This study updated our knowledge of UK primary care neuropathic pain incidence rates and prescribing practices.Patients with a first diagnosis of post-herpetic neuralgia (PHN), painful diabetic neuropathy (PDN) or phantom limb pain (PLP) were identified from the General Practice Research Database (2006 – 2010) and incidence rates were calculated. Prescription records were searched for pain treatments from diagnosis of these conditions and the duration and daily dose estimated for first-line and subsequent treatment regimens. Recording of neuropathic back and post-operative pain was investigated.The study included 5,920 patients with PHN, 5,340 with PDN, and 185 with PLP. The incidence per 10,000 person-years was 3.4  for PHN; and 0.11  for PLP. Validation of the PDN case definition suggested that was not sensitive. Incident PHN increased over the study period. The most common first-line treatments were amitriptyline or gabapentin in the PDN and PLP cohorts, and amitriptyline or co-codamol (codeine-paracetamol) in PHN. Paracetamol, co-dydramol (paracetamol-dihydrocodeine) and capsaicin were also often prescribed in one or more condition. Most first-line treatments comprised only one therapeutic class. Use of antiepileptics licensed for neuropathic pain treatment had increased since 2002–2005. Amitriptyline was the only antidepressant prescribed commonly as a first-line treatment.The UK incidence of diagnosed PHN has increased with the incidence of back-pain and post-operative pain unclear. While use of licenced antiepileptics increased, prescribing of therapy with little evidence of efficacy in neuropathic pain is still common and consequently treatment was often not in-line with current guidance. A fifth of adults in Europe report moderate or severe chronic pain with 2% managed by a specialist . NeuropaA 2006 European task force on pharmacological treatment of neuropathic pain reported that treatment remained unsatisfactory despite a substantial increase in the number of clinical trials . These tNeuropathic back pain and post-operative pain other than phantom limb pain were not studied in the previous UK primary care database analyses, as the identification of these less well defined neuropathic pain conditions was expected to be more difficult from a primary care database. However, these conditions affect large populations. The adult annual rate for consulting general practice for back pain is 6.4% , of whicThe objectives of this study were to update the incidence rates and prescribing practices for post-herpetic neuralgia, phantom limb pain and painful diabetic neuropathy in UK primary care and to report any time trends, and to examine the recording and treatment of neuropathic back pain and post-operative pain.The source population and prescribing data were retrieved from the General Practice Research Database (GPRD). The GPRD is an observational database containing information collected in computerised primary care practices throughout the UK. Details of demographics, primary care diagnoses and prescription treatment are routinely recorded against date in individual patient records. Details of referrals, secondary care diagnoses and deaths are also captured because of the structure of the UK National Health Service. Major events from before computerisation are added retrospectively. Data on preventive medicine can also be recorded. Medical events are automatically coded at entry using the Read coding system . Each past December 2010. Five neuropathic pain cohorts  were identified from this study population by searching individual patient records for either a single specific Read code, or a combination of Read and therapy codes as specified in a case definition. Post-herpetic neuralgia was defined as a specific code for post-herpetic neuralgia, or a code for acute zoster plus either a code for neuropathy, or neuropathic pain, between three and six months after the first acute zoster entry. Phantom limb pain (PLP) was defined as a specific code, or a code for amputation plus either a code for neuropathy or neuropathic pain between three and twenty-four months after the first amputation code. The painful diabetic neuropathy cohort included patients with a specific code for painful diabetic neuropathy; those with a code for diabetes and a general code for neuropathic pain and a third group with a code for diabetic neuropathy  with a prescription for a neuropathic pain treatment which was initiated within 28 days of the date of the neuropathy/neuralgia code.The study population comprised all patients who were permanently registered at a GPRD practice at any time in the study period, from 1st January 2005 to 31There is no specific code for neuropathic back pain in the Read dictionary. The condition was defined as a code for back pain plus either a code for neuropathy or neuropathic pain within 28 days, or a code for radiculopathy or back pain with a specific neuropathic pain treatment  initiated within 28 days of the back pain date. To identify patients with neuropathic post-operative pain preliminary database searches looked for patients with codes for surgery followed by a record of post-operative pain, or surgery plus either a code for neuropathic pain, or neuropathy or persistent pain and a prescription for a specific neuropathic pain treatment  initiated within 28 days of the pain record date. Few patients were found to meet these criteria, so to investigate the recording of this condition, patients with a code for breast or hernia surgery were identified as the prevalence of pain has been reported in this group . For thist January 2006 were excluded. Patients could be included in more than one cohort, but not in both phantom limb pain and post-operative pain. A period of observation was set for each subject with a start date of 1st January 2005 or, if later, the date that the patient record was suitable for research plus twelve months. The twelve months was added to allow time for the recording of prevalent conditions before the study started. The end date was the first of the following: the end of the study period, death, transfer-out of the practice, or the final data collection.The cohort entry date for each patient was the date of the first Read code for the specific condition , neuropathic pain, neuropathy, neuralgia, or post-operative pain in the case definition. Prevalent cases with a cohort entry date before 1Questionnaires were sent to the general practitioners (GPs) of a random sample of patients to confirm the diagnosis. The sample comprised 108 patients with post-herpetic neuralgia and 54 patients within the study definition of painful diabetic neuropathy. An additional group of 52 questionnaires tested for false negatives among those patients whose records did not meet the case definition but who did have a record of diabetes and treated neuropathy; for example when a diabetic patient had peripheral neuropathy but was already on prescription treatment for an analgesic at the time of the first mention of peripheral neuropathy.A neuropathic pain treatment was defined as a prescription for an analgesic (excluding aspirin 100 mg or less), an anaesthetic , an antiepileptic (with no history of epilepsy), or an antidepressant. Therapeutic class was based on the British National Formulary (BNF) ; antiepiThe details of prescriptions for neuropathic pain treatments were identified for the cohorts. For post-herpetic neuralgia, painful diabetic neuropathy and phantom limb pain the first-line treatment was defined as a neuropathic pain treatment started within 28 days of the cohort entry date. The case definitions for neuropathic back pain and post-operative pain included only those treatments specifically recommended or indicated in neuropathic pain which might be second-line treatments. Earlier prescribing was included in the treatment analysis in order to include first-line treatment with less specific agents. The first-line treatment for neuropathic back pain was therefore defined as the first neuropathic pain treatment in a treatment episode that spanned the cohort entry date, but did not start before the back pain or radiculopathy code, or that started in the 28 days after the back pain or radiculopathy code.Daily dose was estimated from the details on the prescription and the duration of each prescription was estimated from the daily dose and number of items prescribed. When a prescription described a dose titration, then the final dose was included. When the duration could not be calculated from details on a prescription, it was assumed to last 28 days. If more than one therapy was prescribed on the same day then the first-line treatment was considered to be the combination of these therapies. If more than one therapy was prescribed, but on different days, the first-line treatment regimen included only items on the first prescription.Duration of the first-line treatment was the sum of the individual prescription durations until discontinuation, or prescription, of one or more treatments. A second-line treatment regimen started when any change was made to the original regimen without a break in all treatment as a break in treatment was assumed to indicate a new episode of pain. The change could be prescription of a new treatment or discontinuation of part of the first-line treatment. A therapy was considered to have been discontinued when no additional prescription was issued within 62 days of the end of the last prescription. Third-line treatment was defined in the same way as any addition or discontinuation without a break in treatment.st July of the recorded year of birth. Incidences were standardised to the 2010 UK age-sex distribution [The incidence per person-years observation for 2006 to 2010 was estimated for post-herpetic neuralgia, phantom limb pain and painful diabetic neuropathy. A rate (rather than incidence) of identified new cases of neuropathic back pain was estimated as the case definition for this condition was not specific. Those with a first record of their neuropathic pain dated during their period of observation were counted as incident cases. The denominator (person-years observation) was the sum of the difference between the start date plus one year and end date for each patient. The age and sex distribution at cohort entry was estimated assuming a date of birth of 1ribution .Descriptive analyses reported the number of patients with an first-line treatment identified, the treatments prescribed (including number and type of therapy and mean duration) and the percentage of use as first, second and third line therapy for treatments prescribed to more than 100 patients at any stage. The analysis was completed by condition for patients with at least 18 months prescribing data after the cohort entry date to provide sufficient prescribing history. The number of patients with each daily dosing regimen was counted by year for all first prescriptions for gabapentin or pregabalin.The study cohorts included 5,920 patients with post-herpetic neuralgia, 5,340 with painful diabetic neuropathy, 185 with phantom limb pain and 90,941 with neuropathic back pain. This provided annual incidence rates per 10,000 population of 3.4  3.4, 3.5), for post-herpetic neuralgia, 3.1  for painful diabetic neuropathy and 0.1 , for phantom limb pain. When standardised to 2010 UK age and sex distribution, the annual incidence per 10,000 population were 3.0  for post-herpetic neuralgia, 2.8  for painful diabetic neuropathy and 0.11  for phantom limb pain. The incidence of these three conditions increased with age  and 56% for painful diabetic neuropathy . In those patients who did not meet the full case definition for painful diabetic neuropathy 7% were identified as false negatives .Across the study conditions, between 80 and 87% of patients had an available follow-up period of 18 months and so were included in the prescription treatment analysis Table . The numAn antidepressant or an antiepileptic was prescribed as part of a first-line treatment for 57.0% of post-herpetic neuralgia patients, 70.5% of the painful diabetic neuropathy cohort and 61.1% of the phantom limb pain cohort. Analgesics alone (opioid +/− non-opioid) were prescribed first-line for 36.3% of patients with post-herpetic neuralgia, 25.4% of patients in the painful diabetic neuropathy cohort and 37.7% of patients with phantom limb pain , oxycodone, fentanyl, and meptazinol were usually prescribed following another first-line regimen as were nefopam, duloxetine, lidocaine patches and lower doses of mirtazapine. Lidocaine patches were infrequently used in post-herpetic neuralgia and duloxetine and venlafaxine were prescribed to less than 100 patients <2%) as a first-line treatment in the painful diabetic neuropathy cohort  in 2004 resulted in GPs increasingly making a preliminary diagnosis of painful diabetic neuropathy which is then not confirmed at secondary care. Within this government initiative, primary care physicians are paid to review chronically ill patients, including diabetic patients, with some payment dependent on evidence of checking for complications such as neuropathy. A record of neuropathy testing increased sharply around the time of QoF introduction with one study reporting a rise from 8% of diabetic patient records in the 15 months to April 2003 to 66% in the 15 months to April 2005 with rates of recording then levelling . There hMost other studies assessing the incidence of these neuropathic pain conditions have been within specific sub-populations, such as people with acute herpes zoster, diabetes or post-amputation. One earlier UK general population study reported incidence per 10,000 population of 5.4 for diabetic polyneuropathy and 1.1 for post-herpetic neuralgia . A studyAmitriptyline was the most commonly prescribed treatment in a first-line therapy for the post-herpetic neuralgia and painful diabetic neuropathy cohorts and the second most frequent after gabapentin in phantom limb pain. Gabapentin was also frequently prescribed as a first-line treatment in the painful diabetic neuropathy cohort and in post-herpetic neuralgia, with the use of both gabapentin and pregabalin increasing over the study period. This demonstrates a maintained shift from predominant use of opioid and non-opioid analgesics in the late 1990’s to use of tricyclic antidepressants and antiepileptics, with initiation of these therapies now evident in primary, rather than secondary, care. This shift appears to be the case across conditions as our painful diabetic neuropathy cohort will have included other neuropathic pain. Compared to the 2002–2005 data, amitriptyline remains a common first-line treatment although use has decreased in post-herpetic neuralgia and phantom limb pain . Antiepileptic prescribing has moved from carbamazepine to gabapentin and pregabalin, both of which are now used more frequently in phantom limb pain (2002–2005 versus 2006–2010: 17% versus 38%). Opioid use has increased slightly with tramadol now prescribed more often than co-codamol (codeine phosphate and paracetamol) as a first-line treatment in phantom limb pain. The changes may be due to a combination of an increasing evidence of efficacy in both placebo-controlled and head-to-head trials, education and marketing.The prescribing analysis period of 2006–2010 was, for the most part, prior to the publication of the current UK and European recommendations on neuropathic pain treatment, although after the publication of key randomised controlled trials for the newer antiepileptics, antidepressants and opioids in neuropathic pain . They weCo-codamol was still one of the five most commonly prescribed first-line treatments in post-herpetic neuralgia and painful diabetic neuropathy and co-dydramol (paracetamol and dihydrocodeine) in post-herpetic neuralgia. While neither of these options is generally recommended as a first line treatment  it is noThe analysis of treatments in more than 100 patients showed that the most commonly prescribed daily doses for amitriptyline and pregabalin were those recommended by NICE (10 mg and 150 mg per day respectively) while higher dosage regimens were not uncommon. EFNS recommends a higher daily dose of tricyclic antidepressants (25–150 mg/day) and their suggested dose of gabapentin (1200–3600 mg/day) was prescribed first-line to a minority of the post-herpetic neuralgia and painful diabetic neuropathy cohorts. The analysis of pregabalin dosage regimen did not show a shift from a three to twice a day dosing although this has been suggested as a cost saving exercise. The majority of patients were prescribed one item as a first prescription and one therapeutic category. This is in-line with current guidance although there is some evidence that less than half of patients achieve significant benefit with any single treatment and that combined treatment may be more effective . PatientThe inclusion of neuropathic back pain and post-operative pain was considered exploratory, because these are less well defined than the other study conditions with no specific Read code to simplify recording by the GP. The initial strategy for identifying post-operative pain involved identifying records with a code for surgery followed by a record of post-operative pain, plus any marker that this was neuropathic. When few cases were identified, the search focused on breast and hernia surgery, which are associated with post-operative pain ,24. The Neuropathic back pain within the study definition increased over the study period from 49 to 62 per 10,000 patient-years. This cannot be considered to be a true incidence because, without a specific code for neuropathic back pain, the study definition lacked specificity. For example, patients with back pain or radiculopathy treated with tramadol would have been included in the analysis although tramadol is often also used in nociceptive, rather than neuropathic pain. Conversely patients with neuropathic back pain but without a neuropathic code and treated with opioid/non-opioid combinations would not have been identified. Additionally, radicular back pain is not always considered to be neuropathic. The prescribing patterns in the neuropathic back pain cohort differed from the other pain conditions, with tramadol the most frequent first-line therapy and other opioid/non-opioid analgesics commonly prescribed. This may be because of co-existing nociceptive pain for which tramadol efficacy is established  or indicThis study was based solely on primary care records, which provides a picture of routine treatment but has a number of resultant limitations. In particular, not all cases of post-herpetic neuralgia, painful diabetic neuropathy and phantom limb pain were identified using specific disease codes. The incidence of painful diabetic neuropathy is considered a maximum rate as the study definition will include diabetic patients with neuropathic pain which is not related to diabetes or non-painful neuropathy if this was diagnosed at the same time as the patient started a neuropathic pain therapy but for a different indication. The rates of disease we report are those recorded by the GP so any pain not reported to the GP will not be included. Additionally, treatments for pain other than neuropathic pain will have been included in the treatment analysis if they were started at the time of the first neuropathic pain record. More than a third of patients with neuropathic pain are known to have other chronic pain-related disease . We coulWhile treatment for many patients with the neuropathic pain conditions complied with guidelines available at that time, this prescribing was often inconsistent with published evidence of efficacy which is now incorporated into updated guidelines. Use of antiepileptics with demonstrated efficacy as first-line therapy has increased. Unlike post-herpetic neuralgia, painful diabetic neuropathy is difficult to identify from primary care coded records alone, which has implications for future attempts to establish incidence using this method. Few cases of post-operative pain were identified and further research is needed to understand whether this is due to low rates of diagnosis, identification or if published rates include mild intermittent pain.BNF: British national formulary; EFNS: European federation of neurological sciences; (EFNS) NICE: National institute for clinical excellence; PDPN: Painful diabetic neuropathy; PHN: Post-herpetic neuralgia; PLP: Phantom limb pain; QoF: Quality and outcomes framework.The study was funded by Pfizer UK, without restriction on publication. Gillian Hall, Henry McQuay, and Steve Morant were funded by Pfizer to design and run the study to answer objectives provided by Pfizer. No payment was made for the development of the manuscript. Gillian Hall and Henry McQuay have received funding for research and consultancy from a number of pharmaceutical companies and charities. Steve Morant has received funding for consultancy from a number of pharmaceutical companies. Dawn Carroll and Zahava Gabriel were both employed by Pfizer at the time of the study and original development of the manuscript.GH contributed to all aspects of the study. SM contributed to the analysis and interpretation of data. DC and HM contributed to the design of the study and interpretation of the results. ZG contributed to the conception and design. All authors commented on and approved the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/14/28/prepubFirst-, second-, or third-line treatment for therapies prescribed to more than 100 patients by neuropathic pain condition; n (% with this therapy and dose included in this treatment regimen).Click here for fileDrugs used in the identification of cases of neuropathic pain .Click here for file


Purpose. Chronic low back pain (LBP) is often characterized by both nociceptive and neuropathic components. While various monotherapies have been reported of only limited efficacy, combining drugs with different mechanisms of action and targets appears a rational approach. Aim of this systematic review is to assess the efficacy and safety of different combined pharmacological treatments, compared to monotherapy or placebo, for the pharmacological treatment of chronic LBP. Methods. Published papers, written or abstracted in English from 1990 through 2011, comparing combined pharmacological treatments of chronic LBP to monotherapy or placebo were reviewed. Results. Six articles met the inclusion criteria. Pregabalin combined with celecoxib or opioids was shown to be more effective than either monotherapy. Oxycodone-paracetamol versus previous treatments and tramadol-paracetamol versus placebo were also reported as effective, while morphine-nortriptyline did not show any benefit over any single agent. Conclusions. In spite of theoretical advantages of combined pharmacological treatments of chronic LBP, clinical studies are remarkably few. Available data show that combined therapy, including antinociceptive and antineuropathic agents is more effective than monotherapy, with similar side effects.  Successful treatment of chronic pain depends on identification of the involved mechanism and use of appropriate therapeutic approaches. Woolf et al.  proposedmore preclinical, clinical, and translational studies are needed to improve the efficacy of combination drug therapy that is an integral part of a comprehensive approach to the management of chronic pain” [Even if there is increasing knowledge that different mechanisms of pain require appropriate treatments and often polypharmacotherapy, and although drug combination is frequently empirically adopted in the clinical practice –5, prospic pain” .Although many patients have self-limited episodes of acute low-back pain (LBP) and do not seek medical care , this coMedications are the most frequently recommended intervention for low back pain , 18. In Chronic LBP has been shown to be the result of neuropathic as well as nociceptive pain mechanisms and has therefore been classified as a mixed pain syndrome –25. NonsBased on this evidence, it has been suggested that antidepressants and/or anticonvulsants in combination with either opioids, traditional nonsteroidal anti-inflammatory drugs, or muscle relaxants could be useful in the treatment of this condition , 29, 30.http://www.google.com/, and http://www.yahoo.com/. Inclusion criteria were the following:Published papers written in English or including an English abstract, published from 1990 through 2011 and reporting the results of a combined pharmacological treatment of chronic lowback pain (LPB), compared with monotherapy or placebo, were reviewed. To this aim, we searched international databases, including EMBASE, PubMed/Medline, Google Scholar, SCOPUS, CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, papers written or with an abstract in English;papers concerning the results of management of chronic low-back pain (symptoms duration >6 months);treatment using a combination of two or more drugs, versus monotherapy or placebo.Two investigators, CR and ML, searched and reviewed independently the literature and classified the references found in terms of whether they should be included on basis of the title and the abstract of the paper. In addition to original study reports, review articles were also included and the reference lists from all reviewed articles were assessed to complete the literature search. At the end of the reviewing process, the two reviewers' lists of papers were compared and if any discrepancy occurred, reclassification was performed according to the consensus reached.This strategy identified 112 articles, the abstracts of which were hand searched to identify a subset with the specific focus of pharmacological treatment of chronic LBP of relevance to the current review. Six studies on pharmacological management of chronic LBP (irrespective of the cause) were identified as relevant and were included in this paper .n = 318), three-month treatment with tramadol 37.5 mg/paracetamol 325 mg yielded significantly greater improvements in pain VAS score (P < 0.015) and Pain Relief Rating Scale score (P < 0.001) than placebo. Significant improvements were also observed for Roland Disability Questionnaire (RDQ) scores, several of the sensory Short-Form McGill Pain Questionnaire (SF-MPQ) items, and the Role-Physical, Bodily Pain, Role-Emotional, Mental Health, Reported Health Transition and Mental Component items of the Short Form 36 . The rates of discontinuation due to insufficient pain relief were significantly lower with tramadol plus paracetamol (22.1%) than for placebo , and the proportion of patients and investigators rating treatment as “good” or “very good” was higher with combination therapy than with placebo . Adverse events were more common with the combination (68.9%) than with placebo (46.5%), as were adverse drug reactions (23.6% versus 3.8%) and rates of discontinuation due to adverse events (18.6% versus 5.7%). Nausea, somnolence, and constipation were significantly more frequent with combination treatment than with placebo (P < 0.05) [In the first study (P < 0.001). Combination therapy was also associated with significantly improved scores on several measures, including RDQ score and physical-related items on the SF-MPQ and SF-36 (P < 0.05). Similar results to those reported above by Ruoff et al. [In the second study, patients with at least moderate chronic LBP received tramadol 37.5 mg/paracetamol 325 mg in a fixed combination tablet; VAS scores after 3 months were significantly lower with tramadol/paracetamol than with placebo  or prevalent neuropathic pain (n = 72). Combination therapy was associated with an improvement in pain in the majority of compliant patients, although its benefit in patients with neuropathic pain was less marked.Gatti et al., in a prospective observational study  examinedP = 0.01) (nociceptive pain) and in patients with LANSS score >12 (P = 0.03) (neuropathic pain), but not when including all the patients. The drug combination also proved to be more effective than pregabalin alone or than celecoxib alone, except for patients with LANSS score <12, in which treatment combination or monotherapy provided similar results. When all patients were considered, celecoxib alone provided 12.4% pain reduction, pregabalin alone 10.4%, and their combination 38.2%. The largest pain reduction (51.8%) was observed with the association pregabalin/celecoxib in patients with LANSS score > 12. Pregabalin drug consumption, when used in association with celecoxib, was significantly lower (P < 0.05) compared to monotherapy. The occurrence of side effects was similar during either monotherapy or combination treatment [Two papers reported on the efficacy of pregabalin with, respectively, celecoxib  or transreatment .P < 0.01). In the first month of therapy buprenorphine TDS alone provided a meaningful pain reduction ; at the end of the first month, patients were then divided in two groups: Group A receiving one-month therapy with buprenorphine 35 μg/mL plus pregabalin 150 mg and Group B buprenorphine plus placebo. At the end of the treatment, only Group A presented a further reduction of the VAS (P < 0.01). The authors concluded that “buprenorphine TDS determines a notable relief from pain. Moreover the association of low doses of pregabalin allowed a further relief.”Similarly, Pota and coworkers  found thThe unique study evaluating the combination of morphine with nortriptyline , failed This systematic review shows that, in spite chronic LBP is thought to be commonly the result of both nociceptive and neuropathic mechanisms  and hencThis may due to different reasons includingthe difficulty in designing/performing clinical trials involving more treatments at the same time;potential drugs' interactions and possible adverse effects. Any specific combination of agents need to be first evaluated on the basis of the respective pharmacokinetic profile and possible interactions and then clinically tested. In free dose combinations, the onset of adverse events can, to some extent, be overcome by initiating treatment at low doses and slowly escalating the dose until maximum analgesia or intolerable side effects arise; drug combination may also provide reduced consumption of any single drug and adverse events comparable to monotherapy ;unpredictable dosing regimen. At variance with that reported above concerning the possible advantage of free dose combinations, fixed dose are easier to study and to market, being also likely associated with greater patient's compliance than free combinations; however, identifying the best dose ratio for all the patients, balancing the efficacy and tolerability of any single drug within a fixed combination may be a challenging exercise;scarce economical interest of drug companies.All of these potential drawbacks may, to a different extent, concur to explain the limited research on drug combinations, in spite of theoretical positive considerations and notwithstanding the empirical widespread use of drug associations in the clinical practice .Among the six studies that were included in the present review, two examined a fixed-dose regimen of paracetamol and tramadol combination against placebo , 36. TheOn the contrary, the association of pregabalin plus celecoxib  or of prP < 0.05) versus placebo, gabapentin, and morphine. More recently, Gatti et al. reported the Multicenter Italian Study, which compared the efficacy, safety, and quality of life of combination therapy with controlled release (CR) oxycodone plus pregabalin versus monotherapy in patients with neuropathic pain of various origins [P = 0.003) and to improve quality of life (P = 0.0009), while combination therapy also allowed dose reduction of both agents .Gabapentinoids have already been successfully used in combination with other analgesic drugs to improve neuropathic pain control. Gilron et al.  first re origins . This stInterestingly, in our reported study, celecoxib or pregabalin when used alone were shown to be not effective in patients with, respectively, neuropathic or nociceptive low back pain type, as evaluated with the LANSS pain scale . This isA recent systematic review of pharmacological monotherapies for chronic nonspecific low back pain  showed nOther frequently prescribed medications, like muscle relaxants , 20, havIt is worth noting how published comprehensive reviews of clinical trials  and evenPain treatment should be guided by the underlying mechanisms and should take into consideration pain quality as well as pain intensity. Chronic LBP often comprises both nociceptive and neuropathic components, and various monotherapies have been repeatedly reported as only partially effective. Therefore, an individualized, multimodal therapy, combining drugs with different mechanisms of action represents a rational approach. However, available studies investigating drug combinations are remarkably few. In particular, combination of pregabalin and celecoxib or buprenorphine has been demonstrated to be more effective that either monotherapy and relatively safe. The association of paracetamol with tramadol or oxycodone has also been shown to be effective for reducing chronic low-back pain, even if not evaluated against respective monotherapy. Further research in combined pharmacological treatment of chronic LBP with well-designed studies may offer valuable tools for the clinical practice and is strongly suggested.


We set out to review all available published data on mismanagement of TACs and HC patients in order to understand and avoid its causes. The search strategy identified 22 published studies. The most frequent errors described in the management of patients with TACs and HC are: referral to wrong type of specialist, diagnostic delay, misdiagnosis, and the use of treatments without overt indication. Migraine with and without aura, trigeminal neuralgia, sinus infection, dental pain and temporomandibular dysfunction are the disorders most frequently overdiagnosed. Even when the clinical picture is clear-cut, TACs and HC are frequently not recognized and/or mistaken for other disorders, not only by general physicians, dentists and ENT surgeons, but also by neurologists and headache specialists. This seems to be due to limited knowledge of the specific characteristics and variants of these disorders, and it results in the unnecessary prescription of ineffective and sometimes invasive treatments which may have negative consequences for patients. Greater knowledge of and education about these disorders, among both primary care physicians and headache specialists, might contribute to improving the quality of life of TACs and HC patients.Trigeminal autonomic cephalalgias (TACs) and hemicrania continua (HC) are relatively rare but clinically rather well-defined primary headaches. Despite the existence of clear-cut diagnostic criteria (The International Classification of Headache Disorders, 2 The trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders that includes cluster headache (CH), paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/cranial autonomic features (SUNCT). Hemicrania continua (HC) is a continuous unilateral headache form that, like PH, is indomethacin-responsive. HC is included in group 4 of The International Classification of Headache Disorders, second edition (ICHD-II) . Howeverrd European Headache and Migraine Trust International Congress, London, September 2012).The aim of this study was to review all published data, available to us, on mismanagement of TACs and HC, in order to understand its causes and help improve the management of these patients. These findings have been reported in preliminary form  AND ”. Only articles in English were considered. We also considered articles from the reference lists of the studies found to be relevant, as well as literature known, by the authors, to be relevant.Two investigators (M.V and F.A.) separately examined the abstracts of all the articles identified in the literature search. Whenever the article title or abstract suggested that the publication might contain relevant data, the entire manuscript was examined. The following relevant data were extracted from the accepted articles: publication information , type of study , sample (number of patients), clinical data . Agreement for data extraction was good. There were only two cases of disagreements that were resolved by consensus.The search strategy identified 169 published articles. Of these 169 papers, 13  were relMigraine seems to be a particularly frequent misdiagnosis. The different temporal patterns of migraine and CH attacks should make it possible to distinguish between these two conditions in the typical case, but if this aspect is not reported by the patient or thoroughly investigated by the physician, confusion may arise, given that many other features of these headaches can overlap. Migraine pain is frequently severe in intensity and unilateral in 2/3 of patients [, and 18% may have side shifts from one cluster period to the next [tooth/jaw problems is likely to be found in the history of CH patients, as 37% to 50% of them reported that the pain radiated to the lower jaw, upper jaw or cheek [Sinus headache (SH) is another misdiagnosis often encountered in clinical practice. According to studies on clinic-based and clinic-based plus non-clinic-based CH populations, this misdiagnosis is made in between 21% [trigeminal neuralgia (TN). Even though this scenario has been clearly reported by just one study (in which 16% of CH patients had previously been diagnosed with TN), [Although recent decades have seen an improvement in the time taken to diagnose CH from onset , the diapatients . In aboupatients . Moreovepatients . Unfortupatients ,30, morepatients . Anotherpatients . Many phpatients . Yet, upthe next . A previor cheek ,18,32. Tween 21%  of CH paween 21% , which, ith TN), ,34.With regard to treatment, many patients, in the course of the long diagnostic work-up of their CH, were administered inappropriate therapies . Moreover, even after the correct diagnosis, many of these patients were still prescribed with treatments not considered first-line options for CH according to the international guidelines  , may explain this confusion with dental-related pain [pain associated with temporomandibular disorder (TMD)[trigeminal neuralgia (TN), especially in the ca. 10% of PH patients in whom attacks can be precipitated by mechanical triggers [, but unusual in TN) [Cervicogenic headache (CEH) is a unilateral side-locked headache associated with evidence of cervical involvement (provocation of pain by movement of the neck or by pressure on the neck) [CH from PH, given the broad clinical overlap between the two conditions, although they did not report specific cases of misdiagnosis [sine qua non for the diagnosis of CPH [Although our literature review revealed few case series and case reports considering diagnostic pitfalls in PH, this condition appears to be most frequently misdiagnosed as ted pain . Howeverder (TMD). Yet, a der (TMD). The exctriggers . Howevertriggers , whereastriggers . Unfortul in TN) . The posl in TN) . Cervicohe neck) . CEH seehe neck) . Becausehe neck) , it can iagnosis . In thiss of CPH . A propes of CPH ,38.TN can be challenging, because the conditions have significantly overlapping clinical phenotypes. The main aspects to take into account include: autonomic features , the localization of the pain (V1 in SUNCT and V2/3 in TN), and refractory periods (absent in SUNCT and present in TN) [Primary stabbing headache (PSH) is an idiopathic condition, commonly experienced also by people with other primary headaches such as migraine (about 40%) and CH (about 30%). PSH is characterized by unilateral but erratic, moderate-to-severe, jabbing or stabbing pain, lasting from a fraction of a second to 3 seconds [dental pain. A review of TACs from the perspective of their implications for dentistry reported cases in which patients with SUNCT, in addition to experiencing facial pain, complained of pain radiating to adjacent teeth [We identified only two published cases of SUNCT misdiagnosed as other conditions; in both cases TN was one of the wrongly diagnosed conditions. Differentiating SUNCT from t in TN) . Primary seconds , and the seconds . SUNCT cnt teeth . This redental pain or TMD. According to a review and case reports on HC, patients can mistake their HC symptoms for toothache or TMD [migraine[CH[CEH. Both CEH and HC are side-locked unilateral headaches with a continuous temporal pattern (CEH can have either an episodic or a continuous fluctuating pattern) that can be accompanied by signs and symptoms of neck involvement  on HC too ) and by n HC too  . The ren HC too . SH as ai et al.  but alsoi et al. . The mosi et al. ,20,21,23In this study, we set out to collect, for the first time, all the original papers referring to diagnostic and therapeutic errors in TACs and HC. Our Medline search strategy detected 13 original articles out of the overall 22 papers that we were able to find in literature  and that were focused on this topic. These 13 manuscripts included all the major studies conducted in this area; indeed, 2593 of the total of 2614 patients were from studies reported in these 13 manuscripts. On this basis, the Pubmed search strategy that we set up can be deemed satisfactory. On the other hand, we cannot exclude the possibility that our search methods missed some articles not specifically focusing on this topic, but nevertheless containing data of interest for our purposes. Moreover, the likelihood that all data on errors in diagnosis and/or management of these conditions cannot be found in the literature is overwhelming. Not all physicians are inclined to report and/or search and publish “errors”. This is true not just for TACs and HC, but generally for all diseases. Nevertheless we have tried to supplement the relatively scarce literature data by also reporting our own experiences in clinical practice, and the experiences of colleagues (reported to us directly or at conferences).A novel aspect of this study was the attempt to identify the causes of errors (and the context in which they occurred) in order to understand them better and offer advice on how they might be avoided.Some of the diagnostic errors identified in this study derived from the fact that non-headache specialists  often are unaware of the less common nosological entities. There is thus a need for specific training in this regard. However, the reported literature also shows that neurologists and headache specialists are liable to making diagnostic mistakes. There may be different reasons for this. The fact that the best diagnostic tool for headache disorders, ICHD-II , fails to mention certain clinical features shared by TACs and HC, such as the localization of the pain  and associated symptoms  might lead even headache experts to making wrong diagnoses. To reduce the frequency of diagnostic errors, we suggest that these elements should be included in the forthcoming ICHD-III, at least in the comments sections.The majority of the observed therapeutic errors are due to misdiagnoses. However, even correct diagnoses are no guarantee of an optimal therapeutic approach. For example, drugs not constituting the first-line treatment were reportedly prescribed for correctly diagnosed CH , in spitIn conclusion, the results of this review underline the need, alongside the current useful international diagnostic criteria and therapeutic guidelines, for more education concerning TACs and HC, in order to improve their recognition and management.The authors declare that they have no competing interests.MV and FA designed this review. MV performed the electronic literature search. MV, FA and OS performed the manual search. MV and FA carried out the data extraction. All authors have made substantial contributions to analysis and interpretation of data, have been involved in drafting the manuscript or revising it critically for important intellectual content. All authors read and approved the final manuscript.


Clinical analgesic trials typically report response as group mean results. However, research has shown that few patients are average and most have responses at the extremes. Moreover, group mean results do not convey response levels and thus have limited value in representing the benefit-risk at an individual level. Responder analyses and numbers-needed-to-treat (NNT) are considered more relevant for evaluating treatment response. We evaluated levels of analgesic response and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score improvement and the associated NNTs.This was a post-hoc analysis of a 6-week, randomized, double-blind study (N = 387) comparing etoricoxib 90 mg, etoricoxib 120 mg, naproxen 1000 mg, and placebo in AS. Spine pain and BASDAI were measured on a 100-mm visual analog scale. The number and percentage of patients achieving ≥30% and ≥50% improvement in both BASDAI and spine pain were calculated and used to determine the corresponding NNTs. Patients who discontinued from the study for any reason were assigned zero improvement beyond 7 days of the time of discontinuation.For etoricoxib 90 mg, etoricoxib 120 mg and naproxen 1000 mg, the NNTs at 6 weeks compared with placebo were 2.0, 2.0, and 2.7 respectively for BASDAI ≥30% improvement, and 3.2, 2.8, and 4.1 for ≥50% improvement. For spine pain, the NNTs were 1.9, 2.0, and 3.2, respectively, for ≥30% improvement, and 2.7, 2.5, and 3.7 for ≥50% improvement. The differences between etoricoxib and naproxen exceeded the limit of ±0.5 units described as a clinically meaningful difference for pain. Response rates and NNTs were generally similar and stable over 2, 4, and 6 weeks.For every 2 patients treated with etoricoxib, 1 achieved a clinically meaningful (≥30%) improvement in spine pain and BASDAI beyond that expected from placebo, whereas the corresponding values were approximately 1 in every 3 patients treated with naproxen. Use of NNTs and responder analyses provide additional, complementary information beyond population mean responses when assessing efficacy compared to placebo and amongst active therapies. Clinical trials of analgesic medications in ankylosing spondylitis (AS) and other disease states typically report response as group mean results. However, research has shown that few patients are average and most have analgesic responses at the extremes -4. For eA more practical measure to estimate response is an individual patient responder analysis, which calculates the distribution of the magnitude of responses across individual patients, as has been done for osteoarthritis  and fibrThe numbers-needed-to-treat (NNT) approach allows a comparison to placebo in a single number, and conveys additional information about expected treatment benefits, beyond that expected for with placebo in a straightforward manner. It has been suggested that a difference of ± 0.5 NNT units is a clinically meaningful difference -10.The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group suggested that responder analyses in pain should be based on established thresholds of change considered to be important . SpecifiThe purpose of this post-hoc analysis was to evaluate the proportions of patients achieving improvements from baseline in BASDAI and spine pain of 15%, 30%, 50%, and 70% and their associated NNTs over time in a study of etoricoxib, naproxen, and placebo in AS . SpecifiThe methods of the trial have been previously published in detail . BrieflyPatients were ≥18 years of age, had a diagnosis of AS based on the modified New York criteria for AS  ≥6 monthClinical assessments were performed at screening, flare/randomization, and at weeks 2, 4, 6, 8, 16, 26, 43, and 52, and/or at the discontinuation visit. The co-primary endpoints of the original study were the patient assessment of spinal pain (100-mm VAS), patient global assessment of disease activity (100-mm VAS), and the Bath Ankylosing Spondylitis Functional Index (100-mm VAS). Secondary endpoints included patient global assessment of response to therapy  and BASDAI (100-mm VAS).The present responder analysis was limited to the initial 6-week placebo-controlled portion of the trial, and followed principles from IMMPACT  and ACTIThe PGART is a straightforward assessment of response, on a simple 5-point scale. For each treatment arm we calculated the number and percentage patients at each PGART level at Week 6. For both BASDAI and spine pain, the number and percentage of patients achieving ≥15%, ≥30%, ≥50%, and ≥70% improvement from baseline were calculated at Weeks 2, 4, and 6 and these values were used to determine the corresponding NNTs. Patients who discontinued from the study for any reason were assigned zero improvement beyond 7 days from the time of discontinuation.Since this exploratory analysis was descriptive in nature, no formal statistical hypothesis testing was performed, nor was adjustment made for multiplicity.Baseline patient characteristics are shown in Table As shown in Figure Predictably, for both BASDAI Figure  and spinConsistent with the results for the percentages of responders, NNTs were higher  when higher thresholds of response were required for both BASDAI Figure  and spinIn most cases for both spine pain and BASDAI score, the NNTs for etoricoxib were at least 0.5 units below those for naproxen, suggesting a clinically relevant difference favoring etoricoxib.The purpose of this study was to perform a responder analysis and calculate the associated NNTs to examine the influence of response thresholds and the time point chosen for analysis, in a trial comparing etoricoxib, naproxen, and placebo in AS . It was The primary report of this trial showed average improvement in BASDAI at 6 weeks of approximately 50% for the etoricoxib groups and 44% for the naproxen group. By examining the percentage of patients achieving various levels of improvements ranging from 15 to 70%, we found that at week 6, 70% of patients receiving etoricoxib and 57% of patients receiving naproxen experienced moderate improvement (≥30%) in BASDAI, and that approximately 48% and 38% experienced substantial improvement (≥50%), with 30% and 20% experiencing extensive (≥70%) improvement. Further, the percentages for spine pain response were generally similar. This provides a very different picture of response than mean changes, and would seem more relevant in communicating treatment expectations with patients. Consistent with the original report and the group mean analysis, substantially more patients receiving etoricoxib or naproxen achieved various thresholds of response for both BASDAI and spine pain than did patients receiving placebo, where active treatments were significantly more effective than placebo for both measures (p < 0.001) .The percentages of responders at 6 weeks for a given threshold were numerically higher for etoricoxib than naproxen, by about 10% for both BASDAI and spine pain. These differences favoring etoricoxib are reflected in the lower (better) NNTs with etoricoxib: after 6 weeks, approximately 1 in 2 patients receiving etoricoxib will achieve a 30% improvement beyond that seen with placebo, 1 in 3 will achieve a 50% improvement, and 1 in 4 will achieve a 70% improvement. By contrast, the corresponding values for naproxen are approximately 1 in 3, 1 in 4, and 1 in 6, respectively.Although a difference of 1 or 2 NNT units may not appear to be consequential, a difference of ± 0.5 NNT units has been previously cited as a meaningful difference ,15. SuchSome important patterns emerged. As noted, the percentages of responders in the active treatment groups were generally stable over time, whereas the percentages of responders in the placebo group tended to decrease over time. This likely reflects the extent and duration that placebo can exert a positive effect in a highly inflammatory condition. This observation likely accounts for the decreasing (improving) NNTs for active treatment over time despite the generally stable percentages of responders. This is interesting, and confirms that effective therapies generate stable, low NNTs in AS, as has been demonstrated in osteoarthritis . Where tNNTs in the range 2-3 at ≥30% improvement and 3-4 at ≥50% improvement for etoricoxib and naproxen for AS were much lower than the NNT of 7 seen for etoricoxib 60 mg or 90 mg after 12 weeks about in chronic low back pain . This spGroup mean results are usually a mandatory requirement for regulatory approvals and, despite the limitations described here, are valuable in demonstrating that a therapy works in general. In addition, statistics using group means are the most efficient clinical trial designs relative to a comparison of proportions. Further, group mean responses are often used by clinicians to make cross-study comparisons among agents, which is often necessary since this is the most common method of reporting in the literature. However, mm-based measurements of population means is likely to be a fairly abstract concept to most patients, and does not inform the individual's likelihood of response. On the other hand, NNTs are more straightforward to understand and likely more easily conveyed to patients. NNTs alone do not present a full efficacy profile, in the same way that group mean results also do not present a full profile, and it would be beneficial to include both types of results in studies to allow a more complete efficacy profile for clinicians accessing the literature. These NNTs have been calculated using outcomes regarded as important both by clinicians and patieThere are two other important aspects to this analysis. First, we looked at response at various timepoints and found that both the percentages of responders in the active treatment groups and the related NNTs were reasonably stable over time, consistent with previous research showing that early response to coxibs is highly predictive of later response . TherefoThe main limitation of this analysis is that it was post-hoc, although we did use established definitions for meaningful response . BecauseIn conclusion, we found that individual patient response is not normally distributed, and rather tends to fall toward the extremes, and as such is not accurately represented by group mean responses. Group mean data are important for understanding that a drug is clearly superior to placebo, but are less valuable for informing patients of expected responses. Responder analyses and NNTs should be presented alongside group mean clinical trial results as they provide a complementary view of efficacy data facilitate doctor-patient discussions of expected benefits, and are more clinically relevant.The original study and the present analysis were sponsored by Merck & Co., Inc. Drs. Peloso, Smugar, and Gammaitoni are employees of Merck, and may own or have options to own company stock. Dr. Wang was an employee of Merck when the analysis was performed. Dr. Moore has received research grants, consulting, or lecture fees from pharmaceutical companies, including Pfizer, Merck, GlaxoSmithKline, AstraZeneca, and Grünenthal, but received no remuneration for this work.HW performed the statistical analysis. SSS wrote the first draft. All authors analyzed and interpreted the data, reviewed and critically revised the initial draft, and all authors approved of the final submitted manuscript. No outside writing assistance was provided.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/12/165/prepub


Pain resulting from chronic pancreatitis is often debilitating and difficult to manage. Many approaches have been used to treat these patients, including narcotic analgesia, antidepressants, pancreatic enzymes, octreotide, denervation procedures, such as celiac plexus block, and various palliative, decompression, or drainage procedures. Many of these procedures can be performed endoscopically, while others require a more invasive, surgical approach. The effectiveness of these therapies is not only highly variable but also often controversial. This review will discuss the endoscopic options for pain management in patients with chronic pancreatitis and their utility in treating this difficult disease. Pain resulting from chronic pancreatitis is often difficult to manage. Many approaches have been used to treat these patients, including narcotic analgesia, antidepressants, pancreatic enzymes, octreotide, denervation procedures (most commonly CPB), and various palliative, decompression, or drainage procedures –13. The The celiac plexus lies anterior to the aorta at the level of the celiac artery. Most of the sensory nerves returning from the pancreas and other intraabdominal viscera pass through the celiac ganglion and splanchnic nerves. Interruption of these fibers may lessen pain in patients with chronic pancreatitis . Celiac CPB has traditionally been performed via various percutaneous and surgical approaches . RecentlSeveral studies have shown that EUS-guided CPB has a beneficial role in the treatment of pain induced by chronic pancreatitis , 24. An CPB is a generally effective, safe, and well-tolerated procedure. The three most common complications are transient hypotension (20% to 40%), transient diarrhea (4% to 38%), and transient increase in pain (9%), which are expected in CPB performed via any route , 26, 27.Patients with chronic pancreatitis associated with dilation of the main pancreatic duct, stone disease, or strictures may develop symptoms of severe abdominal pain. In addition to celiac plexus block, this pain can be treated endoscopically with procedures aimed at draining the main pancreatic duct, removing stones, and dilating strictures. ERCP with pancreatic sphincterotomy, dilation of strictures, placement of stents, and stone extraction has become a mainstay of therapy in patients with painful chronic pancreatitis as recent studies have shown that on average, over 65% of patients with strictures or stones treated with endoscopic therapy have shown improvement in their pain . Many stExperienced practitioners with advanced ERCP skills should only perform endoscopic therapies for chronic pancreatitis. In experienced hands, endoscopic pancreatic sphincterotomy is safe and effective and allows the therapeutic endoscopist access to the main pancreatic duct. This is usually performed under direct visualization with a pull-type sphincterotome after deep cannulation and guidewire insertion. The major risks of the procedure include pancreatitis, bleeding, and perforation. In addition, there is a risk of pancreatic sphincter stenosis that is considered a late complication after pancreatic sphincterotomy . Once ac Pancreatic duct strictures are usually caused by fibrosis around the main pancreatic duct as a result of the chronic inflammation seen in the disease process. Strictures that are focal and located towards the head and neck region of the pancreas are more amenable to endoscopic therapy. A recent prospective study was able to show a decrease in pain after ERCP with dilation and stent placement in 89% of patients; however after 2 years of follow-up 30% of patients had relapsed and required further therapy . In atteP = 0.001) [P = 0.042). Although endoscopic therapy is still considered first-line treatment, these randomized trials comparing surgical and endoscopic therapy should give the endoscopist pause to think about the procedures being offered to a patient for the treatment of pain in chronic pancreatitis.It is the prevailing belief by most endoscopists, including the authors, that endoscopic therapy should be attempted prior to surgical intervention. Endoscopic therapy is less invasive and shows similar results in the short term compared with surgical alternatives. Díte and colleagues presented data on the first randomized controlled trial comparing endoscopic versus surgical therapy, the latter consisting of resection and drainage procedures . A total= 0.001) . They al In conclusion, endoscopic therapy aimed at treating pain in patients with chronic pancreatitis consists of EUS-guided celiac plexus block and therapeutic ERCP procedures combined with ESWL that are all aimed at draining an obstructed pancreatic duct. As a result they have the potential to work well in patients with large duct disease, but they do not work well in patients with small duct chronic pancreatitis. Endoscopic management is safe and effective for many patients, but pain relief is often short lived requiring multiple repeat procedures. Endoscopic technologies as well as therapeutic techniques continue to evolve, and as such, improvements will likely be seen in the endoscopic management of chronic pancreatitis in the future.


Pain experience makes a serious anxiety for both patient and clinician before and after root canal treatment. Pain is a complex psychophysiologic phenomenon.The aim of this randomized control trial study was to evaluate the analgesic effect of Odontopaste® and a corticosteroid containing compound medicament between root canal therapy appointments.One hundred and twenty lower first and second mandibular molars with spontaneous pain and sensitivity to percussion were selected and divided into three groups (40 patients per each group). After root canal preparation, patients were entered one of these groups randomly. Root canals in group 1 were dressed with Odontopaste, in group 2 with a compound intracanal medicament, and in group 3 with placebo. Patients determined their pain rate and percussion sensitivity on Heft-parker VAS diagram, before the first appointment and 24 hours and 7 days after that.Spontaneous pain and Percussion sensitivity score averages of 24 hours after the first appointment in group 1 and group 2 were less than group 3, which indicates statistically significant difference between these groups. There was no statistically significant difference between these groups after 7 days neither on spontaneous pain nor percussion sensitivity.Odontopaste® and compound intracanal medicaments resulted in statistically significant reduction in postoperative pain and percussion sensitivity after 24 hours, but there was no statistically significant difference after 7 days with placebo. Pain experience makes a serious anxiety for both patient and clinician before and after root canal treatment. Pain is a complex psychophysiologic phenomenon . InflammMaintaining of patency during root canal cleaning and shaping, directly irritates periapical tissue and inadvertently extrudes bacteria, its byproducts, necrotic debris, and irritant solutions beyond the apex , 8. TherThe aim of this randomized control trial study was to evaluate the analgesic effect of Odontopaste® and a corticosteroid containing compound medicament between root canal therapy appointments.This randomized control trial study was performed on 120 patients (18-35 years old) at the endodontic department of Ahvaz dental school from December 2011 to October 2012. Sample size was calculated after a pilot study with 30 patients by using statistical software (SPSS version 16).The outline of this clinical control trial was approved by the Ethics in Clinical Research Committee of Ahvaz University of Medical Sciences.The inclusion criteria were:- Selected patients should have just one lower posterior first or second molar with spontaneous pain or sensitivity to percussion before the treatment.- Patients should not have history of any oral disease, sensitivity to antibiotic or corticosteroid, and should be without any systemic problems.- Female patients should not be pregnant or lactescent.- Selected teeth should be completely formed without any root resorption and pathological problems such as periapical lesions.- The patients should not have used NSAIDs at least 3 hours before the treatment.The exclusion criteria were:- Any procedural accident during the treatment.- Use of analgesics by the patient between appointments.- Those patients who could not be followed after seven days or had not been satisfied to continue the study or the pain rate was not recorded at 24 hours after the first appointment.- Any time after the first appointment, those cases who had severe pain, would be given analgesics and excluded from the study.Total 120 patients were selected and divided into three groups randomly by random number table. Canals were dressed with: Odontopaste medicament (Group 1), a compound medicament containing triamcinolone acetonide and clindamycin hydrochloride (Group 2), and placebo (Group 3). The procedural risks and benefits of treatment were explained to each patient and a written consent was taken before endodontic treatment. English Heft-parker diagram  was tranPatients determined their spontaneous pain and percussion sensitivity rates on the Heft-parker VAS diagram, in the beginning of any appointment. Complete anesthesia was achieved by local anesthetic solution . Access preparation was performed after rubber dam isolation by using a high speed hand piece with size 02 tapered fissure diamond bur. Coronal half of canals were prepared by No. 4, 3, 2 Gates-Glidden burs with crown down technique. After pulpectomy, working length (WL) was determined by digital radiography using ISO K-file #15 . Optimal length has been 1 to 2 mm short of the apex, and then canals were cleaned and shaped according to Protaper®  manufacturer orders. During canal preparation with crown-down technique by Gates Glidden and rotary Ni-Ti files, apical canal patency was maintained. After each file, root canals were irrigated with 5.25% sodium hypochlorite (NaOCl), and then 17% EDTA, finally canals were irrigated with normal saline. Canals were dried by absorbent paper points and the intracanal medicament of each group was inserted to each canal by a spiral lentulo. Finally a #25 K-file was inserted up to working length to confirm complete root canal filing with the medicament. The practitioner was blind about intracanal medicament and the assistant gave appropriate medicament on the glass pad, according to random number table. To avoid recontamination of the canal, access cavity was loosely packed with a sterile cotton pellet and was covered by Cavisol  between appointments. The patients were recalled to record the intensity of spontaneous pain and percussion sensitivity, on the Heft-parker VAS diagram, 24 hours after the first appointment. In the beginning of the 7-day appointment, patients determined their pain rates on the VAS diagram. The canals were obturated by gutta-percha with lateral condensation up to working length. The assistant also recorded a code for each medicament (Q-R-S) on patient file. Data was given to statistician blindly by codes, so the patient, practitioner and statistician were blind, and this study was triple-blind. If the patient required analgesics at any time, it would be prescribed and he or she would be excluded from the study. The placebo contained: Gel form Hydroxyl ethyl cellulose 6%, methyl paraben 0.2%, Sodium metabisulphide 0.2%, Sodium sulfate 1%, and Zinc oxide 2%.All of the 120 patients in this study had acute apical periodontitis and spontaneous pain. Patients were equally divided into three groups. In group 1, patients were treated with Odontopaste®, in group 2 patients were treated with a compound intracanal medicament containing corticosteroid, and patients in group 3 received placebo. Overall spontaneous pain score average of all patients in the three groups before the treatment was 128.8 ± 18.71 which decreased to 33.2 ± 11.31and 1.6 ± 3.87, 24 hours and 7 days after the first appointment respectively . Also, oPercussion sensitivity score average of 24 hours after the first appointment in groups 1 to 3 were 32.42 ± 12.44, 33.80 ± 12.18, and 44.37 ± 13.17, respectively. Although there was a significant difference between both medicaments  and placebo (group 3) , the difference between the results of groups 1 and 2 was not significant (P = 0.877) . For paiPatients with Odontopaste® and compound intracanal medicament experienced significantly less spontaneous pain and percussion sensitivity than placebo group (P = 0.00) after 24 hours from the first appointment. Welch analysis could not find any significant difference between percussion sensitivity score average of groups, 7 days after the first appointment (P = 0.203). The average score of spontaneous pain in groups 1 and 2 was 0 after 7 days, so it was not possible to compare groups at this period of time.The most significant finding of this study was reduction in spontaneous pain and percussion sensitivity by use of corticosteroid containing material as an interappointment medicament compared to control group. Endodontic literature contains few studies regarding the efficacy of Ledermix  a corticosteroid/antibiotic mixture in comparison with other intracanal medicaments, but there is a few studies about Odontopaste. Ehrmann et al. found that the flare-up (pain and/or swelling) scores mean of Ledermix was significantly lower than the flare-up scores mean of control group . Our stuIt seems that there is no real advantage for mixing calcium hydroxide with Ledermix or Odontopaste. There is no significant antibacterial enhancement in these calcium hydroxide combinations when compared to calcium hydroxide alone . So in tCorticosteroids containing intracanal medicaments like Odontopaste® reduce postoperative spontaneous pain rate and percussion sensitivity significantly, 24 hours after the first appointment, but our study did not show any significant effect 7 days after the first appointment.


Osteoarthritis (OA) is a common cause of disability and consultation with a GP. However research suggests the majority of sufferers choose not to consult their GP regarding their symptoms. Understanding the reasons for consulting is central to optimising patient outcomes. This review aims to summarise existing literature to identify what influences patients with OA to consult their GP.Due to the diversity of both qualitative and quantitative research that has addressed this research question a narrative review of literature has been conducted, backed up by a systematic literature search.Nineteen papers were identified describing influences on consulting behaviour in patients with likely OA. Health beliefs, such as perceiving OA as an inevitable part of older age about which nothing can be done, in addition to perceiving a negative attitude of the GP, are disincentives to consulting. Severity of pain and disruption of daily activities are important influences towards consultation. Social issues such as the availability of support networks are also likely to be influential. Evidence is lacking about the impact of multi-morbidity on consulting behaviour.Pain and disruption of activities appear to push towards consulting and negative attitudes regarding OA (from either the patient or GP) appear to be disincentives to consulting. Findings are limited by estimates of consultation frequency and research involving observation of consultations may improve understanding of these issues. Specifically, further research may address how pain and disrupted function are addressed and if negative attitudes are evident in the consultation. Osteoarthritis (OA) is a leading cause of pain and morbidity, and globally, is the fastest increasing cause of disability . DespiteUnderstanding the precursors or antecedents to the consultation is important for researchers and clinicians who aim to enhance the care of patients with osteoarthritis in primary care for two reasons. Firstly, the reasons for consultation are intertwined with an individual’s ideas, concerns and expectations , and theA number of studies have evaluated the influences on patients’ decision making around seeking healthcare for OA symptoms. This review aims to summarise what is currently understood about why patients with OA consult their GP, and was conducted within a wider programme of research aiming to enhance the care of patients with OA in primary care.An initial literature search, performed as a scoping exercise identified relevant research using a wide range of both quantitative and qualitative research methods. Due to the diversity of studies, a narrative review was therefore felt to be most appropriate to confer the flexibility needed to review the relevant literature. A narrative review is described as a 'first generation 'traditional’ literature review’; narrative reviews have a useful place for identifying themes and gaps in the literature and for informing direction of further research . This reInclusion of papers was deliberately not restricted. The aim was to include the broadest possible sample of papers, to determine all possible influences on consulting. Studies reporting consulting behaviour that have sampled older adults with joint pain, in contrast to clinically or radiologically diagnosed osteoarthritis have been included with two assumptions: that the factors affecting consulting rates are likely to be similar, and that patients with osteoarthritis are likely to account for the majority of respondents. Similarly, no exclusions were made on the basis of study design or patient population studied with the assumption that all studies may further understanding about consulting behaviours. 'Primary care consultations’ were defined as consultations between a GP and a patient for the purpose of this review, with consultations with other members of the primary care team excluded. To appraise the evidence, no single tool was appropriate for the diverse range of studies included. Particular attention has been paid to the characteristics of the sample and setting which may affect the transferability of the findings.In a number of papers identified in this review, the Andersen- Newman model was used to describe influences on consulting ,10-13. T1. Predisposing factors, the social and cultural characteristics of a person (including factors that may have existed prior to illness)2. Enabling factors, the logistical issues affecting accessing care3. Need factors, which are the most immediate cause for seeking healthcare and are usually related to the illness itself.The influences on consulting behaviour have been classified under these headings in the results and discussion, in order to provide a framework for the narrative review and to organise discussion of similar themes.Table A prospective study of consulting behaviour of older adults with knee pain demonstrated that female gender was a significant predictor of a new episode of consultation  and thisSimilarly, there does not appear to be a clear influence of age on consulting. Jordan et al.  found a Jordan et al.  and ThorThe influence of health beliefs on consulting was considered in both qualitative work looking at individuals’ perspectives and in quantitative population studies. Qualitative research reveals the nature of the beliefs and quantitative studies are useful for establishing the effect of the beliefs on behaviour. Prevalent disorders, such as joint pain, in the elderly may be regarded as less serious or as a normal consequence of ageing ,18, and Some patients hold the belief that OA is not a treatable condition, that 'nothing can be done’, and this may have been reinforced by previous visits to GPs ,19. CoxoPopulation studies demonstrated significant effects of health beliefs on consulting. Mitchell et al.  reportedSelf-efficacy has been shown to inversely correlate with total healthcare visits in patients with OA in another study, and was the psychological variable which best predicted healthcare use .Depression is an important condition that may be a barrier to consulting but again, the evidence here is somewhat contradictory. Consulters with severe knee pain in a study reported by Jordan et al.  were sigIn summary, the pre-disposing factors which appear to have the clearest association with consulting are health beliefs. Holding beliefs that OA can be treated successfully and perceiving severe consequences of pain have been associated with consulting in population studies, whereas believing OA is a 'normal’ consequence of ageing or that the GP may have a negative attitude towards OA are described as disincentives to consulting. Anger, frustration and depression may also be associated with consulting but the evidence here, particularly for depression is less clear.Jordan et al.  reportedRosemann et al.  reportedLiving in an urban area has been reported as a strong predictor of consulting with hip and/ or knee pain, whereas deprivation scores were not significantly related to consultation rates . In contIn summary, in terms of enabling factors, few studies have evaluated the impact of deprivation on consulting and none have looked at the influence of social networks. Living alone appears to be associated with higher consultation frequency. The influence of previous use of healthcare is an area where conflicting findings exist between quantitative and qualitative research, the former suggesting a positive influence.Studies show that pain severity is higher in consulters compared to non-consulters ,5,10,16 The data on consultation frequency would suggest that a large proportion of patients with severe pain are not consulting their GP about joint pain but are consulting with other problems ; consultRecent onset of pain (within one year) has been significantly associated with consulting with knee pain . In contCharacteristics of the pain, such as being of sudden onset, may lead patients to identify symptoms they perceive as less likely to be 'ageing related’ or normal for them and therefore more in need of medical attention .Linsell et al.  comparedDisruption of normal activities appears to be clearly related to consulting behaviours. Mobility problems were the most significant predictor of consulting a GP in a study of patients with self-reported hip and knee pain . The extOA patients have more multi-morbidity than age and sex matched controls ; howeverIn contrast, Schellevis et al.  report aBedson et al.  report tIn summary, disrupted function is a clear influence on consulting. Characteristics of joint pain including severity, duration and distribution also appear to influence consulting decision making. Multi-morbidity appears not to be associated with increased frequency of consultation for joint pain in patients with OA; however this finding may be limited by under-representation of patients in studies or by the completeness of medical record data.We have reported the influences on consulting a General Practitioner with OA using Andersen and Newman’s model of healthcare utilisation which incorporates biological, psychological and social factors.Health beliefs appear to be important predisposing factors in deciding whether or not to seek health care. The belief that OA is an inevitable part of ageing, about which little effective treatment exists and a perceived negative attitude of the GP are reported as disincentives to consulting. Health beliefs are also likely to interact with other identified themes; for example age, and the influence of previous healthcare use on consulting. Previous healthcare use has been associated with increased consulting, but could also result in fewer subsequent consultations if the patient perceived a negative response from the healthcare practitioner consulted. Other important health beliefs include perceiving severe consequences of pain and frustration, which are associated with increased likelihood of consulting. Depression is a further psychological variable for which the evidence is contradictory, and which is likely to be closely related to social context.The 'need’ factors, in the context of OA are mostly represented by joint related symptoms, impact of the symptoms or comorbidities. Disruption of daily activities appears to be an important driver to seeking medical help. Severity of pain is higher in consulters compared to non-consulters although tests of statistical significance yield contradictory results; individual patients have reported pain as of importance in qualitative research and the lack of statistical evidence to support this may be related to limits of the quantitative measures used. Qualitative research has demonstrated a vast range of descriptors that patients use to describe pain which suggests the questionnaire tools used may be limited in ability to capture the full pain experience , which mPatients with OA who consult their GP appear to have more comorbid conditions but how comorbidity affects consulting frequency about joint pain is not clear. Related to this is the finding that patients with severe pain are visiting their GP frequently about issues other than their joints. The literature would suggest these patients are not having their symptomatic joint pain managed, but this may be due to limitations in the various methods of estimating consultation frequency and content. Furthermore, the ways in which patients and doctors prioritise symptoms in the context of multi-morbidity is not well characterised in the literature.In general, the social aspects and 'enabling’ factors are reported on less frequently than other variables in research in this area, although living alone and the area of GP practice appear to be important. The healthcare system is a further important contextual influence and some of the observed differences in findings may be explained by variation in healthcare access and availability, for example, the relationship between health insurance and financial status and consulting. Furthermore, differences in GP training across countries may impact on the consulting behaviours.The predisposing, enabling and need factors are not mutually exclusive and there is some overlap between categories. For example, co-morbidities may be 'pre-disposing’ in the case of long term conditions that existed prior to the current illness, or 'need’ factors that are directly influencing the need for seeking health care. A further example are health beliefs, which may be classified as 'predisposing’, 'need’ or 'enabling’ factors. The model has been criticised for generally underplaying psychological factors .An alternative theoretical lens through which to consider access to healthcare is the notion of 'candidacy’ , althougOne of the general methodological limitations of the studies included relates to estimates of consultation frequency. Consultation prevalence that is calculated using only diagnostic codes may underestimate consultation prevalence as there is evidence that GPs exercise caution when using diagnostic codes and may favour symptom descriptors . Coded dA further limitation of the included studies that used quantitative measures to calculate influences on consulting are that these may underplay the interaction between variables. Depression for example, is an example where the evidence was weak and there may be variation in how this factor could influence consulting. One could argue that depression could both increase or decrease consultation frequency due to coping difficulties and lack of social support or due to isolation. Qualitative research may be better placed to explore complex influences, taking into account the social and environmental context.This review highlights two particular aspects of the consultation itself that require further evaluation and research. Pain and disrupted activities appear to be important drivers to consulting and so there is therefore a need to establish how these issues are addressed within the consultation. Not all aspects of the consultation may be recorded or remembered and therefore observation research is well placed to explore this further. Secondly, perceived 'negative’ attitudes to osteoarthritis have emerged as disincentives to consulting and a further need exists to establish whether this is evident in consultations. The subjective issue of negativity is also a difficult topic to research using retrospective measures such as post-consultation interviews, and would require a research approach that incorporated multiple perspectives on the consultation.GP: General practitioner; JP: Joint pain; OA: Osteoarthritis.The authors have no competing interests.ZP conceived the review, conducted literature searches, conducted the narrative review and drafted the manuscript. TS and ABH contributed to the narrative review and the manuscript. All authors read and approved the final manuscript.ZP is a Clinical Lecturer and Honorary Consultant Rheumatologist and conducted this review as part of a PhD using mixed methods to explore the osteoarthritis consultation in primary care. This is part of a larger programme of work aiming to enhance the care of osteoarthritis in primary care. TS is a Senior Research fellow with an interest in consultation research, and supervisor to ZP. ABH is a Professor of Medical Education and Consultant Rheumatologist and PhD supervisor to ZP.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/14/195/prepub


Although neuroimaging techniques have provided insights into the function of brain regions involved in Trigeminal Neuropathic Pain (TNP) in humans, there is little understanding of the molecular mechanisms affected during the course of this disorder. Understanding these processes is crucial to determine the systems involved in the development and persistence of TNP.in vivo  of TNP patients with positron emission tomography (PET) using the μOR selective radioligand [11C]carfentanil. Four TNP patients and eight gender and age-matched healthy controls were examined with PET. Patients with TNP showed reduced μOR BPND in the left nucleus accumbens (NAc), an area known to be involved in pain modulation and reward/aversive behaviors. In addition, the μOR BPND in the NAc was negatively correlated with the McGill sensory and total pain ratings in the TNP patients.In this study, we examined the regional μ-opioid receptor (μOR) availability Our findings give preliminary evidence that the clinical pain in TNP patients can be related to alterations in the endogenous μ-opioid system, rather than only to the peripheral pathology. The decreased availability of μORs found in TNP patients, and its inverse relationship to clinical pain levels, provide insights into the central mechanisms related to this condition. The results also expand our understanding about the impact of chronic pain on the limbic system. Trigeminal neuropathic pain (TNP) disorders, such as classical, atypical and postherpetic neuralgias, are persistent pain conditions that can be either spontaneous, or elicited by light touch to the face. The fac11C]diprenorphine) radiotracers or 11C]carfentanil, a selective μ-opioid receptor (μOR) radiotracer, have shown reduced opioid receptor availability in chronic pain syndromes such as rheumatoid arthritiscarfentanil was administered  through an intravenous line . 11C]carfentanil was synthesized at high specific activity (> 2000 Ci/mmol) by the reaction of 11C]methyliodide and a non-methyl precursor as previously described = 9.2 ms, echo time [TE] = 1.9 ms, inversion recovery preparation 500 ms, flip angle = 15°, 25/26 FOV, number of excitations [NEX] = 1, 144 contiguous slices, 1.0 mm slice thickness, 256 x 256 matrix. VBM8 toolbox . Cluster size is reported for voxels with p < 0.01 in the area of statistical significance.The control subjects and patients with TNP were compared voxel-by-voxel using unpaired t-test on μOR BPNo age differences were found between groups . TNP patients had average pain duration of 5.4 ± 1.6 years; two patients presented with either spontaneous or evoked pain, while the other two presented both pain modalities. On a scale from 0 to 10 (zero representing no pain and ten representing worst pain possible) the average of spontaneous pain intensity (n = 3) was 5.5 ± 1.3, while the average of evoked pain (n = 3) was 5.4 ± 3.9. All TNP patients had previously tried medications for pain control, including: carbamazepine (subject TNP 3), oxcarbazepine, gabapentin (subjects TNP1 and TNP4), pregabalin (subjects TNP 2 and TNP 4) and amitriptyline (subject TNP 2). Subjects TNP1, TNP2 and TNP3 were under pain control medication during the study. As described before, patients taking opioids were not recruited for this study. The FigureND in the ventral striatal area  of the basal ganglia, with the greatest difference being found in the left nucleus accumbens (NAc) (peak MNI coordinates x/y/z: -4/4/-5).  was also shown after treatment with radiofrequency thermocoagulation (RFTC) in patients with trigeminal pain[The present study compared the μOR BPrthritis, complexrthritis, clusterrthritis and neurrthritis,17,18. Tnal pain. Our finND were identified in fibromyalgia patients when compared to healthy controls. Conversely, short- and long-term increases in the μOR BPND were observed in the same area after traditional chinese acupuncture, which were associated with improvements in clinical pain ratings in fibromyalgia patients[[In our study, the most significant peak in binding potential reduction of μ-opioid receptors was in the left nucleus accumbens (NAc) of TNP patients when compared to age-matched healthy subjects FigureD. The NApatients. The resatients[,34.ND in the left NAc and the McGill scores (MPQPRI and MPQ sensory) in sample of four TNP patients (FigureND, and subjects with lower McGill scores displayed higher μOR BPND. Although the reduced sample size limits the conclusions about this relationship, the results suggest a relationship between the clinical presentation of TNP disorders, and μ-opioid neurotransmission in the NAc, an area related to both pain processing and motivational mechanism. Based on our results, it is possible to hypothesize that the chronicity of trigeminal neuropathic pain is also related to central nervous system molecular neuroplasticity at the level of the μORs in the limbic area of the basal ganglia. This initial proof of concept study supports the initiation of further studies to examine the central molecular mechanisms, such as endogenous opioid neurotransmission, that may influence the clinical course and treatment responses of patients afflicted with persistent TNP.Differences in function of NAc μ-opioid receptors could ultimately contribute to the clinical pain in trigeminal neuropathic pain disorders. A negative relationship was detected between the μOR BPs FigureE. SubjecND: μ-opioid receptor non-displaceable binding potential; NAc: Nucleus accumbens; IHS: International Headache Society; AAOP: American Academy of Orofacial Pain; IASP: International Association for the Study of Pain; VAS: Visual analogue scale; WMA: World Medical Association; MPQ: McGill Pain Questionnaire; PRI: Pain Rating Index; PPI: Present Pain Intensity; MRI: Magnetic resonance imaging; SPGR: Spoiled gradient recalled; TE: Echo time; TR: Repetition time; TI: Inversion time; NEX: Number of excitations; SPM: Statistical Parametric Mapping; MNI: Montreal Neurological Institute.TNP: Trigeminal neuropathic pain; PET: Positron emission tomography; μOR: μ-opioid receptor; μORs BPThe authors declare that they have no competing interests.MFD participated in the design of the study, carried out the experiments, analyzed the data, and drafted the manuscript. IKM analyzed the data, participated in the experiments and drafted the manuscript. TDN, MD participated in the experiments. TML participated in the design of the study and data analysis. EM contributed to the methods and illustrations. AAM and MBV participated in the design of the study. JKZ participated in the design of the study and drafted the manuscript. AFD, mentored, conceived, designed, obtained funding, coordinated the study, and participated in the writing of the manuscript. All authors read and approved the final manuscript.