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Responder analysis for pain relief and numbers needed to treat in a meta-analysis of etoricoxib osteoarthritis trials: Bridging a gap between clinical trials and clinical practice
Abstract and Figures
Population mean changes from clinical trials are difficult to apply to individuals in clinical practice. Responder analysis may be better, but needs validating for level of response and treatment duration.
The numbers of patients with pain relief over baseline (> or =15%, > or =30%, > or =50%, > or =70%) at 2, 4, 8 and 12 weeks of treatment were obtained using the WOMAC 100 mm visual analogue pain subscale score for each treatment group in seven randomised placebo-controlled trials of etoricoxib in osteoarthritis lasting > or =6 weeks. Dropouts were assigned 0% improvement from baseline from then on. The numbers needed to treat (NNTs) were calculated at each level of response and time point.
3554 patients were treated with placebo, etoricoxib 30 mg and 60 mg, celecoxib 200 mg, naproxen 1000 mg or ibuprofen 2400 mg daily. Response rates fell with increasing pain relief: 60-80% experienced minimally important pain relief (> or =15%), 50-60% moderate pain relief (> or =30%), 40-50% substantial pain relief (> or =50%) and 20-30% extensive pain relief (> or =70%). NNTs for etoricoxib, celecoxib and naproxen were stable over 2-12 weeks. Ibuprofen showed lessening of effectiveness with time.
Responder rates and NNTs are reproducible for different levels of response over 12 weeks and have relevance for clinical practice at the individual patient level. An average 10 mm improvement in pain equates to almost one in two patients having substantial benefit.
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... OA is characterized by the progressive destruction of the articular cartilage and joint integrity [3]. Pain is the major problem for patients with osteoarthritis [4], and commonly used analgesics have moderate efficacy or cause significant side effects upon chronic administration [5][6][7]. Pain relief and improvement in quality of life are crucial outcomes of the therapy. ...
... We compared Ms 9a-1 (positive modulator of TRPA1) with APHC3 (a modulator of the TRPV1 channel), and non-steroidal anti-inflammatory drugs (NSAIDs) such as meloxicam (a selective cyclooxygenase (COX)-2 inhibitor) and ibuprofen (a non-selective COX inhibitor). NSAIDs are often insufficient to relieve pain, but they are still the most commonly recommended and used drugs in OA treatment [6,7]. Different COX inhibitors can produce variable effects on induced arthritis in rats [31,49] that could be the result of the pharmacological action of their metabolites [49]. ...
... The first injection of Ms 9a-1 at 0.1 mg/kg significantly reversed joint swelling, supporting the important role of neurogenic inflammation maintained by TRPA1-expressing neurons in this process. The doses of meloxicam and ibuprofen corresponded to the maximum recommended doses for human treatment [6,7,51]. Ibuprofen also showed a significant effect of single dose, but meloxicam was unable to reduce the inflamed joint diameter after the first administration. ...
Progressive articular surface degradation during arthritis causes ongoing pain and hyperalgesia that lead to the development of functional disability. TRPA1 channel significantly contributes to the activation of sensory neurons that initiate neurogenic inflammation and mediates pain signal transduction to the central nervous system. Peptide Ms 9a-1 from the sea anemone Metridium senile is a positive allosteric modulator of TRPA1 and shows significant anti-inflammatory and analgesic activity in different models of pain. We used a model of monosodium iodoacetate (MIA)-induced osteoarthritis to evaluate the anti-inflammatory properties of Ms 9a-1 in comparison with APHC3 (a polypeptide modulator of TRPV1 channel) and non-steroidal anti-inflammatory drugs (NSAIDs) such as meloxicam and ibuprofen. Administration of Ms 9a-1 (0.1 mg/kg, subcutaneously) significantly reversed joint swelling, disability, thermal and mechanical hypersensitivity, and grip strength impairment. The effect of Ms 9a-1 was equal to or better than that of reference drugs. Post-treatment histological analysis revealed that long-term administration of Ms9a-1 could reduce inflammatory changes in joints and prevent the progression of cartilage and bone destruction at the same level as meloxicam. Peptide Ms 9a-1 showed significant analgesic and anti-inflammatory effects in the model of MIA-induced OA, and therefore positive allosteric modulators could be considered for the alleviation of OA symptoms.
... Systematic reviews of the benefits of CBD for pain management reveal mixed recommendations [1][2][3][4]. A recent review aimed at evaluating the effectiveness of CBD in relieving pain in patients with malignant disease showed significant analgesic effect in 15 of the 18 trials compared with placebo [5]. ...
... Although the same overall conclusions were drawn, this systematic review and meta-analysis is based on additional methodological information and is therefore supported by higher quality data (as the included studies were considered to have a lower risk of bias). In addition, the primary outcome in this systematic review is a more sensitive outcome for detecting minimal changes in pain [3]. This systematic review provides good evidence that cannabinoids have no role in cancer-related pain. ...
... Reasons are the limited generalizability of RCTs to clinical practice conditions, the enormous costs and the mainly short-term duration associated with this trial design, the inability to obtain adequate patient numbers for trials in rare diseases or subgroups of patients and the introduction of personalized medicine. Moreover, even in the failed RCTs (i.e., those which do not meet their primary predefined end point), there is often an identifiable group of 'responders' who benefit from treatment but is not large enough to make the mean of the test group significantly positive [29,30]. Such responder analysis might help bridge the gap between RCTs and clinical practice where personalized medicine will be practiced [30]. ...
... Moreover, even in the failed RCTs (i.e., those which do not meet their primary predefined end point), there is often an identifiable group of 'responders' who benefit from treatment but is not large enough to make the mean of the test group significantly positive [29,30]. Such responder analysis might help bridge the gap between RCTs and clinical practice where personalized medicine will be practiced [30]. Regulatory authorities such as the FDA and EMA have developed strategies to develop and adopt RWE and to integrate this evidence into the decision making process [31]. ...
Treatment of neuropathic pain (NP) is challenging. Interest in real-world evidence (RWE) for benefit-risk assessments of NP treatments increases given the paucity of drugs showing efficacy in randomized controlled trials and restricted labels of available medicines. To provide further context, a literature review regarding regulatory use of RWE and a clinical trial registry search for randomized controlled trials over the last 10 years was carried out. Taken together, and especially for available NP treatments, there is increasing support to consider RWE when evaluating their benefit-risk profile. Examples are provided in which RWE could be used effectively for updating the product label and informing treatment recommendations. Collected and analyzed according to state-of-the-art standards, RWE can inform treatment recommendations and product label decisions.
... Эффективный контроль боли -необходимый элемент ведения пациентов с ревматическими заболеваниями (РЗ), а анальгетические средства, прежде всего нестероидные противовоспалительные препараты (НПВП), -первая линия фармакотерапии таких распространенных РЗ, как остеоартрит (ОА) и хроническая неспецифическая боль в спине (ХНБС) [1][2][3]. Однако монотерапия НПВП далеко не всегда позволяет добиться хорошего клинического ответа: по данным серии рандомизированных контролируемых исследований (РКИ), на фоне такого лечения уменьшение боли на ≥50% отмечается примерно у 40-50% пациентов [4,5]. ...
The vitamin B 1 , B 6 and B 12 complex (VBC) is frequently used to treat acute and chronic low back pain.
Objective: to investigate the effect of a combination of a non-steroidal anti-inflammatory drug (NSAID) and a VBC on the main manifestations of nociceptive system dysfunction in patients with combination of osteoarthritis (OA) and chronic non-specific low back pain (NSLBP).
Material and methods. The study group consisted of 99 patients (82% women, mean age 63.6±17.2 years) with OA of various localization and
NSLBP who had moderate to severe pain (≥4 on a numerical rating scale, NRS 0–10). All patients received etoricoxib 60 mg/day (up to 14 days) and a course of intramuscular (IM) injections of VBC (a drug for parenteral administration containing solutions of thiamine 100 mg, pyridoxine 100 mg, cyanocobalamin 1.0 mg and lidocaine 20 mg) 2.0 ml №10. Treatment outcome was assessed after 14 days.
Results and discussion. During treatment, the vast majority of patients showed a significant improvement: the median severity of pain on movement (NRS) decreased from 6.3 [5.0; 8.0] to 3.7 [3.0; 5.0], p=0.0001; functional impairment – from 3.8 [2.0; 6.0] to 2.2 [1.0; 3.0], p=0.001; fatigue – from 5.6 [4.0; 8.0] to 3.5 [0.0; 2.0], p=0.0001. 71.6% of patients rated the treatment results as good or excellent. Six patients had adverse reactions: 2 – local pain at the site of the intramuscular injections, 1 – arterial hypertension, 3 – epigastric pain. No serious adverse events were recorded.
Conclusion. The combined use of NSAIDs and VBC can provide significant improvement in patients with a combination of OA and NSLBP.
... All phase III trials discussed in the review revealed no true analgesic benefit from cannabinoids, while one phase II study witnessed a decrease in pain scores with cannabinoids [3]. The effect on the absolute change in mean pain intensity was assessed using the Numeric Rating Scale (NRS) pain scores and compared the outcomes to a placebo [72,73]. The results suggested that cannabinoids are not effective in reducing cancer pain, with the cannabinoid treatment group experiencing significant adverse effects and higher participant dropouts. ...
In light of the current International Association for the Study of Pain (IASP) clinical practice guidelines (CPGs) and the European Society for Medical Oncology (ESMO) guidelines, the topic of cannabinoids in relation to pain remains controversial, with insufficient research presently available. Cannabinoids are an attractive pain management option due to their synergistic effects when administered with opioids, thereby also limiting the extent of respiratory depression. On their own, however, cannabinoids have been shown to have the potential to relieve specific subtypes of chronic pain in adults, although controversies remain. Among these subtypes are neuropathic, musculoskeletal, cancer, and geriatric pain. Another interesting feature is their effectiveness in chemotherapy-induced peripheral neuropathy (CIPN). Analgesic benefits are hypothesized to extend to HIV-associated neuropathic pain, as well as to lower back pain in the elderly. The aim of this article is to provide an up-to-date review of the existing preclinical as well as clinical studies, along with relevant systematic reviews addressing the roles of various types of cannabinoids in neuropathic pain settings. The impact of cannabinoids in chronic cancer pain and in non-cancer conditions, such as multiple sclerosis and headaches, are all discussed, as well as novel techniques of administration and relevant mechanisms of action.
... Different strategies may be used in economic analyses, such as costeffectiveness, cost-utility, cost-minimization, cost-benefit, and cost-consequence, calculated based on the number needed to treat (NNT) [53]. Despite the importance of economic analyses, the complexity of some models may impose comprehension difficulties on clinicians and non-economist policy-makers [54]. ...
Introduction
Epilepsy is a serious neurological disease, ranking high in the top causes of disability. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, approximately 40% of patients suffer from Drug-Resistant Epilepsy (DRE) despite the availability of the latest options called third-generation Anti-Seizure Medications(ASMs). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. The introduction of a new drug increases the number of therapeutic options available, making it important to compare it with existing alternatives in terms of clinical benefit and efficiency.
Purpose
This study aimed to compare the clinical benefit, in terms of the Number Needed to Treat (NNT), and the efficiency, in terms of Cost per NNT (CNT), associated with cenobamate versus third-generation ASMs used in Spain for the adjunctive treatment of FOS in patients with DRE.
Methods
The Number Needed to Treat data was calculated based on the ≥50% responder rate and seizure freedom endpoints (defined as the percentage of patients achieving 50% and 100% reduction in seizure frequency, respectively), obtained from pivotal clinical trials performed with cenobamate, brivaracetam, perampanel, lacosamide, and eslicarbazepine acetate. The NNT was established as the inverse of the treatment responder rate minus the placebo responder rate and was calculated based on the minimum, mid-range Daily Defined Dose (DDD), and maximum doses studied in the pivotal clinical trials of each ASM. CNT was calculated by multiplying the annual treatment cost by NNT values for each treatment option.
Results
In terms of NNT, cenobamate was the ASM associated with the lowest values at all doses for both ≥50% responder rate and seizure freedom compared with the alternatives. In terms of CNT, for ≥50% responder rate, cenobamate was the ASM associated with the lowest CNT values at DDD and lacosamide and eslicarbazepine acetate at the minimum and maximum dose, respectively. For seizure freedom, cenobamate was associated with the lowest CNT value at DDD and the maximum dose and lacosamide at the minimum dose.
Conclusions
Cenobamate could represent the most effective ASM in all doses studied compared to the third-generation ASMs and the most efficient option at DDD for both ≥50% responder rate and seizure freedom. This study could represent an important contribution towards informed decision-making regarding the selection of the most appropriate therapy for FOS in adult patients with DRE from a clinical and economical perspective in Spain.
... Moore et al. first expressed skepticism regarding the validity of VAS as an outcome measure in 2005 (Moore et al., 2005). A series of studies showed that pain intensity and pain relief were highly skewed data that cannot be appropriately reported as means (Moore et al., 2010;Moore et al., 2011). This was confirmed in the 10-year experience of acute pain service in Italy, in which the mean VAS was relatively low in clinical practice because most patients achieved satisfactory pain relief (Deni et al., 2019). ...
Purpose: Intravenous patient-controlled analgesia (IV-PCA) has been widely used; however, regimen criteria have not yet been established. In China, the most often used opioid is sufentanil, for which repeated doses are a concern, and empirical flurbiprofen axetil (FBP) as an adjuvant. We hypothesized that hydromorphone would be a better choice and also evaluated the effectiveness of FBP as an adjuvant.
Methods: This historical cohort study was conducted in two tertiary hospitals in China and included 12,674 patients using hydromorphone or sufentanil for IV-PCA between April 1, 2017, and January 30, 2021. The primary outcome was analgesic insufficiency at static (AIS). The secondary outcomes included analgesic insufficiency with movement (AIM) and common opioid-related adverse effects such as postoperative nausea and vomiting (PONV) and dizziness.
Results: Sufentanil, but not the sufentanil-FBP combination, was associated with higher risks of AIS and AIM compared to those for hydromorphone (OR 1.64 [1.23, 2.19], p < 0.001 and OR 1.42 [1.16, 1.73], p < 0.001). Hydromorphone combined with FBP also decreased the risk of both AIS and AIM compared to those for pure hydromorphone (OR 0.74 [0.61, 0.90], p = 0.003 and OR 0.80 [0.71, 0.91], p < 0.001). However, the risk of PONV was higher in patients aged ≤35 years using FBP (hydromorphone-FBP vs. hydromorphone and sufentanil-FBP vs. hydromorphone, OR 1.69 [1.22, 2.33], p = 0.001 and 1.79 [1.12, 2.86], p = 0.015).
Conclusion: Hydromorphone was superior to sufentanil for IV-PCA in postoperative analgesia. Adding FBP may improve the analgesic effects of both hydromorphone and sufentanil but was associated with an increased risk of PONV in patients <35 years of age.
... 23 Pain reported as the percentage of patients reaching a desirable state can provide more interpretable data. 23,31,[33][34][35] Reporting pain as a dichotomous value allows for analysis of responders vs. nonresponders within the treatment group. In addition, treatment effects in subgroups can be assessed, which may be missed when reporting results as a mean or median for a continuous variable. ...
Background:
Pain is the most common and bothersome symptom experienced by people with hidradenitis suppurativa (HS) and has been prioritised as an outcome domain by the HIdradenitis SuppuraTiva cORe outcomes set International Collaboration (HISTORIC).
Objectives:
To perform a scoping review of pain measurement in randomized control trials (RCTs) of painful skin conditions (PSCs) and use of pain numeric rating scale (NRS) and visual analogue scale (VAS) in rheumatoid arthritis (RA) RCTs to inform HISTORIC efforts to reach consensus on how to measure pain intensity in HS trials.
Methods:
A search was conducted on several publication databases. Inclusion criteria were RCTs with a minimum of 10 participants that measured pain intensity.
Results:
Pain NRS and VAS were used in 68% of PSCs trials. 77% and 87% of PSCs and RA RCTs did not specify the recall window. The commonest recall window in PSCs when specified was 24 hours. 33% of PSC trials assessed maximum pain intensity and 3% average pain intensity while 87% of RA trials did not provide details. Pain data were reported as mean difference by 76% of PSC trials and 75% of RA trials. 10% and 11%of PSC and RA studies reported pain as the percentage reaching a desirable state and only 1% and 2% reported number needed to treat (NNT).
Conclusions:
While pain NRS and VAS are standard methods to measure pain intensity in PSCs, key details such as recall window are often omitted and there is no consensus on how to report pain NRS data.
Objectives
Randomized clinical trials are used to evaluate the efficacy of various pain treatments individually, while a limited number of observational studies have portrayed the overall relief experienced by persons living with chronic pain. This study aimed to describe pain relief in real-world clinical settings and to identify associated factors.
Methods
This exploratory web-based cross-sectional study used data from 1,419 persons recruited in the community. Overall pain relief brought by treatments used by participants was assessed using a 0%–100% scale (10-unit increments).
Results
A total of 18.2% of participants reported minimal pain relief (0%–20%), 60.0% moderate to substantial pain relief (30%–60%), and 21.8% extensive pain relief (70%–100%). Multivariable multinomial regression analysis revealed factors significantly associated with greater pain relief, including reporting a stressful event as circumstances surrounding the onset of pain, living with pain for ≥10 years, milder pain intensity, less catastrophic thinking, use of prescribed pain medications, use of nonpharmacological pain treatments, access to a trusted healthcare professional, higher general health scores, and polypharmacy. Factors associated with lower pain relief included surgery as circumstances surrounding pain onset, use of over-the-counter pain medications, and severe psychological distress.
Discussion
In this community sample of persons living with chronic pain, 8 out of 10 persons reported experiencing at least moderate relief with their treatment. The analysis has enabled us to explore potential modifiable factors as opportunities for improving the well-being of persons living with chronic pain.
Pain sensitization is a phenomenon that occurs to protect tissues from damage and recent studies have shown how a variety of non-noxious stimuli included in our everyday lives can lead to pain sensitization Consumption of large amounts of alcohol over a long period of time invokes alcohol use disorder (AUD), a complex pathological state that has many manifestations, including alcohol peripheral neuropathy (neuropathic pain). We asked if ‘non-pathological’ alcohol consumption can cause pain sensitization in the absence of other pathology? Studies have pointed to glia and other immune cells and their role in pain sensitization that results in cell and sex-specific responses (Wang et al., 2010; Obad et al., 2018). Using a low-dose and short-term ethanol exposure model, we investigated whether this exposure would sensitize mice to a subthreshold dose of an inflammatory mediator that normally does not induce pain, or cause hypersensitivity. We observed female mice exhibited specific mechanical and higher thermal sensitivity than males. We also observed an increase in CD68⁺ macrophages in the ipsilateral dorsal root ganglia (DRG) and Iba1⁺ microglia in the ipsilateral spinal dorsal horn of animals that were exposed to ethanol and injected with subthreshold prostaglandin E2. Our findings suggest that short-term ethanol exposure stimulates peripheral and central, immune, and glial activation, respectively to induce pain sensitization. This work begins to reveal a possible mechanism behind the development of alcoholic peripheral neuropathy.
Duloxetine hydrochloride is a reuptake inhibitor of 5-hydroxytryptamine and norepinephrine used to treat depression, generalized anxiety disorder, neuropathic pain, and stress incontinence in women. We investigated the efficacy of duloxetine in painful diabetic neuropathy and fibromyalgia to allow comparison with other antidepressants.
We searched PubMed, EMBASE (via Ovid), and Cochrane CENTRAL up to June 2008 for randomised controlled trials using duloxetine to treat neuropathic pain.
We identified six trials with 1,696 patients: 1,510 were treated with duloxetine and 706 with placebo. All patients had established baseline pain of at least moderate severity. Trial duration was 12 to 13 weeks. Three trials enrolled patients with painful diabetic neuropathy (PDN) and three enrolled patients with fibromyalgia. The number needed to treat (NNT) for at least 50% pain relief at 12 to 13 weeks with duloxetine 60 mg versus placebo (1,211 patients in the total comparison) was 5.8 (95% CI 4.5 to 8.4), and for duloxetine 120 mg (1,410 patients) was 5.7 (4.5 to 5.7). There was no difference in NNTs between PDN and fibromyalgia. With all doses of duloxetine combined (20/60/120 mg) there were fewer withdrawals for lack of efficacy than with placebo (number needed to treat to prevent one withdrawal 20 (13 to 42)), but more withdrawals due to adverse events (number needed to harm (NNH) 15 (11 to 25)). Nausea, somnolence, constipation, and reduced appetite were all more common with duloxetine than placebo (NNH values 6.3, 11, 11, and 18 respectively). The results for duloxetine are compared with published data for other antidepressants in neuropathic pain.
Duloxetine is equally effective for the treatment of PDN and fibromyalgia, judged by the outcome of at least 50% pain relief over 12 weeks, and is well tolerated. The NNT of 6 for 50% pain relief suggests that this is likely to be a useful drug in these difficult-to-treat conditions, where typically only a minority of patients respond. Comparing duloxetine with antidepressants for pain relief in DPN shows inadequacies in the evidence for efficacy of antidepressants, which are currently recommended in PDN care pathways.
Systematic reviews summarize large amounts of information and are more likely than individual trials to describe the true clinical effect of an intervention. Traditional statistical outputs from systematic reviews cannot immediately be applied to clinical practice. The number needed to treat (NNT) has that clinical immediacy. This number can be calculated easily from raw data or from statistical outputs, and the principle involved in its calculation can be applied to different outcomes: treatment efficacy, adverse events (harm), or other end points. The NNT defines the treatment-specific effect of an intervention, and we suggest it as a currency for making decisions about individual patients. Knowing the NNT for different interventions that have the same outcome for the same disorder can help shape individual and institutional practice. Knowing or estimating the number needed to harm is also an important part of the equation. Knowing or estimating an individual patient's risk can, with the NNT, be a guide to the overall or net value of a prophylactic intervention. We advocate an approach to systematic reviews that distills information into, in effect, one number: the NNT. This is simple to remember and directly supports efforts to work with patients to make the best possible clinical decisions for their care.
To say a drug “works” is only half the storyDoctors say that a drug “works” if, in comparison with the control arm of a clinical trial, significantly more people in the treatment arm respond. Unfortunately, this is a naive oversimplification, and it breeds complacency among patients and physicians alike.Criticisms of this perspective have been lodged before. One is that researchers often pick outcomes that are not patient centred—patients do not care if a tumour shows “shrinkage upon radiological visualisation” but rather whether they are in less pain. Another criticism is that when side effects of drugs are factored in, many patients do not think that a drug works very well at all, even as the doctor or drug company extols its virtues; drop-out rates in the active agent arm of trials often exceed those of the placebo arm, providing evidence of patients’ distaste for the overall effects of a drug.But one problem that has received far less attention is that when patients say a drug “works” they typically mean something quite different from what doctors mean. Patients mean …
The objective was to investigate the relationship between pain relief scores produced by placebo and by active interventions in randomised controlled trials (RCTs). Individual patient categorical pain relief scores from 5 placebo-controlled single-dose parallel-group RCTs in acute postoperative pain were used to calculate the percentage of the maximum possible pain relief score (%maxTOTPAR) for the different treatments. One hundred and thirty of the 525 patients in the 5 trials had a placebo. Individual patients' scores with placebo varied from 0 to 100% of the maximum possible pain relief. The proportion who obtained more than 50% of the maximum possible pain relief with placebo varied from 7% to 37% across the trials; with the active drugs the variation was from 5 to 63%. Mean placebo scores were related to the mean score for the active treatments in each study; the higher the mean active score, the higher the mean placebo score. This relationship disappeared when median values were used. Medical folklore has it that the amount of relief obtained with placebo is one-third of the maximum possible (and does not vary), and that one-third of patients respond to placebo. The results show that the amount of relief obtained with placebo varies considerably between patients, that 38% of patients obtained more than 10% of the maximum possible relief, and 16% obtained greater than 50%. In double-blind, randomised parallel-group studies of high quality placebo scores should not vary. Despite these conditions being met the placebo scores did vary. The previous explanation, of a relationship between the mean placebo scores and the mean scores for the active treatments was not supported.
To review key mechanisms underlying the transmission of nociceptive information from the periphery to the central nervous system implicated in different acute pain states.
Advances in molecular and transgenic approaches have helped to identify novel therapeutic targets for the treatment of pain from tissue and nerve damage such as acid-sensing ion channels, transient receptor potential and NaV channels. The subsequent development of selective pharmacological ligands has also strengthened the role of other receptors such as hyperpolarization-activated cyclic nucleotide-gated channels and the further development of subunit specific antagonists, such as those available for NR2B, will further advance our understanding of the mechanisms involved in nociceptive transmission.
Inflammatory and neuropathic pain differ considerably in their peripheral mechanisms but certain central spinal and brain mechanisms are common to both. The mechanisms of pain are not fully established but are thought to be underpinned by changes in the expression of receptors (nociceptive plasticity), central spinal hyperexcitability (central sensitization) and alterations in descending control from the midbrain. This review considers these mechanisms and highlights recent advances in the understanding of pain perception.
Functional neuroimaging has made a huge impact scientifically, not least within the field of pain research. The noninvasive identification of pain mechanisms that underpin chronicity, such as central sensitization and other amplification processes related to the cognitive or emotional state of the patient, is of considerable interest to the clinical pain community and pharmaceutical industry. Relating data to a person's specific pain report or measure of pain relief provide a clearer understanding of the mechanisms driving and maintaining this complex experience. It is timely, therefore, to review the advances in neuroimaging applications to pain.
New data have emerged to further support the descending modulatory system's critical role in chronic pain. The neural correlates that underpin tonic, ongoing and spontaneous pain in patients are being identified. Additionally, the prefrontal cortex is emerging as a critical brain region for pain processing, especially in patients. Finally, data from structural and molecular imaging studies are highlighting the extent of damage the brain sustains when patients live with their chronicity unrelieved.
Neuroimaging tools have advanced our understanding of central pain mechanisms in normals and patients, forcing us to reconsider issues related to diagnosis and provision of treatment.