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Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results.

Several different reporting biases cited in scientific literature have raised concerns about the overestimation of effects and the subsequent potential impact on the practice of evidence-based medicine and human health. Up to 7-8% of the population experiences neuropathic pain, and established treatment guidelines are based predominately on published, clinical trial results. Therefore, we examined published randomized controlled trials (RCTs) of first-line drugs for neuropathic pain and assessed the relative proportions with statistically significant (i.e., positive) and non-significant (i.e., negative) results and their rates of citation. We determined the relationships between reported study outcome and the frequency of their citations with journal impact factor, sample size, time to publication after study completion, and study quality metrics. We also examined the association of study outcome with maximum study drug dosage and conflict of interest. We found that of 107 published RCTs, 68.2% reported a statistically significant outcome regarding drug efficacy for chronic peripheral and central neuropathic pain. Positive studies were cited nearly twice as often as negative studies in the literature (P=0.01), despite similar study sample size, quality metrics, and publication in journals with similar impact factors. The time to publication, journal impact factor, and conflict of interest did not differ statistically between positive and negative studies. Our observations that negative and positive RCTs were published in journals with similar impact at comparable time-lags after study completion are encouraging. However, the citation bias for positive studies could affect the validity and generalization of conclusions in literature and potentially influence clinical practice.

Agonists to subtype C of the Mas-related G-protein-coupled receptors (MrgC) induce pain inhibition after intrathecal (i.t.) administration in rodent models of nerve injury. Here, we investigated whether tolerance develops after repeated MrgC agonist treatments and examined the underlying mechanisms. In animal behavior studies conducted in male rats at 4 to 5 weeks after an L5 spinal nerve ligation (SNL), the ability of dipeptide MrgC agonist JHU58 (0.1 mM, 10 μL, i.t.) to inhibit mechanical and heat hypersensitivity decreased after 3 days of treatment with a tolerance-inducing dose (0.5 mM, 10 μL, i.t., twice/day). In HEK293T cells, acute treatment with JHU58 or BAM8-22 (a large peptide MrgC agonist) led to MrgC endocytosis from the cell membrane and later sorting to the membrane for reinsertion. However, chronic exposure to JHU58 increased the coupling of MrgC to β-arrestin-2 and led to the ubiquitination and degradation of MrgC. Importantly, pretreatment with TAK-243 (0.2 mM, 5 μL, i.t.), a small-molecule inhibitor of the ubiquitin-activating enzyme, during tolerance induction attenuated the development of tolerance to JHU58-induced inhibition of mechanical and heat hypersensitivity in SNL rats. Interestingly, morphine analgesia was also decreased in SNL rats that had become tolerant to JHU58, suggesting a cross-tolerance. Furthermore, i.t. pretreatment with TAK-243, which reduced JHU58 tolerance, also attenuated the cross-tolerance to morphine analgesia. These findings suggest that tolerance can develop to MrgC agonist-induced pain inhibition after repeated i.t. administrations. This tolerance development to JHU58 may involve increased coupling of MrgC to β-arrestin-2 and ubiquitin-mediated receptor degradation.

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.

Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.

Neuropathic pain (NP) resulting from injury or disease of the somatosensory system is a common, debilitating chronic disorder that significantly undermines quality of life. Preclinical and clinical studies have considerably advanced our understanding of the myriad peripheral and central changes in neuronal and non-neuronal cells associated with persistent pain states. Disappointingly, advances in clinical therapies for NP have not paralleled the substantial advances in basic science. Most drugs currently used for the treatment of NP bind to receptors that are widely expressed in the peripheral and central nervous systems, and hence are frequently associated with adverse effects. Therefore, identifying key targets involved in the initiation and maintenance of NP in the periphery, with guidance from meticulous clinical evidence, merits renewed focus. We consider the relative importance of peripheral and central mechanisms and present several lines of clinical and preclinical evidence supporting the tenet that spontaneous and ectopic activity in primary afferent neurons plays a critical role in NP. Several potential peripheral “pain generator” sites have been identified, and defining their role in NP states of different etiologies is important for targeted therapy. Hyperexcitability of peripheral neurons may represent a “low-hanging target” in the development of safe therapies for a subset of patients with NP. We summarize work from our group and others that identifies potential peripheral drug targets, including peripheral opioid receptors, involved in the modulation of NP. In future drug development efforts, therapies directed at peripheral mechanisms may offer potential advantages over current CNS-penetrating drugs, including minimal adverse effects.

Several reports support the idea that μ- and δ-opioid receptors (ORs) may exist as heterodimers in brain regions involved in pain signaling. The unique pharmacology of these heteromers may present a novel analgesic target. However, the role of μ-δ heteromers in sensory neurons involved in pain and opioid analgesia remains unclear, particularly during neuropathic pain. We examined the effects of spinal nerve injury on μ-δ heteromer expression in dorsal root ganglion (DRG) neurons and the effects of a μ-δ heteromer–targeting agonist, CYM51010, on neuropathic pain behavior in rats and mice. An L5 spinal nerve ligation (SNL) in rats significantly decreased μ-δ heteromer expression in L5 DRG, but increased heteromer levels in uninjured L4 DRG. Importantly, in SNL rats, subcutaneous (s.c.) injection of CYM51010 inhibited mechanical hypersensitivity in a dose-related manner (EC(50): 1.09 mg/kg) and also reversed heat hyperalgesia and attenuated ongoing pain (2 mg/kg, s.c.). HEK-293T cells surface-labeled with μ- and δ-ORs internalized both receptors after exposure to CYM51010. In contrast, in cells transfected with μ-OR alone, CYM51010 was significantly less effective at inducing receptor internalization. Electrophysiologic studies showed that CYM51010 inhibited the C-component and windup phenomenon in spinal wide-dynamic range neurons of SNL rats. The pain inhibitory effects of CYM51010 persisted in morphine-tolerant rats, but was markedly attenuated in μ-OR knockout mice. Our studies show that spinal nerve injury may increase μ-δ heterodimerization in uninjured DRG neurons and that μ-δ heteromers may be a potential therapeutic target for relieving neuropathic pain, even under conditions of morphine tolerance.

Opioid use for chronic pain is limited by severe central adverse effects. We examined whether activating mu-opioid receptors (MORs) in the peripheral nervous system attenuates spinal cord injury (SCI) pain-like behavior in mice. We produced a contusive SCI at the T10 vertebral level and examined motor and sensory dysfunction for 6 weeks. At 6 weeks, we tested the effect of subcutaneous (s.c.) injection of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a peripherally acting MOR-preferring agonist, on mechanical and heat hypersensitivity. Basso mouse scale score was significantly decreased after SCI, and mice showed hypersensitivity to mechanical and heat stimulation at the hind paw beginning at 2 weeks, as indicated by increased paw withdrawal frequency to mechanical stimulation and decreased paw withdrawal latency to heat stimulation. In wild-type SCI mice, DALDA (1 mg/kg, s.c.) attenuated heat but not mechanical hypersensitivity. The effect was blocked by pretreatment with an intraperitoneal injection of methylnaltrexone (5 mg/kg), a peripherally restricted opioid receptor antagonist, and was also diminished in Pirt-MOR conditional knockout mice. DALDA did not adversely affect exploratory activity or induced preference to drug treatment in SCI mice. In vivo calcium imaging showed that DALDA (1, 10 mg/kg, s.c.) inhibited responses of small dorsal root ganglion neurons to noxious heat stimulation in Pirt-GCaMP6s mice after SCI. Western blot analysis showed upregulation of MOR in the lumbar spinal cord and sciatic nerves at 6 weeks after SCI. Our findings suggest that peripherally acting MOR agonist may inhibit heat hypersensitivity below the injury level with minimal adverse effects.

Cross-over trials are typically more efficient than parallel group trials in that the sample size required to yield a desired power is substantially smaller. It is important, however, to consider some issues specific to cross-over trials when designing and reporting them, and when evaluating the published results of such trials. This systematic review evaluated the quality of reporting and its evolution over time in articles of cross-over clinical trials of pharmacologic treatments for chronic pain published between 1993 and 2013. Seventy-six (61%) articles reported a within-subject primary analysis, or if no primary analysis was identified, reported at least 1 within-subject analysis, which is required to achieve the gain in power associated with the cross-over design. For 39 (31%) articles, it was unclear whether analyses conducted were within-subject or between-group. Only 36 (29%) articles reported a method to accommodate missing data (eg, last observation carried forward, n = 29), and of those, just 14 included subjects in the analysis who provided data from only 1 period. Of the articles that identified a within-subject primary analysis, 21 (51%) provided sufficient information for the results to be included in a meta-analysis (ie, estimates of the within-subject treatment effect and variability). These results and others presented in this article demonstrate deficiencies in reporting of cross-over trials for analgesic treatments. Clearer reporting in future trials could improve readers' ability to critically evaluate the results, use these data in meta-analyses, and plan future trials. Recommendations for proper reporting of cross-over trials that apply to any condition are provided.

Multiple recent pharmacological clinical trials in neuropathic pain have failed to show beneficial effect of drugs with previously demonstrated efficacy, and estimates of drug efficacy seems to have decreased with accumulation of newer trials. However, this has not been systematically assessed. Here, we analyze time-dependent changes in estimated treatment effect size in pharmacological trials together with factors that may contribute to decreases in estimated effect size. This study is a secondary analysis of data from a previous published NeuPSIG systematic review and meta-analysis, updated to include studies published up till March 2017. We included double-blind, randomized, placebo-controlled trials examining the effect of drugs for which we had made strong or weak recommendations for use in neuropathic pain in the previously published review. As the primary outcome, we used an aggregated number needed to treat for 50% pain reduction (alternatively 30% pain reduction or moderate pain relief). Analyses involved 128 trials. Number needed to treat values increased from around 2 to 4 in trials published between 1982 and 1999 to much higher (less effective) values in studies published from 2010 onwards. Several factors that changed over time, such as larger study size, longer study duration, and more studies reporting 50% or 30% pain reduction, correlated with the decrease in estimated drug effect sizes. This suggests that issues related to the design, outcomes, and reporting have contributed to changes in the estimation of treatment effects. These factors are important to consider in design and interpretation of individual study data and in systematic reviews and meta-analyses.

This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings.

Electrical stimulation of low-threshold Aβ-fibers (Aβ-ES) is used clinically to treat neuropathic pain conditions that are refractory to pharmacotherapy. However, it is unclear how Aβ-ES modulates synaptic responses to high-threshold afferent inputs (C-, Aδ-fibers) in superficial dorsal horn. Substantia gelatinosa (SG) (lamina II) neurons are important for relaying and modulating converging spinal nociceptive inputs. We recorded C-fiber-evoked excitatory postsynaptic currents (eEPSCs) in spinal cord slices in response to paired-pulse test stimulation (500 μA, 0.1 millisecond, 400 milliseconds apart). We showed that 50-Hz and 1000-Hz, but not 4-Hz, Aβ-ES (10 μA, 0.1 millisecond, 5 minutes) induced prolonged inhibition of C-fiber eEPSCs in SG neurons in naive mice. Furthermore, 50-Hz Aβ-ES inhibited both monosynaptic and polysynaptic forms of C-fiber eEPSC in naive mice and mice that had undergone spinal nerve ligation (SNL). The paired-pulse ratio (amplitude second eEPSC/first eEPSC) increased only in naive mice after 50-Hz Aβ-ES, suggesting that Aβ-ES may inhibit SG neurons by different mechanisms under naive and nerve-injured conditions. Finally, 50-Hz Aβ-ES inhibited both glutamatergic excitatory and GABAergic inhibitory interneurons, which were identified by fluorescence in vGlut2-Td and glutamic acid decarboxylase-green fluorescent protein transgenic mice after SNL. These findings show that activities in Aβ-fibers lead to frequency-dependent depression of synaptic transmission in SG neurons in response to peripheral noxious inputs. However, 50-Hz Aβ-ES failed to induce cell-type-selective inhibition in SG neurons. The physiologic implication of this novel form of synaptic depression for pain modulation by Aβ-ES warrants further investigation.

Mas-related G-protein-coupled receptor subtype C (mouse MrgC11 and rat rMrgC), expressed specifically in small-diameter primary sensory neurons, may constitute a novel pain inhibitory mechanism. We have shown previously that intrathecal administration of MrgC-selective agonists can strongly attenuate persistent pain in various animal models. However, the underlying mechanisms for MrgC agonist-induced analgesia remain elusive. Here, we conducted patch-clamp recordings to test the effect of MrgC agonists on high-voltage-activated (HVA) calcium current in small-diameter dorsal root ganglion (DRG) neurons. Using pharmacological approaches, we show for the first time that an MrgC agonist (JHU58) selectively and dose-dependently inhibits N-type, but not L- or P/Q-type, HVA calcium channels in mouse DRG neurons. Activation of HVA calcium channels is important to neurotransmitter release and synaptic transmission. Patch-clamp recordings in spinal cord slices showed that JHU58 attenuated the evoked excitatory postsynaptic currents in substantia gelatinosa (SG) neurons in wild-type mice, but not in Mrg knockout mice, after peripheral nerve injury. These findings indicate that activation of endogenously expressed MrgC receptors at central terminals of primary sensory fibers may decrease peripheral excitatory inputs onto SG neurons. Together, these results suggest potential cellular and molecular mechanisms that may contribute to intrathecal MrgC agonist-induced analgesia. Because MrgC shares substantial genetic homogeneity with human MrgX1, our findings may suggest a rationale for developing intrathecally delivered MrgX1 receptor agonists to treat pathological pain in humans and provide critical insight regarding potential mechanisms that may underlie its analgesic effects.

Chronic neuropathic pain is often refractory to current pharmacotherapies. The rodent Mas-related G-protein-coupled receptor subtype C (MrgC) shares substantial homogeneity with its human homologue, MrgX1, and is located specifically in small-diameter dorsal root ganglion neurons. However, evidence regarding the role of MrgC in chronic pain conditions has been disparate and inconsistent. Accordingly, the therapeutic value of MrgX1 as a target for pain treatment in humans remains uncertain. Here, we found that intrathecal injection of BAM8-22 (a 15-amino acid peptide MrgC agonist) and JHU58 (a novel dipeptide MrgC agonist) inhibited both mechanical and heat hypersensitivity in rats after an L5 spinal nerve ligation (SNL). Intrathecal JHU58-induced pain inhibition was dose dependent in SNL rats. Importantly, drug efficacy was lost in Mrg-cluster gene knockout (Mrg KO) mice and was blocked by gene silencing with intrathecal MrgC siRNA and by a selective MrgC receptor antagonist in SNL rats, suggesting that the drug action is MrgC dependent. Further, in a mouse model of trigeminal neuropathic pain, microinjection of JHU58 into ipsilateral subnucleus caudalis inhibited mechanical hypersensitivity in wild-type but not Mrg KO mice. Finally, JHU58 attenuated the miniature excitatory postsynaptic currents frequency both in medullary dorsal horn neurons of mice after trigeminal nerve injury and in lumbar spinal dorsal horn neurons of mice after SNL. We provide multiple lines of evidence that MrgC agonism at spinal but not peripheral sites may constitute a novel pain inhibitory mechanism that involves inhibition of peripheral excitatory inputs onto postsynaptic dorsal horn neurons in different rodent models of neuropathic pain.

Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials.

Studies in experimental models and controlled patient trials indicate that opioids are effective in managing neuropathic pain. However, side effects secondary to their central nervous system actions present barriers to their clinical use. Therefore, we examined whether activation of the peripheral mu-opioid receptors (MORs) could effectively alleviate neuropathic pain in rats after L5 spinal nerve ligation (SNL). Systemic loperamide hydrochloride (0.3-10 mg/kg, s.c.), a peripherally acting MOR-preferring agonist, dose-dependently reversed the mechanical allodynia at day 7 post-SNL. This anti-allodynic effect produced by systemic loperamide (1.5mg/kg, s.c.) was blocked by systemic pretreatment with either naloxone hydrochloride (10 mg/kg, i.p.) or methyl-naltrexone (5 mg/kg, i.p.), a peripherally acting MOR-preferring antagonist. It was also blocked by ipsilateral intraplantar pretreatment with methyl-naltrexone (43.5 microg/50 microl) and the highly selective MOR antagonist CTAP (5.5 microg/50 microl). However, this anti-allodynic effect of systemic loperamide was not blocked by intraplantar pretreatment with the delta-opioid receptor antagonist naltrindole hydrochloride (45.1 microg/50 microl). The anti-allodynic potency of systemic loperamide varied with time after nerve injury, with similar potency at days 7, 28, and 42 post-SNL, but reduced potency at day 14 post-SNL. Ipsilateral intraplantar injection of loperamide also dose-dependently (10-100 microg/50 microl) reversed mechanical allodynia on day 7 post-SNL. We suggest that loperamide can effectively attenuate neuropathic pain, primarily through activation of peripheral MORs in local tissue. Therefore, peripherally acting MOR agonists may represent a promising therapeutic approach for alleviating neuropathic pain.

For genetic research to contribute more fully to furthering our knowledge of neuropathic pain, we require an agreed, valid, and feasible approach to phenotyping, to allow collaboration and replication in samples of sufficient size. Results from genetic studies on neuropathic pain have been inconsistent and have met with replication difficulties, in part because of differences in phenotypes used for case ascertainment. Because there is no consensus on the nature of these phenotypes, nor on the methods of collecting them, this study aimed to provide guidelines on collecting and reporting phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity and feasibility; and (3) meeting of experts to reach consensus on the optimal phenotype(s) to be collected from patients with neuropathic pain for genetic studies. A basic "entry level" set of phenotypes was identified for any genetic study of neuropathic pain. This set identifies cases of "possible" neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration, any formal diagnosis). This NeuroPPIC "entry level" set of phenotypes can be expanded by more extensive and specific measures, as determined by scientific requirements and resource availability.

Neuropathic pain is a priority health issue [5], which currently is the topic of the 2014–2015 Global Year Against Neuropathic Pain campaign of the International Association for the Study of Pain (http://www.iasp-pain.org/GlobalYear/NeuropathicPain). Between 6% and 10% of adults are affected by chronic pain with neuropathic features [6,14,25], and this prevalence is significantly greater among individuals with specific conditions. For example, neuropathic pain is a common comorbidity in infectious diseases such as HIV, leprosy, and herpes zoster, and in non-infectious conditions such as diabetes mellitus, stroke, multiple sclerosis, and traumatic limb and spinal cord injury [7,13,16,19,21]. The pain is associated with significant decreases in quality of life and socioeconomic well-being, even more so than non-neuropathic chronic pain [9,20,22]. Developing and emerging countries share the greatest burden of conditions that predispose to development of neuropathic pain [5,10], and can ill afford the negative consequences of this pain. There are medicines with proven efficacy in the treatment of neuropathic pain [11,12]. Nevertheless, the pain can be difficult to treat, with significant inter-individual variation in efficacy within and between drug classes, independent of the presumed aetiology of the neuropathy [2,4]. Effective management of neuropathic pain within a population therefore requires access to a small, but crucial group of drug classes with proven efficacy. The World Health Organization’s (WHO) model list of essential medicines (http://www.who.int/selection_medicines/list/en/) presents those medicines deemed necessary to meet priority health needs, and local implementation of essential medicines policies is associated with improved quality use of medicines [15,18]. But, none of the analgesic medicines included in the WHO model list are recommended as first-line treatments for neuropathic pain [11]. Thus the WHO model list is not a good framework from which national policies on managing neuropathic pain can be structured and countries routinely adapt the model list according to local needs and resources [18]. To estimate the nominal availability of medicines recommended for the treatment of neuropathic pain in developing and emerging countries, we assessed national essential medicines lists (NEMLs) for the inclusion of recommended treatments. We also assessed whether the coverage of recommended drugs classes on these NEMLs was dependent on countries’ economic status.

Nitric oxide (NO) acts as a neurotransmitter or neuromodulator involving in the modulation of thermal and/or inflammatory hyperalgesia. The neuronal nitric oxide synthase (nNOS) is a key enzyme for NO production in normal neuronal tissues, but its functional role in chronic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to address the role of nNOS in the central mechanism of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. Targeted disruption of the nNOS gene significantly reduced CFA-induced mechanical pain hypersensitivity during the maintenance (but not the development) of inflammatory pain, while it failed to attenuate either development or maintenance of CFA-induced thermal pain hypersensitivity. Intraperitoneal administration of L-N G -nitro-arginine methyl ester (L-NAME), a non-specific NOS inhibitor, blocked CFA-evoked thermal and mechanical pain hypersensitivity at both development (2 h) and maintenance (24 h) phase in wild type mice, but had no effect in the knockout mice. Furthermore, intrathecal injection of either L-NAME or 7-nitroindazole, a selective nNOS inhibitor, markedly attenuated mechanical pain hypersensitivity at both 2 and 24 h after CFA injection. Finally, spinal cord nNOS (but not endothelial NOS or inducible NOS) expression was up-regulated at 24 h after CFA injection, occurring mainly in the ipsilateral superficial dorsal horn. Together, these data indicate that spinal cord nNOS may be essential for the maintenance of mechanical pain hypersensitivity and that it may also be sufficient for the development of mechanical pain hypersensitivity and for the development and maintenance of thermal pain hypersensitivity after chronic inflammation. Our findings suggest that spinal cord nNOS might play a critical role in central mechanisms of the development and/or maintenance of chronic inflammatory pain.

P2X3 is an ATP-gated cation channel subtype expressed by a subpopulation of primary sensory neurons. In vivo spinal cord recordings in mice lacking P2X3 ( P 2 X 3 − / − ) have suggested that this protein may be important for the coding of peripheral warm stimuli. To explore this possibility more thoroughly, we examined behavioral and electrophysiological responses to thermal stimuli in P 2 X 3 − / − mice. As previously reported, recording from the spinal cord dorsal horn of anesthetized P 2 X 3 − / − mice revealed a blunted response of wide dynamic range neurons to hind paw heating. When placed in a thermal gradient, however, P 2 X 3 − / − mice exhibited an unexpectedly enhanced avoidance of both hot and cold temperatures, relative to controls. In the tail immersion test, mutant mice exhibited shorter withdrawal latencies at temperatures above and below thermoneutrality. Consistent with these changes, P 2 X 3 − / − mice exhibited enhanced induction of spinal cord c-FOS following hind paw heating to 45 °C. Thus, gain- and loss-of-function thermosensory phenotypes coexist in P 2 X 3 − / − mice. No changes in thermal preference were observed in wild-type mice injected subcutaneously with the P2X3 antagonist, A317491 or intrathecally with the P2X3 and P2X1 antagonist TNP-ATP. The reason for this apparent discrepancy is unclear, but we cannot exclude the possibility that compensatory events contribute, at least in part, to the P 2 X 3 − / − phenotype. Regardless, this study illustrates the utility of thermal preference assays as part of a comprehensive approach to the analysis of mouse thermosensation.

Postoperative pain significantly impacts patient recovery. However, postoperative pain management remains suboptimal, perhaps because treatment strategies are based mainly on studies using inflammatory pain models. We used a recently developed mouse model of incisional pain to investigate peripheral and spinal mechanisms contributing to heat hyperalgesia after incision. Behavioral experiments involving TRPV1 KO mice demonstrate that, as previously observed in inflammatory models, TRPV1 is necessary for heat (but not mechanical) hyperalgesia after incision. However, in WT mice, neither the proportion of TRPV1 immunoreactive neurons in the DRG nor the intensity of TRPV1 staining in the sciatic nerve was different from that in controls up to 4 days after incision. This result was corroborated by immunoblot analysis of sciatic nerve in rats subjected to an incision, and is distinct from that following inflammation of the rat hind paw, a situation in which TRPV1 expression levels in sciatic nerve increases. In the absence of heat exposure, spinal c-Fos staining was similar between incised TRPV1 KO and WT mice. However, differences in c-Fos staining between heat exposed TRPV1 KO and WT mice after incision suggest that the incision-mediated enhancement of heat-evoked signaling to the spinal cord involves a TRPV1-dependent mechanism. Finally, heat hyperalgesia after incision was reversed by antagonism of spinal non-NMDA receptors, unlike inflammatory hyperalgesia, which is mediated via NMDA receptors . Thus, TRPV1 is important for the generation of thermal hyperalgesia after incision. Our observations suggest that all experimental pain models may not be equally appropriate to guide the development of postoperative pain therapies.

Post-herpetic neuralgia (PHN) is a neuropathic pain state that is often difficult to treat. Although frequently discussed in the clinical literature, little is known about the impact of pain on daily function and the extent to which psychosocial factors, in particular pain coping strategies, influence adaptation to this chronic illness. In the context of a crossover pharmacological trial, 68 patients with PHN completed a battery of psychological measures during a first drug-free baseline period. Following discontinuation of approximately 8 weeks of treatment, 49 of these patients completed data collection during a second drug-free assessment prior to beginning a second drug phase. Twice-weekly telephone pain ratings were combined with questionnaire measures of perceived interference due to pain, overall activity level, depressive symptoms, and pain coping strategies. Cross-sectional hierarchical regression analyses indicated that catastrophizing correlated with depressive symptoms but not pain, and coping self-statements were correlated with higher levels of overall activity. Prospective hierarchical regression analyses indicated that catastrophizing at baseline predicted level of pain 8 weeks later, an effect that was independent of baseline pain and depressive symptoms. Patients who reported increasing their activity in response to pain also reported more perceived interference due to pain 8 weeks later. Higher levels of ignoring pain sensations at baseline were prospectively correlated with more depressive symptoms 8 weeks later. These findings support a role for the continued investigation of cognitive-behavioral factors affecting the adaptation of elderly individuals experiencing PHN.

The development of adrenergic sensitivity in nociceptors has been suggested as a mechanism of neuropathic pain. We sought to determine if nociceptors in the skin of normal subjects exhibit adrenergic sensitivity. We investigated the effects of intradermal administration of norepinephrine, phenylephrine, and brimonidine on heat pain sensitivity. Norepinephrine and phenylephrine (in concentrations ranging from 0.1 to 10 microM by factors of 10), brimonidine (at 0.01-1 microM), and saline were injected (30 microl volume) in a random, double-blind manner to different sites on the volar surface of the forearm in ten subjects. Before and after the injections, heat testing was performed with a non-contact laser thermal stimulator. Heat pain threshold was measured by means of a 'Marstock' technique in which subjects pressed a reaction time key when they perceived that a slowly increasing heat stimulus (1 degrees C/s ramp from a 36 degrees C base) was painful. In addition, the subjects used magnitude estimation techniques to rate the intensity of pain to a suprathreshold heat stimulus (47 degrees C, 2 s). Mechanical testing was done using 200-microm diameter probes attached to calibrated weights that provided forces over the range of 16-512 mN. The intradermal injections of norepinephrine, phenylephrine and brimonidine produced little evoked pain. However, a dose-dependant decrease in heat pain threshold, but not mechanical pain threshold, was observed. At the highest drug dose injected, all three adrenergic compounds produced a significant decrease in heat pain threshold compared to the saline injection. A significant increase in response to the suprathreshold heat stimulus was also found. One possible explanation for this apparent heat hyperalgesia is that the decrease in perfusion due to the localized vasoconstriction may alter the heat response. However, in control studies we found that the non-adrenergic vasoconstrictors, angiotensin II and vasopressin did not produce heat hyperalgesia at doses that produced comparable decreases in blood flow. In addition, occlusion of blood flow with a blood pressure cuff did not lead to heat hyperalgesia. Thus, the heat hyperalgesia observed with the adrenergic agonists is not due to a decrease in perfusion associated with the injection. These results indicate that alpha(1)- and alpha(2)-adrenoceptor-mediated mechanisms may play a role in sensitization of nociceptors to heat stimuli in normal skin.

Tissue injuries, with or without involvement of nerves, may lead to ongoing pain and hyperalgesia to external stimuli. In a subset of patients, the pain is maintained by sympathetic efferent activity (SMP). We investigated if the peripheral administration of the alpha-adrenergic agonist, norepinephrine (NE), in physiologically relevant doses resulted in pain in patients with SMP. To establish the dose of intradermal NE required to induce cutaneous vasoconstriction, NE (1 nM-10 microM, 30 microl) was injected under a laser Doppler probe on the volar forearm of seven normal subjects. A decrease in blood flow was evident at a dose of 10 microM. Twelve patients (five male, seven female) diagnosed to have SMP based on the decrease in pain by a local anesthetic sympathetic blockade (70+/-6%) were enrolled in the study. Pain ratings were obtained continuously for 5 min after intradermal injections of saline and NE (0.1-10 microM) into their hyperalgesic zone and the mirror-image contralateral side. Injections were done during the period of pain relief following a local anesthetic sympathetic blockade. Similar injections were made in eight control subjects. On the affected side of the patients, the two highest concentrations of NE (1 and 10 microM) caused significantly more pain than saline (P

The L5 spinal nerve ligation model of neuropathic pain in rats has been proposed as a model for sympathetically maintained pain (SMP) based on the effects of surgical or chemical sympathectomy on nerve injury induced behavior. In an attempt to confirm that the lesion produces an animal model of SMP, surgical sympathectomies were independently conducted in two different laboratories (Johns Hopkins and University Kiel) using male Sprague-Dawley (n = 30) or Wistar rats (n = 14). The L5 spinal nerve was ligated or cut and ligated. Using von Frey hairs, paw withdrawal threshold and incidence of paw withdrawal were tested concurrently before and after the sympathectomy. The sympathectomy was either verified by (a) glyoxylic acid staining of peripheral blood vessels of the hindpaw or (b) skin temperature measurements of the hindpaws. To blind the experimenter, surgeries and behavioral tests were performed by two different investigators and a sham sympathectomy was performed at Johns Hopkins. Decreased paw withdrawal thresholds and increased frequencies of paw withdrawal on the lesioned side were observed after the L5 lesion. Thus, the L5 spinal nerve ligation resulted in behavioral signs of allodynia and hyperalgesia to mechanical stimuli. Lumbar surgical sympathectomy 1-3 weeks after the lesion or prior to lesion with bilateral removal of the sympathetic ganglia L2-L4, however, did not reverse or prevent the behavioral changes induced by the nerve injury. The lack of effect of the sympathectomies was independent of the testing paradigm used. Experiments in Wistar and Sprague-Dawley rats yielded the same results. Potential reasons for the discrepancies between the present study and earlier reports are discussed. These results indicate that an L5 spinal nerve injury rat model is not a reliable model for SMP.

Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost-effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia, with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic–pharmacodynamic relationships, and minimization of missing data. Efficiency of single-dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N-of-1 designs, enriched designs, adaptive designs, and sequential parallel comparison designs, are summarized, and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.

Peripherally acting opioids are potentially attractive drugs for the clinical management of certain chronic pain states due to the lack of centrally mediated adverse effects. However, it remains unclear whether tolerance develops to peripheral opioid analgesic effects under neuropathic pain conditions. We subjected rats to L5 spinal nerve ligation (SNL) and examined the analgesic effects of repetitive systemic and local administration of loperamide hydrochloride, a peripherally acting opioid agonist. We found that the inhibition of mechanical hypersensitivity, an important manifestation of neuropathic pain, by systemic loperamide (1.5 mg/kg subcutaneously) decreased after repetitive drug treatment (tolerance-inducing dose: 0.75 to 6.0 mg/kg subcutaneously). Similarly, repeated intraplantar injection of loperamide (150 μg/50 μL intraplantarly) and D-Ala2-MePhe4-Glyol5 enkephalin (300 μg/50 μL), a highly selective mu-opioid receptor (MOR) agonist, also resulted in decreased inhibition of mechanical hypersensitivity. Pretreatment with naltrexone hydrochloride (5 mg/kg intraperitoneally) and MK-801 (0.2 mg/kg intraperitoneally) attenuated systemic loperamide tolerance. Western blot analysis showed that repetitive systemic administration of morphine (3 mg/kg subcutaneously), but not loperamide (3 mg/kg subcutaneously) or saline, significantly increased MOR phosphorylation in the spinal cord of SNL rats. In cultured rat dorsal root ganglion neurons, loperamide dose-dependently inhibited KCl-induced increases in [Ca2+]i. However, this drug effect significantly decreased in cells pretreated with loperamide (3 μM, 72 hours). Intriguingly, in loperamide-tolerant cells, the delta-opioid receptor antagonist naltrindole restored loperamide’s inhibition of KCl-elicited [Ca2+]i increase. Our findings indicate that animals with neuropathic pain may develop acute tolerance to the antiallodynic effects of peripherally acting opioids after repetitive systemic and local drug administration.

Patients with reflex sympathetic dystrophy or causalgia characteristically have ongoing pain and pain to light touch (hyperalgesia). Some of these patients obtain relief of their pain following interruption of sympathetic function to the affected area and, therefore, have sympathetically maintained pain (SMP). Evidence suggests that the pain and hyperalgesia in SMP are related to activation of peripheral adrenergic receptors. We wished to determine the contribution of alpha 1- and alpha 2-adrenergic receptors in SMP and thus examined the effects of local application of adrenergic agents in patients with SMP. The alpha 2-adrenergic agonist clonidine, available as a transdermal patch, was delivered topically to the patients' hyperalgesic skin. In four patients with SMP, clonidine eliminated or substantially reduced hyperalgesia to mechanical and cold stimuli. In three of these patients the effects were confined to the skin region beneath the patch, suggesting a peripheral and not central effect. The relief of hyperalgesia was not due to a local anesthetic effect since touch thresholds were unaffected. Topical clonidine did not relieve hyperalgesia of similar severity for two other patients whose hyperalgesia and pain were unaffected by sympathetic ganglion blocks (i.e., diagnosed as having sympathetically independent pain). In two SMP patients, intradermal injection of norepinephrine or phenylephrine (a specific alpha 1-adrenergic agonist) at a site treated with clonidine evoked intense pain and rekindled the pre-clonidine hyperalgesia at that site. It is likely that clonidine locally blocks the release of norepinephrine via activation of alpha 2 receptors on the sympathetic terminals. This study suggests, therefore, that SMP is mediated via alpha 1-adrenergic receptors located in the affected tissue.

The development of α -adrenergic sensitivity in cutaneous nociceptors has been postulated as a mechanism for sympathetically maintained pain (SMP). In order to characterize the adrenergic receptors involved, we investigated the effects of intraplantar administration of α 1 -(prazosin) and α 2 -(yohimbine) adrenergic antagonists and systemic injection of phentolamine, a non-specific α -adrenergic blocker, on allodynic/hyperalgesic behavior in an animal model thought to mimic SMP in humans. Peripheral neuropathy in rats was induced by tight ligation of the L5/L6 spinal nerves. Mechanical hyperalgesia was quantified with von Frey hairs applied either for 3 s or repetitively to the plantar surface of the hindpaw. Responses to the 3 s duration stimulus were used to determine the paw withdrawal threshold with the up–down paradigm and repetitive stimuli were used to determine the response incidence of paw withdrawal to a given von Frey hair. Mechanical thresholds on the ipsilateral paw decreased significantly after ligation and were stable over the following 3 weeks. Intradermal administration of yohimbine or prazosin did not significantly alleviate mechanical hyperalgesia in L5/L6 ligated animals. Also systemic administration of phentolamine (1 and 5 mg/kg) did not alleviate the increased incidence of paw withdrawal in L5/L6 spinal nerve ligated animals. These results suggest that an alpha adrenergic interaction between sympathetic efferent and somatic afferent fibers does not play a critical role for the maintenance of mechanical hyperalgesia in this model for neuropathic pain.

Systemic phentolamine administration has been suggested as a diagnostic tool for identifying patients with sympathetically maintained pain (SMP) (Raja et al. 1991). The dose of phentolamine to produce adequate blockade of peripheral alpha-adrenoceptor function has, however, not been previously determined. In this study, the effects of two different doses of phentolamine on peripheral sympathetic vasoconstrictor function were investigated. One-hundred and seventeen (117) patients with chronic extremity pain underwent 130 phentolamine diagnostic tests using two different doses of phentolamine (0.5 mg/kg over 20 min (n = 60) and 1 mg/kg over 10 min (n = 59)). Eleven (11) patients did not receive phentolamine during the test. Cutaneous temperature was measured in the distal extremity before and after administration of phentolamine. In a subset of patients, baseline blood flow and sympathetically mediated vasoconstrictor response (SMR) to deep inhalation were measured on glabrous skin using laser Doppler flowmetry. SMR was elicited with a 5-sec maximal inspiratory gasp. A dose-related increase in cutaneous temperature was observed. In addition, baseline blood flow increased and SMR was attenuated after both doses of phentolamine, but to a greater degree after the 1 mg/kg dose. However, SMR was not completely attenuated, even after administration of the higher phentolamine dose. These results indicate that a phentolamine dose of 1 mg/kg over 10 min more completely blocks alpha-adrenoceptor function than a dose of 0.5 mg/kg over 20 min. We therefore recommend that to ensure adequate alpha-adrenoceptor blockade the higher phentolamine dose be used in the phentolamine diagnostic test for SMP.

Bradykinin is an endogenous peptide that is thought to be a chemical mediator of the hyperalgesia following inflammation. In rat, bradykinin has been postulated to cause hyperalgesia to mechanical stimuli by releasing prostaglandin from sympathetic post-ganglionic terminals. The aim of this study was to determine whether bradykinin-induced cutaneous hyperalgesia in humans requires post-ganglionic sympathetic terminals. In humans, intradermal injection of bradykinin produces dramatic hyperalgesia to heat but not mechanical stimuli. Therefore, we measured the magnitude and duration of pain and hyperalgesia to heat stimuli following intradermal injection of bradykinin into the leg of a woman before and 6 months after an ipsilateral, surgical, lumbar sympathectomy. The pain and hyperalgesia to heat following bradykinin was found to be unaffected by the sympathectomy. These results suggest that the algesic effects of cutaneous bradykinin in human are independent of the sympathetic nervous system.

We sought to determine the effects of a cut injury on the thermal responsiveness of C-fiber nociceptors sensitive to heat and mechanical stimuli (CMHs). Teased fiber techniques were used to record from single CMHs that innervated the hairy skin of the monkey arm. Responses to heat stimuli ranging from 41 to 49°C were compared before and after injury. In 11 CMHs, the injury was applied 4 mm peripheral to the edge of the receptive field. The response to the heat sequence was not significantly altered by this adjacent injury. In 16 CMHs, a cut was applied directly to the receptive field. This direct injury led to a significant increase in response to the sequence of heat stimuli (i.e., sensitization). It is concluded that spreading sensitization of C-fiber nociceptors to a cut injury does not occur in monkey.

Pain to light touching of the skin is a hallmark sign of causalgia. The purpose of this study was to determine whether myelinated or unmyelinated afferent fibers signal this hyperalgesia. Sensory testing was performed in 17 patients with long-standing hyperalgesia after nerve injury. The patients underwent a differential ischemic block of nerve function of the involved area. At a time when touch sensation in adjacent normal skin was eliminated, but when sensibility to warming and cooling stimuli was unaffected, the hyperalgesia to mechanical stimuli was abolished in 15 of the subjects. In 2 of these 15 patients, a differential local anesthetic block of the injured nerve was performed proximal to the site of injury. When temperature sensibility was absent, but when touch sensation was intact, hyperalgesia was present. In a third study, latency measurements in response to 400 micron stepped displacement stimuli were made in two patients who had hyperalgesia on the foot. The mean latency for detection of pain in the hyperalgesic region was 414 +/- 18 msec, compared to 458 +/- 16 msec for the detection of touch to the same stimuli applied to the opposite normal foot. These 3 lines of evidence indicate that myelinated primary afferents, perhaps A beta fibers, signal the hyperalgesic pain in causalgia. These fibers may be sensitized A beta nociceptors or low-threshold mechanoreceptors.