocaïne systémique et de ses analogues oraux en douleur neuropathique pour mettre à jour nos connaissances, mesurer leurs bénéfices et effets délétères et mieux définir leur rôle dans le traitement. OBJECTIFS: Évaluer le soulagement de la douleur et les effets indésirables entre les médicaments de type anesthésique local systémique et d'autres interventions de contrôle. STRATÉGIE DE RECHERCHE DOCUMENTAIRE: Nous avons effectué une recherche dans MEDLINE (de 1966 au 15 mai 2004), EMBASE (de janvier 1980 à décembre 2002), Cancer Lit (jusqu'au 15 décembre 2002), le registre Cochrane des essais contrôlés (2ème trimestre 2004),le Système pour l'Information en Littérature Grise en Europe (SIGLE), et LILACS, de janvier 1966 à mars 2001. Nous avons également recherché des actes de conférences, des ouvrages, des articles originaux et des revues. CRITÈRES DE SÉLECTION: Nous avons inclus des essais à assignation aléatoire, en double aveugle, avec un plan d'étude parallèle ou croisé. L'intervention de contrôlé était un placebo ou un médicament analgésique contre la douleur neuropathique quelle qu'en soit la cause. RECUEIL ET ANALYSE DES DONNÉES: Nous avons recueilli des données sur l'efficacité et la sécurité à partir de tous les essais publiés et non publiés. Nous avons calculé les quantités d'effet combinées en utilisant les données continues et binaires pour le soulagement de la douleur et les effets indésirables en tant que critères de jugement principal et secondaire, respectivement. RÉSULTATS PRINCIPAUX: Trente­deux essais cliniques contrôlés satisfaisaient aux critères de sélection ; deux d'entre eux étaient des articles en double. Les médicaments de traitement étaient la lidocaïne intraveineuse (16 essais), la mexilétine (12 essais), la lidocaïne plus la mexilétine séquentiellement (un essai) et la tocainide (un essai). Vingt­et­un essais étaient des études croisées et neuf étaient des études parallèles. La lidocaïne et la mexilétine se sont avérées supérieures au placebo [différence moyenne pondérée (DMP) = ­11 ; IC à 95 % : ­15 à ­7 ; P < 0,00001], et des données limitées n'ont mis en évidence aucune différence de l'efficacité (DMP = ­0,6 ; IC à 95 % : ­7 à 6) ou des événements indésirables versus carbamazépine, amantadine, gabapentine ou morphine. Dans ces essais, les anesthésiques locaux systémiques étaient sûrs, avec la non occurrence de toxicités mortelles ou dangereuses. L'analyse de la sensibilité a permis d'identifier la distribution des données dans trois essais comme étant une source probable d'hétérogénéité. Aucun biais de publication n'a été observé. CONCLUSIONS DES AUTEURS: Ces essais cliniques contrôlés sur la douleur neuropathique ont permis de déterminer qu la lidocaïne et ses analogues oraux sont des médicaments sûrs, plus efficaces que le placebo et aussi efficaces que d'autres analgésiques. Les prochains essais devraient porter sur des maladies spécifiques et tester de nouveaux analogues de la lidocaïne avec de meilleurs profils de toxicité. Il est nécessaire de se centrer plus particulièrement sur les résultats mesurant la satisfaction des patients pour déterminer si le soulagement de la douleur significatif du point de vue statistique est pertinent cliniquement.

Scope and Nature of Pain- and Analgesia-Related Content of the United States Medical Licensing Examination (USMLE).

Background: "The ongoing opioid crisis lies at the intersection of two substantial public health challenges-reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications" [1]. Improved pain education for health care providers is an essential component of the multidimensional response to both still-unmet challenges [2,3]. Despite the importance of licensing examinations in assuring competency in health care providers, there has been no prior appraisal of pain and related content within the United States Medical Licensing Examination (USMLE). Methods: An expert panel developed a novel methodology for characterizing USMLE questions based on pain core competencies and topical and public health relevance. Results: Under secure conditions, raters used this methodology to score 1,506 questions, with 28.7% (432) identified as including the word "pain." Of these, 232 questions (15.4% of the 1,506 USMLE questions reviewed) were assessed as being fully or partially related to pain, rather than just mentioning pain but not testing knowledge of its mechanisms and their implications for treatment. The large majority of questions related to pain (88%) focused on assessment rather than safe and effective pain management, or the context of pain. Conclusions: This emphasis on assessment misses other important aspects of safe and effective pain management, including those specific to opioid safety. Our findings inform ways to improve the long-term education of our medical and other graduates, thereby improving the health care of the populations they serve.

Deconstructing One Medical School's Pain Curriculum: II. Partnering with Medical Students on an Evidence-Guided Redesign.

Objective: To reshape medical education about pain to present it as a population-based public health process as well as a neuron-centered phenomenon. Design: Collaborate with students to apply a recent inventory of pain-related preclinical curricular content and clinical training in order to modify the current multiyear presentation and offer a broadened social perspective on pain. Appraise fourth-year medical students' pain-related educational needs by surveying their knowledge, attitudes, experience with the curriculum, and self-reported assessment of pain-related competencies. Setting and subjects: University-affiliated medical school and its fourth-year medical students. Methods: Analysis of a detailed inventory of first- and second-year curricula. Survey of graduating medical students assessing attitudes, skills, and confidence. Construction of a fourth-year pain education elective and collaboration with enrollees to better integrate pain throughout the four-year curriculum. Results: This student-faculty collaboration produced an evidence-guided proposal to reorganize pain-related content across the longitudinal medical curriculum. An attitudes/skills/confidence survey of graduating medical students (104 respondents of 200 polled) found that 70% believed chances for successful outcomes treating chronic pain were low. Self-evaluated competency was high for evaluating (82%) and managing (69%) acute pain; for chronic pain, both were lower (evaluating = 38%; managing = 6%). Self-evaluated knowledge of pain physiology and neurobiology was poor (14%), fair (54%), or good (30%), but rarely excellent (2%). Conclusions: To meet graduating students' desire for increased competency in pain, pain-related curricula can and should be reorganized to include pain as a disease state and a widespread public health burden, not merely a symptom.

Deconstructing One Medical School's Pain Curriculum: I. Content Analysis.

Objective: Inventory one medical school's first- and second-year pain-related curriculum in order to explore opportunities to teach about pain both as a social, population-based process and as a neuron-centered phenomenon. Design: Deconstruction of pain-related curricular content through a detailed content inventory and analysis by students and faculty. Setting and Subjects: University-affiliated US medical school. Methods: Detailed inventory and content analysis of first- and second-year curricular materials. Results: The inventory of pain content showed fragmentation, mostly presenting it as a symptom without an underlying framework. Conclusion: Analysis of one medical school's pain-related curricular materials reveals opportunities for a more unified perspective that includes pain as a widespread disease state (not merely a symptom) and to provide an emphasis in the curriculum consistent with pain's public health burden.

The ACTTION-APS-AAPM Pain Taxonomy (AAAPT) Multidimensional Approach to Classifying Acute Pain Conditions.

Objective: With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (e.g., pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain. Setting: Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM). Methods: As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions. Perspective: The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Conclusions: Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies. Mismanaged acute pain has a broad societal impact as significant numbers of patients may progress to suffer from chronic pain. An acute pain taxonomy provides a much-needed standardization of clinical diagnostic criteria, which benefits clinical care, research, education, and public policy. For the purposes of the present taxonomy, acute pain is considered to last up to seven days, with prolongation to 30 days being common. The current understanding of acute pain mechanisms poorly differentiates between acute and chronic pain and is often insufficient to distinguish among many types of acute pain conditions. Given the usefulness of the AAPT multidimensional framework, the AAAPT undertook a similar approach to organizing various acute pain conditions.

Topical anaesthetics for pain control during repair of dermal laceration.

BACKGROUND: Topical local anaesthetics provide effective analgesia for patients undergoing numerous superficial procedures, including repair of dermal lacerations. The need for cocaine in topical anaesthetic formulations has been questioned because of concern about adverse effects, thus novel preparations of cocaine-free anaesthetics have been developed. This review was originally published in 2011 and has been updated in 2017. OBJECTIVES: To assess whether benefits of non-invasive topical anaesthetic application occur at the expense of decreased analgesic efficacy. To compare the efficacy of various single-component or multi-component topical anaesthetic agents for repair of dermal lacerations. To determine the clinical necessity for topical application of the ester anaesthetic, cocaine. SEARCH METHODS: For this updated review, we searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), Cumulative Index to Nursing and Allied Health Literature (CINAHL; 2010 to December 2016), Embase (2010 to December 2016) and MEDLINE (2010 to December 2016). We did not limit this search by language or format of publication. We contacted manufacturers, international scientific societies and researchers in the field. Weemailed selected journalsand reviewed meta-registers of ongoing trials. For the previous version of this review, we searched these databases to November 2010. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated the efficacy and safety of topical anaesthetics for repair of dermal laceration in adult and paediatric participants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information when needed. We collected adverse event information from trial reports. We assessed methodological risk of bias for each included study and employed the GRADE approach to assess the overall quality of the evidence. MAIN RESULTS: The present updated review included 25 RCTs involving 3278 participants. The small number of trials in each comparison group and the heterogeneity of outcome measures precluded quantitative analysis of data for all but one outcome: pain intensity. In two pooled studies, the mean self-reported visual analogue scale (VAS; 0 to 100 mm) score for topical prilocaine-phenylephrine (PP) was higher than the mean self-reported VAS (0 to 100 mm) score for topical tetracaine-epinephrine-cocaine (TAC) by 5.59 points (95% confidence interval (CI) 2.16 to 13.35). Most trials that compared infiltrated and topical anaesthetics were at high risk of bias, which is likely to have affected their results. Researchers found that several cocaine-free topical anaesthetics provided effective analgesic efficacy. However, data regarding the efficacy of each topical agent are based mostly on single comparisons in trials with unclear or high risk of bias. Mild, self-limited erythematous skin induration occurred in one of 1042 participants who had undergone application of TAC. Investigators reported no serious complications among any of the participants treated with cocaine-based or cocaine-free topical anaesthetics. The overall quality of the evidence according to the GRADE system is low owing to limitations in design and implementation, imprecision of results and high probability of publication bias (selective reporting of data). Additional well-designed RCTs with low risk of bias are necessary before definitive conclusions can be reached. AUTHORS' CONCLUSIONS: We have found two new studies published since the last version of this review was prepared. We have added these studies to those previously included and have conducted an updated analysis, which resulted in the same review conclusions as were presented previously.Mostly descriptive analysis indicates that topical anaesthetics may offer an efficacious, non-invasive means of providing analgesia before suturing of dermal lacerations. Use of cocaine-based topical anaesthetics might be hard to justify, given the availability of other effective topical anaesthetics without cocaine. However, the overall quality of the evidence according to the GRADE system is low owing to limitations in design and implementation, imprecision of results and high probability of publication bias (selective reporting of data). Additional well-designed RCTs with low risk of bias are necessary before definitive conclusions can be reached.

Morphine for chronic neuropathic pain in adults.

BACKGROUND: Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the nervous system. Opioid drugs, including morphine, are commonly used to treat neuropathic pain. Most reviews have examined all opioids together. This review sought evidence specifically for morphine; other opioids are considered in separate reviews. OBJECTIVES: To assess the analgesic efficacy and adverse events of morphine for chronic neuropathic pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials from inception to February 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries. SELECTION CRITERIA: We included randomised, double-blind trials of two weeks' duration or longer, comparing morphine (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables. MAIN RESULTS: We identified five randomised, double-blind, cross-over studies with treatment periods of four to seven weeks, involving 236 participants in suitably characterised neuropathic pain; 152 (64%) participants completed all treatment periods. Oral morphine was titrated to maximum daily doses of 90 mg to 180 mg or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months. Included studies involved people with painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia criteria, phantom limb or postamputation pain, and lumbar radiculopathy. Exclusions were typically people with other significant comorbidity or pain from other causes.Overall, we judged the studies to be at low risk of bias, but there were concerns over small study size and the imputation method used for participants who withdrew from the studies, both of which could lead to overestimation of treatment benefits and underestimation of harm.There was insufficient or no evidence for the primary outcomes of interest for efficacy or harm. Four studies reported an approximation of moderate pain improvement (any pain-related outcome indicating some improvement) comparing morphine with placebo in different types of neuropathic pain. We pooled these data in an exploratory analysis. Moderate improvement was experienced by 63% (87/138) of participants with morphine and 36% (45/125) with placebo; the risk difference (RD) was 0.27 (95% confidence interval (CI) 0.16 to 0.38, fixed-effects analysis) and the NNT 3.7 (2.6 to 6.5). We assessed the quality of the evidence as very low because of the small number of events; available information did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different was very high. A similar exploratory analysis for substantial pain relief on three studies (177 participants) showed no difference between morphine and placebo.All-cause withdrawals in four studies occurred in 16% (24/152) of participants with morphine and 12% (16/137) with placebo. The RD was 0.04 (-0.04 to 0.12, random-effects analysis). Adverse events were inconsistently reported, more common with morphine than with placebo, and typical of opioids. There were two serious adverse events, one with morphine, and one with a combination of morphine and nortriptyline. No deaths were reported. These outcomes were assessed as very low quality because of the limited number of participants and events. AUTHORS' CONCLUSIONS: There was insufficient evidence to support or refute the suggestion that morphine has any efficacy in any neuropathic pain condition.

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) for cancer pain in adults.

BACKGROUND: Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Non-opioid drugs are commonly used to treat cancer pain, and are recommended for this purpose in the World Health Organization (WHO) cancer pain treatment ladder, either alone or in combination with opioids.A previous Cochrane review that examined the evidence for nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005. This review, and another on paracetamol, updates the evidence. OBJECTIVES: To assess the efficacy of oral NSAIDs for cancer pain in adults, and the adverse events reported during their use in clinical trials. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to April 2017, together with reference lists of retrieved papers and reviews, and two online study registries. SELECTION CRITERIA: We included randomised, double-blind, single-blind, or open-label studies of five days' duration or longer, comparing any oral NSAID alone with placebo or another NSAID, or a combination of NSAID plus opioid with the same dose of the opioid alone, for cancer pain of any pain intensity. The minimum study size was 25 participants per treatment arm at the initial randomisation. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: Eleven studies satisfied inclusion criteria, lasting one week or longer; 949 participants with mostly moderate or severe pain were randomised initially, but fewer completed treatment or had results of treatment. Eight studies were double-blind, two single-blind, and one open-label. None had a placebo only control; eight compared different NSAIDs, three an NSAID with opioid or opioid combination, and one both. None compared an NSAID plus opioid with the same dose of opioid alone. Most studies were at high risk of bias for blinding, incomplete outcome data, or small size; none was unequivocally at low risk of bias.It was not possible to compare NSAIDs as a group with another treatment, or one NSAID with another NSAID. Results for all NSAIDs are reported as a randomised cohort. We judged results for all outcomes as very low-quality evidence.None of the studies reported our primary outcomes of participants with pain reduction of at least 50%, and at least 30%, from baseline; participants with Patient Global Impression of Change (PGIC) of much improved or very much improved (or equivalent wording). With NSAID, initially moderate or severe pain was reduced to no worse than mild pain after one or two weeks in four studies (415 participants in total), with a range of estimates between 26% and 51% in individual studies.Adverse event and withdrawal reporting was inconsistent. Two serious adverse events were reported with NSAIDs, and 22 deaths, but these were not clearly related to any pain treatment. Common adverse events were thirst/dry mouth (15%), loss of appetite (14%), somnolence (11%), and dyspepsia (11%). Withdrawals were common, mostly because of lack of efficacy (24%) or adverse events (5%). AUTHORS' CONCLUSIONS: There is no high-quality evidence to support or refute the use of NSAIDs alone or in combination with opioids for the three steps of the three-step WHO cancer pain ladder. There is very low-quality evidence that some people with moderate or severe cancer pain can obtain substantial levels of benefit within one or two weeks.

Oral paracetamol (acetaminophen) for cancer pain.

BACKGROUND: Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Non-opioid drugs are commonly used to treat mild to moderate cancer pain, and are recommended for this purpose in the WHO cancer pain treatment ladder, either alone or in combination with opioids.A previous Cochrane review that examined the evidence for nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005. This review, and another on NSAIDs, updates the evidence. OBJECTIVES: To assess the efficacy of oral paracetamol (acetaminophen) for cancer pain in adults and children, and the adverse events reported during its use in clinical trials. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to March 2017, together with reference lists of retrieved papers and reviews, and two online study registries. SELECTION CRITERIA: We included randomised, double-blind, studies of five days' duration or longer, comparing paracetamol alone with placebo, or paracetamol in combination with an opioid compared with the same dose of the opioid alone, for cancer pain of any intensity. Single-blind and open studies were also eligible for inclusion. The minimum study size was 25 participants per treatment arm at the initial randomisation. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: Three studies in adults satisfied the inclusion criteria, lasting up to one week; 122 participants were randomised initially, and 95 completed treatment. We found no studies in children. One study was parallel-group, and two had a cross-over design. All used paracetamol as an add-on to established treatment with strong opioids (median daily morphine equivalent doses of 60 mg, 70 mg, and 225 mg, with some participants taking several hundred mg of oral morphine equivalents daily). Other non-paracetamol medication included non-steroidal anti-inflammatory drugs (NSAIDs), tricyclic antidepressants, or neuroleptics. All studies were at high risk of bias for incomplete outcome data and small size; none was unequivocally at low risk of bias.None of the studies reported any of our primary outcomes: participants with pain reduction of at least 50%, and at least 30%, from baseline; participants with pain no worse than mild at the end of the treatment period; participants with Patient Global Impression of Change (PGIC) of much improved or very much improved (or equivalent wording). What pain reports there were indicated no difference between paracetamol and placebo when added to another treatment. There was no convincing evidence of paracetamol being different from placebo with regards to quality of life, use of rescue medication, or participant satisfaction or preference. Measures of harm (serious adverse events, other adverse events, and withdrawal due to lack of efficacy) were inconsistently reported and provided no clear evidence of difference.Our GRADE assessment of evidence quality was very low for all outcomes, because studies were at high risk of bias from several sources. AUTHORS' CONCLUSIONS: There is no high-quality evidence to support or refute the use of paracetamol alone or in combination with opioids for the first two steps of the three-step WHO cancer pain ladder. It is not clear whether any additional analgesic benefit of paracetamol could be detected in the available studies, in view of the doses of opioids used.

Computing energy landscape maps and structural excursions of proteins.

BACKGROUND: Structural excursions of a protein at equilibrium are key to biomolecular recognition and function modulation. Protein modeling research is driven by the need to aid wet laboratories in characterizing equilibrium protein dynamics. In principle, structural excursions of a protein can be directly observed via simulation of its dynamics, but the disparate temporal scales involved in such excursions make this approach computationally impractical. On the other hand, an informative representation of the structure space available to a protein at equilibrium can be obtained efficiently via stochastic optimization, but this approach does not directly yield information on equilibrium dynamics. METHODS: We present here a novel methodology that first builds a multi-dimensional map of the energy landscape that underlies the structure space of a given protein and then queries the computed map for energetically-feasible excursions between structures of interest. An evolutionary algorithm builds such maps with a practical computational budget. Graphical techniques analyze a computed multi-dimensional map and expose interesting features of an energy landscape, such as basins and barriers. A path searching algorithm then queries a nearest-neighbor graph representation of a computed map for energetically-feasible basin-to-basin excursions. RESULTS: Evaluation is conducted on intrinsically-dynamic proteins of importance in human biology and disease. Visual statistical analysis of the maps of energy landscapes computed by the proposed methodology reveals features already captured in the wet laboratory, as well as new features indicative of interesting, unknown thermodynamically-stable and semi-stable regions of the equilibrium structure space. Comparison of maps and structural excursions computed by the proposed methodology on sequence variants of a protein sheds light on the role of equilibrium structure and dynamics in the sequence-function relationship. CONCLUSIONS: Applications show that the proposed methodology is effective at locating basins in complex energy landscapes and computing basin-basin excursions of a protein with a practical computational budget. While the actual temporal scales spanned by a structural excursion cannot be directly obtained due to the foregoing of simulation of dynamics, hypotheses can be formulated regarding the impact of sequence mutations on protein function. These hypotheses are valuable in instigating further research in wet laboratories.

Intravenous Ketamine for Rapid Opioid Dose Reduction, Reversal of Opioid-Induced Neurotoxicity, and Pain Control in Terminal Care: Case Report and Literature Review.

OBJECTIVE: We report a case of opioid-induced neurotoxicity (OIN) in an actively dying hospice patient, its reversal and improved analgesia that followed opioid dosage reduction made possible after addition of IV ketamine. We briefly review the diagnosis and treatment of OIN. SETTING: OIN, particularly when associated with high dose opioid therapy in palliative care, may pose difficult diagnostic and treatment challenges. Few publications from end-of-life settings provide systematic approaches to management of OIN. PATIENTS: We describe a case of OIN in a hospice patient receiving medical care at home while actively dying. INTERVENTION: Addition of IV ketamine and reduction of the patient's high-dose opioid regimen. RESULTS: The patient's pain was controlled within 24 hours of initiation of IV ketamine while the total opioid dose was reduced. His symptoms of OIN (delirium, tremor, myoclonus, and hallucinations) also rapidly subsided. CONCLUSION: OIN should be considered as an etiology of CNS dysfunction occurring with prolonged, high-dose opioid therapy. This case highlights the opioid-sparing and analgesic properties of low-dose ketamine, allowing reversal of OIN in the home hospice setting.

Durations of Opioid, Nonopioid Drug, and Behavioral Clinical Trials for Chronic Pain: Adequate or Inadequate?

OBJECTIVES: A recent US federal review and clinical guideline on opioids for chronic pain asserted that the literature contributes no evidence on efficacy because all trials had "inadequate duration." To explore the evidence, we examined durations of studies on opioid, nonopioid drug, and behavioral therapies for chronic pain. METHODS: We retrieved Cochrane reviews of anticonvulsants, antidepressants, NSAIDs, opioids, or behavioral interventions for chronic pain. We also examined all opioid treatment studies retrieved for the federal evidence report but excluded due to "inadequate duration." RESULTS: Of 378 Cochrane reviews retrieved, 72 evaluated one of the five therapies. Six of these 72 were excluded because they were proposals without data or investigated acute pain. Fourteen addressed multiple interventions, leaving 52 for analysis. We graphed numbers of trials vs duration for the five treatments reviewed in the Cochrane Library, compared with durations of opioid trials dropped from the federal evidence report. Most graphs were overdispersed Poisson distributions. Nearly all trials had active treatment durations of 12 weeks or less. CONCLUSIONS: No common nonopioid treatment for chronic pain has been studied in aggregate over longer intervals of active treatment than opioids. To dismiss trials as "inadequate" if their observation period is a year or less is inconsistent with current regulatory standards. The literature on major drug and nondrug treatments for chronic pain reveals similarly shaped distributions across modalities. Considering only duration of active treatment in efficacy or effectiveness trials, published evidence is no stronger for any major drug category or behavioral therapy than for opioids.

A Pooled Analysis Evaluating Renal Safety in Placebo- and Active Comparator-Controlled Phase III Trials of Multiple-Dose Injectable HPßCD-Diclofenac in Subjects with Acute Postoperative Pain.

OBJECTIVE : While injectable nonsteroidal anti-inflammatory drugs (NSAIDs) are a key component of postoperative multimodal analgesia, renal safety concerns may limit use in some patients. This study examined the renal safety of injectable HPßCD-diclofenac when given for ≤ 5 days following orthopedic or abdominal/pelvic surgery. METHODS : Pooled analysis of data from two randomized, placebo- and active comparator-controlled phase III trials in 608 total patients was conducted. Renal safety was assessed by examining treatment-emergent adverse events (AEs) and postoperative blood urea nitrogen (BUN) and serum creatinine shifts. RESULTS : There were three renal AEs each in the HPßCD-diclofenac (n = 318 patients) and placebo (n = 148 patients) groups, and two renal AEs in the ketorolac group (n = 142 patients). No significant difference in renal AE risk was detected for patients receiving HPßCD-diclofenac (RR: 1.40 [0.15,13.3]; P = 0.75) or ketorolac (RR: 2.08 [0.19,22.7]; P = 0.56) versus placebo. All renal AEs were mild or moderate in severity, and a single renal AE (acute renal failure in a patient receiving HPßCD-diclofenac) was treatment-related. One incidence of postoperative shift to high (> upper limit of normal) serum creatinine occurred in the HPßCD-diclofenac group (n = 2 in the ketorolac group). Mean changes in serum creatinine or BUN did not differ significantly between patients receiving HPßCD-diclofenac and placebo. CONCLUSIONS : While this analysis examined relatively brief exposure typical for parenterally administered analgesics in the postoperative setting in patients with largely normal renal function, the results suggest that HPßCD-diclofenac use for acute postoperative pain may not be associated with added renal safety risks over placebo in this patient population.

Single dose intravenous paracetamol or intravenous propacetamol for postoperative pain.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 10, 2011. Paracetamol (acetaminophen) is the most commonly prescribed analgesic for the treatment of acute pain. It may be administered orally, rectally, or intravenously. The efficacy and safety of intravenous (IV) formulations of paracetamol, IV paracetamol, and IV propacetamol (a prodrug that is metabolized to paracetamol), compared with placebo and other analgesics, is unclear. OBJECTIVES: To assess the efficacy and safety of IV formulations of paracetamol for the treatment of postoperative pain in both adults and children. SEARCH METHODS: We ran the search for the previous review in May 2010. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE (May 2010 to 16 February 2016), EMBASE (May 2010 to 16 February 2016), LILACS (2010 to 2016), a clinical trials registry, and reference lists of reviews for randomized controlled trials (RCTs) in any language and we retrieved articles. SELECTION CRITERIA: Randomized, double-blind, placebo- or active-controlled single dose clinical trials of IV paracetamol or IV propacetamol for acute postoperative pain in adults or children. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We contacted study authors for additional information. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence. MAIN RESULTS: We included 75 studies (36 from the original review and 39 from our updated review) enrolling a total of 7200 participants.Among primary outcomes, 36% of participants receiving IV paracetamol/propacetamol experienced at least 50% pain relief over four hours compared with 16% of those receiving placebo (number needed to treat to benefit (NNT) = 5; 95% confidence interval (CI) 3.7 to 5.6, high quality evidence). The proportion of participants in IV paracetamol/propacetamol groups experiencing at least 50% pain relief diminished over six hours, as reflected in a higher NNT of 6 (4.6 to 7.1, moderate quality evidence). Mean pain intensity at four hours was similar when comparing IV paracetamol and placebo, but was seven points lower on a 0 to 100 visual analog scale (0 = no pain, 100 = worst pain imaginable, 95% CI -9 to -6, low quality evidence) in those receiving paracetamol at six hours.For secondary outcomes, participants receiving IV paracetamol/propacetamol required 26% less opioid over four hours and 16% less over six hours (moderate quality evidence) than those receiving placebo. However, this did not translate to a clinically meaningful reduction in opioid-induced adverse events.Meta-analysis of efficacy comparisons between IV paracetamol/propacetamol and active comparators (e.g., opioids or nonsteroidal anti-inflammatory drugs) were either not statistically significant, not clinically significant, or both.Adverse events occurred at similar rates with IV paracetamol or IV propacetamol and placebo. However, pain on infusion occurred more frequently in those receiving IV propacetamol versus placebo (23% versus 1%). Meta-analysis did not demonstrate clinically meaningful differences between IV paracetamol/propacetamol and active comparators for any adverse event. AUTHORS' CONCLUSIONS: Since the last version of this review, we have found 39 new studies providing additional information. Most included studies evaluated adults only. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides high quality evidence that a single dose of either IV paracetamol or IV propacetamol provides around four hours of effective analgesia for about 36% of patients with acute postoperative pain. Low to very low quality evidence demonstrates that both formulations are associated with few adverse events, although patients receiving IV propacetamol have a higher incidence of pain on infusion than both placebo and IV paracetamol.