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The current International Association for the Study of Pain (IASP) definition of pain as "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" was recommended by the Subcommittee on Taxonomy and adopted by the IASP Council in 1979. This definition has become accepted widely by health care professionals and researchers in the pain field and adopted by several professional, governmental, and nongovernmental organizations, including the World Health Organization. In recent years, some in the field have reasoned that advances in our understanding of pain warrant a reevaluation of the definition and have proposed modifications. Therefore, in 2018, the IASP formed a 14-member, multinational Presidential Task Force comprising individuals with broad expertise in clinical and basic science related to pain, to evaluate the current definition and accompanying note and recommend whether they should be retained or changed. This review provides a synopsis of the critical concepts, the analysis of comments from the IASP membership and public, and the committee's final recommendations for revisions to the definition and notes, which were discussed over a 2-year period. The task force ultimately recommended that the definition of pain be revised to "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage," and that the accompanying notes be updated to a bulleted list that included the etymology. The revised definition and notes were unanimously accepted by the IASP Council early this year.

Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of noninvasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multiday repetitive transcranial magnetic stimulation (rTMS) can induce long-lasting, potentially therapeutic brain plasticity. Nearby ferromagnetic or electronic implants are contraindications. Adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. Transcranial magnetic stimulation devices are marketed for depression and migraine in the United States and for various indications elsewhere. Although multiple studies report that high-frequency rTMS of the motor cortex reduces neuropathic pain, their quality has been insufficient to support Food and Drug Administration application. Harvard's Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters and improve strategies for sham and double blinding. Subjects should have common well-characterized pain conditions amenable to motor cortex rTMS and studies should be adequately powered. They recommended standardized assessment tools (eg, NIH's PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (eg, IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion and exclusion criteria, baseline and posttreatment means and SD, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months after initiation with prespecified statistical analyses. Multigroup collaborations or registry studies may be needed for pivotal trials.

Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.

Few placebo-controlled trials have investigated the treatment of breakthrough pain (BTP) in patients with chronic pain. We evaluated the efficacy and safety of intranasal ketamine for BTP in a randomized, double-blind, placebo-controlled, crossover trial. Twenty patients with chronic pain and at least two spontaneous BTP episodes daily self-administered up to five doses of intranasal ketamine or placebo at the onset of a spontaneous BTP episode (pain intensity > or =5 on a 0-10 scale). Two BTP episodes at least 48 h apart were treated with either ketamine or placebo. Patients reported significantly lower BTP intensity following intranasal ketamine than after placebo (P < 0.0001) with pain relief within 10 min of dosing and lasting for up to 60 min. No patient in the ketamine group required his/her usual rescue medication to treat the BTP episode, while seven out of 20 (35%) patients in placebo group did (P = 0.0135). Intranasal ketamine was well tolerated with no serious adverse events. After ketamine administration, four patients reported a transient change in taste, one patient reported rhinorrhea, one patient reported nasal passage irritation, and two patients experienced transient elevation in blood pressure. A side effect questionnaire administered 60 min and 24 h after drug or placebo administration elicited no reports of auditory or visual hallucinations. These data suggest that intranasal administration of ketamine provides rapid, safe and effective relief for BTP.

Ultralow doses of naloxone (0.001-0.1 microg/kg) produce analgesia in animal models. However, no clinical study has evaluated the combination of ultralow dose naloxone and morphine using patient-controlled analgesia (PCA). This randomized, double blind controlled study sought to determine if the combination of ultralow dose naloxone and morphine in PCA solutions affects opioid requirements, analgesia, and side effects. Two-hundred and sixty-five patients (18-65 years old) undergoing operations were randomized to receive PCA morphine 1 mg/ml (n=129) or PCA morphine 1 mg/ml plus naloxone 0.6 microg/ml (n=136). We evaluated the numbers of supplemental rescue doses, the cumulative dose of each PCA solution, pain intensity, pain relief, and opioid side effects during the first 24 h after surgery. We found that opioid requirements did not differ significantly between groups. The morphine+naloxone group on average required 0.07 mg more morphine (95% CI -1.1 to 1.3) during the 24 h than the morphine group. Pain intensity levels were also similar in both groups. The morphine+naloxone group had 0.06 units lower (95% CI -0.5 to 0.4) pain intensity levels than the morphine group. The morphine+naloxone group had a lower incidence of nausea and pruritus than the morphine group (P=0.01 for both symptoms). However, the incidence of vomiting, time to tolerate fluids, sedation, and urinary retention were similar between groups (all P values >0.1). The combination of ultralow dose naloxone and morphine in PCA does not affect analgesia or opioid requirements, but it decreases the incidence of nausea and pruritus.

To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of data, encourage more complete reporting of outcomes, simplify the preparation and review of research proposals and manuscripts, and allow clinicians to make informed decisions regarding the risks and benefits of treatment.Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 27 specialists from academia, governmental agencies, and the pharmaceutical industry participated in a consensus meeting and identified core outcome domains that should be considered in clinical trials of treatments for chronic pain.There was a consensus that chronic pain clinical trials should assess outcomes representing six core domains: (1) pain, (2) physical functioning, (3) emotional functioning, (4) participant ratings of improvement and satisfaction with treatment, (5) symptoms and adverse events, (6) participant disposition (e.g. adherence to the treatment regimen and reasons for premature withdrawal from the trial). Although consideration should be given to the assessment of each of these domains, there may be exceptions to the general recommendation to include all of these domains in chronic pain trials. When this occurs, the rationale for not including domains should be provided. It is not the intention of these recommendations that assessment of the core domains should be considered a requirement for approval of product applications by regulatory agencies or that a treatment must demonstrate statistically significant effects for all of the relevant core domains to establish evidence of its efficacy.

Despite widespread use of the 0-10 numeric rating scale (NRS) of pain intensity, relatively little is known about the meaning of decreases in pain intensity assessed by means of this scale to patients. We aimed to establish the meaning to patients of declines in pain intensity and percent pain reduction. Upon arrival to the postanesthesia care unit, postsurgical patients rated their baseline pain intensity on both a 0-10 NRS and on a 4-point verbal scale. Patients whose NRS was higher than 4/10 received intravenous opioids until their pain intensity declined to 4/10 or lower. During opioid titration, patients were asked every 10 min to rate pain intensity on a NRS and to indicate the degree of pain improvement on a 5-point Likert scale from 'no improvement' to 'complete pain relief'. Seven hundred adult patients were enrolled. For patients with moderate pain, a decrease of 1.3 units (20% reduction) corresponded to 'minimal' improvement, a decrease of 2.4 (35% reduction) to 'much' improvement, a decrease of 3.5 units (45% reduction) corresponded to 'very much' improvement. For patients with severe pain, the decrease in NRS pain score and the percentage of pain relief had to be larger to obtain similar degrees of pain relief. The change in pain intensity that is meaningful to patients increases as the severity of their baseline pain increases. The present findings are applicable in the clinical setting and research arena to assess treatment efficacy.

The continuous infusion of low doses of naloxone has been reported to decrease postoperative opioid requirements and opioid side effects. However, there is no study that evaluates the effectiveness of the combination of a low dose of naloxone and morphine using patient-controlled analgesia (PCA). This prospective, randomized double-blind controlled study sought to determine if the combination of a low dose of naloxone and morphine in a PCA solution decreases postoperative opioid requirements and pain intensity. One hundred sixty-six patients (18-65 years old) undergoing operations of less than 3 h duration with an American Society of Anesthesiologist physical status I or II were randomized to receive PCA morphine 1 mg/cc plus normal saline or PCA morphine 1 mg/cc plus naloxone 6 microg/cc. Initial PCA settings were 0.5 cc per demand with a lockout time of 10 min. The numbers of 2.5 cc supplemental rescue doses and the cumulative dose of each solution were recorded in the first 24 h after the surgical procedure. Pain intensity and opioid side effects were evaluated every 10 min in the post-anesthesia care unit and every 4 h afterwards. Patient satisfaction was assessed at the end of the 24 h of observation. The morphine+naloxone group had more treatment failures (P=0.0001), higher opioid requirements (P=0.0097), greater pain intensity (P=0.04), less pain relief (P=0.004), and less satisfaction (P=0.01) than the morphine group. The incidence of side effects was similar in both groups (P=0.3). Contrary to previous reports, adding low doses of naloxone to a morphine PCA solution increases opioid requirements and pain.

Recent animal models of experimental nerve injury have proven useful in evaluating potential sympathetic involvement in neuropathic pain syndromes. We have employed a widely adopted unilateral L 5 /L 6 spinal nerve ligation model to compare the development of mechanical allodynia with neurochemical changes both at the site of peripheral nerve injury and in the dorsal root ganglia (DRG). We have focused on the expression of neuropeptide Y (NPY), a well-studied regulatory peptide and phenotypic marker of sympathetic neurons, and functionally related Y-receptor binding sites following nerve injury. In sympathetic neurons, NPY is colocalized and coreleased with norepinephrine (NE) at peripheral sites of action. Furthermore, NPY gene expression is induced within the population of medium- and large-diameter DRG neurons of the A β -fiber class after experimental nerve injury. We therefore hypothesized that concurrent alterations in NPY and NE expression by sympathetic and sensory neurons may be a contributing factor to sympathetically-maintained neuropathic conditions. Animals with unilateral L 5 /L 6 spinal nerve ligation developed mechanical allodynia of the hind paw ipsilateral to the site of injury that persisted until sacrifice at postoperative day 10. A significant induction of preproneuropeptide Y-encoding (PPNPY) mRNA, as detected by in situ hybridization histochemistry (ISHH), occurred in populations of medium- and large-diameter DRG neurons ipsilateral to the site of injury. Immunohistochemical analysis indicated a marked decline in the number of labeled sympathetic axons positive for tyrosine hydroxylase-like and NPY-like immunoreactivities (TH-Ll and NPY-LI, respectively) proximal to the site of nerve injury and almost complete elimination of immunopositive fibers distal to the site of ligation. Whereas, the extent of colocalization of NPY-LI to TH-LI-positive sympathetic axons in unaffected L 4 or L 5 nerve segments exceeded 80%, this figure declined to approximately 50% in regenerating axons of ligated spinal nerve L 5 . The portion of NPY-LI that was not colocalized to sympathetic TH-LI-positive fibers was most likely contributed by regenerating sensory axons, consistent with marked de novo synthesis of NPY by DRG neurons. In end bulb axon terminals, i.e. morphological profiles characteristic of neuromas, NPY-LI-positive elements that were not colocalized to TH-LI-positive sympathetic elements appeared to be spatially segregated from those of sympathetic origin with colocalized TH-LI and NPY-LI. Receptor autoradiography indicated that small- and medium-diameter DRG somata of the C-fiber class normally express both Y 1 and Y 2 receptor subtypes. The pattern of the distribution of Y-receptor binding sites appeared to be relatively unaffected by spinal nerve ligation. In contrast, there was a marked increase in the density of Y 2 receptor binding sites in the proximal segment of ligated spinal nerve L 5 , consistent with previously published data indicating differential transport of the Y 2 autoregulatory receptor subtype to nerve terminals. Induction of NPY gene expression in injured DRG neurons is consistent with appearance of NPY-LI-positive end bulbs derived from regenerating sensory axons that are found in developing neuromas containing a relatively high density of transported prejunctional Y 2 receptors. Newly established functional interactions of spatially segregated sensory- and sympathetically-derived end bulbs in developing neuromas may enhance neuronal hyperexcitability engendered by aberrant electrical activity at the site of injury. Injury-related alterations in the regulatory activities of NPY released within the DRG at somally-distributed Y-receptors may also contribute to the development and/or persistence of symptoms characteristic of sympathetically-maintained pain. Finally, at later times NPY-mediated modulation of NE release from invading sympathetic axon terminals within the DRG may affect the extent of α 2 receptor-mediated neuronal hyperexcitability associated with neuropathic pain.

To determine the level of pain that acutely burned children experience, we obtained pain scores before, during and after burn dressing change (BDC). Pain scores were higher during the BDC, consistent with severe pain during this procedure. A positive correlation between pain scores and the body surface area (BSA) burned suggests that pain increases with the size of the burn. Contrary to widely held beliefs, comparison of mean pain scores and the percent of 3rd degree burn revealed that the larger the area of full-thickness injury, the greater the pain. Regardless of wide variations in patient characteristics, fixed doses of oral narcotics were usually prescribed for pain. Patients with BSA greater than 70% experienced severe pain during BDC despite the type, dose or route of opioids. These findings suggest the need for (a) education to correct the myth that 'third-degree burns don't hurt'; (b) revision of analgesic prescribing patterns in the burned child; and (c) research to determine the mechanisms (e.g., tolerance or deafferentation) underlying the opioid-resistant nature of pain after large burns.

The need for better analgesia during burn dressing changes (BDCs) in acutely burned children led us to assess pain during BDC with a large 0-10 thermometer-like scale which was well accepted and appeared to reflect the varying degrees of pain that patients experienced. Pain scores were obtained at least once each minute throughout 33 BDCs in 15 patients of 8-17 years. Plasma levels of beta-endorphin immunoactivity (iB-EP) were measured at 5 intervals before and after BDC; mean values (+/- S.E.M.) ranged from 30.5 +/- 4.63 pg/ml (before BDC and analgesic) to 19.2 +/- 3.02 pg/ml (immediately following BDC). The mean pain score (MPS) for each BDC was inversely related to the iB-EP levels of that day (P less than 0.001 with 4 of the 5 iB-EP determinations). The MPS varied directly with the extent of burn injury and inversely with weight; the 2 variables together predicted MPS as well as the iB-EP alone (r2 = 43 and 36% respectively).