To investigate the response of patients with peripheral neuropathic pain (PNP) to capsaicin 8% patch treatment in a clinical setting.Retrospective analysis.The Clinic for Pain Therapy and Palliative Medicine at the Medical Centre for the region of Aachen, Germany.Patients diagnosed with PNP who attended the clinic for capsaicin 8% patch treatment between January 13, 2010 and February 7, 2011.Pain intensity was assessed using the Numeric Pain Rating Scale (NPRS) at baseline and following each capsaicin 8% patch treatment. Changes in prescribed concomitant neuropathic pain (NP) medications and response duration were recorded.P < 0.001) 54% reduction in the mean number of prescribed concomitant NP medications taken by patients.Overall, 68 patients with PNP conditions, including facial neuropathy , polyneuropathy, post-herpetic neuralgia, and mononeuropathies, received 96 treatments with the capsaicin 8% patch. The 53 patients with a follow-up of ≥8 weeks demonstrated a 48.4% mean reduction in NPRS score from baseline to Weeks 1–8. Among the 37 responders (those exhibiting ≥30% reduction in NPRS score from baseline to Weeks 1–8), the median time to re-treatment was 125 days. Following treatment, there was a significant (This analysis demonstrates that in clinical practice, the capsaicin 8% patch provides rapid and sustained pain reductions in patients with a variety of PNP conditions and a significant reduction in prescribed concomitant NP medications. The capsaicin 8% patch can be a valuable addition to the NP treatment armory for certain patients. Neuropathic pain (NP) is pain that arises as a result of disease or damage to the somatosensory system related to a variety of underlying causes, including infections and physical injury Epidemiologic data suggest that NP affects up to 8% of the population in Europe The capsaicin 8% patch (Qutenza™) is an alternative treatment option for NP that is designed to deliver a high dose of capsaicin topically where the pain is experienced. Capsaicin, the active component of chili peppers, is an agonist of transient receptor potential vanilloid 1 (TRPV1) channels, which play an important role in the transmission of pain signals The capsaicin 8% patch was approved in the European Union (EU) in 2009 for the treatment of PNP in nondiabetic adults either alone or in combination with other medicinal products based on an extensive clinical trial program investigating its efficacy and safety for the treatment of NP, particularly in patients with PHN or HIV-AN In Phase III trials, the capsaicin 8% patch was generally well tolerated. The majority of adverse events were mild to moderate transient application-site reactions, such as pain and erythema The capsaicin 8% patch is a relatively new treatment modality in Europe, and here the authors describe an analysis of over 60 patients who have received this treatment at the Clinic for Pain Therapy and Palliative Medicine at the Medical Centre for the region of Aachen, Germany. Patients are treated for a variety of PNP conditions at this center, including PHN, radiculopathy, polyneuropathy, FBSS, facial neuropathy , and different types of mononeuropathies including posttraumatic and surgical. The aim of this retrospective analysis was to evaluate the efficacy and tolerability of the capsaicin 8% patch in a real-life clinical setting as a treatment for a variety of PNP conditions, including a number that were not investigated during the pivotal clinical trials.All patients with a diagnosis of PNP attending the clinic for treatment with the capsaicin 8% patch were included in the analysis. Patients receiving capsaicin 8% patch treatment included some with FBSS and radiculopathy whose pain was neuropathic in nature. Most patients were treated with the capsaicin 8% patch in accordance with the manufacturer's treatment guidelines. Exceptions were that two patients were treated on the face for severe trigeminal neuralgia in V2, 15 patients were treated with the capsaicin 8% patch without topical anesthetic pretreatment (please see below), and five patients were re-treated with the capsaicin 8% patch less than 90 days following their prior treatment, at Days 55, 57, 77, and 84.Duration of illness was estimated as the difference in months between the date of PNP diagnosis  and the date of first treatment with the capsaicin 8% patch. All treatments and assessments were consistent with usual standard of care.The application procedure for the capsaicin patch was carried out as described previously Following removal of the topical anesthetic, the capsaicin 8% patch was applied for 30 minutes to the feet and for 60 minutes to all other areas of the body. To enhance adhesion, the patch was either bandaged to the treatment site using elastic bandages or pressed against the skin using sandbags. After patch removal, the area was cleaned with cleansing gel to remove any residual capsaicin, and cooling measures, such as cool packs wrapped in thin cloth placed on the treatment area, were initiated to reduce any treatment-related discomfort. The duration of cooling was variable, depending on the needs of each individual patient, and it was recommended that patients continue to use cooling measures at home, as necessary.Treatment-related discomfort was monitored during and after the application procedure; for moderate pain, patients were offered oral analgesic medication, such as metamizol and/or cooling measures, while for more severe pain, patients were offered intravenous opioid treatment, such as oxycodone. Although not available in all countries, metamizol is an effective analgesic and is commonly used in Germany.Pain levels were assessed using the 11-point Numeric Pain Rating Scale (NPRS), asking patients the question “what is your pain now?” All patients received a baseline assessment in the clinic on the day of capsaicin 8% patch treatment to determine pretreatment pain levels. The patient's pain was assessed immediately after capsaicin 8% patch treatment, and then on Days 1 and 3, and during Weeks 1, 4, 8, and 12 following. Follow-up was carried out by telephone call or face to face clinic contact on Days 1 and 3, and Weeks 1, 4, 8, and 12.Change in pain was assessed both in absolute terms (unit of NPRS change) and as a percentage change from baseline (prior to the first capsaicin 8% patch treatment). Pain response to the first capsaicin 8% patch treatment was calculated as the percentage change between the baseline NPRS value and the average of NPRS scores at Weeks 1, 4, and 8. As in the capsaicin 8% clinical trials Patients were re-treated with the capsaicin 8% patch when their pain significantly increased and they were in discomfort again; pain did not have to return to baseline levels for re-treatment to be undertaken.Prescribed concomitant pain medications taken by patients were assessed throughout the follow-up period, and these medications were modified as appropriate. At the 4-week follow-up, potential changes to prescribed concomitant NP medications were discussed with the patient and initiated, as appropriate. Prescribed concomitant NP medications were recorded, and classified as opioids, anticonvulsants, or antidepressants.t-test, and concomitant pain medication change by Wilcoxon signed ranks. Subgroup differences were analyzed with independent-samples comparisons; one-way analysis of variance was used to assess difference in percentage change in pain between PNP subtypes.Inferential tests appropriate to the distribution of the dependent variables were selected. Within-subject differences before and after treatment were assessed by paired-samples comparison, pain score differences from baseline to follow-up by paired sample The re-treatment interval was calculated by the Kaplan–Meier method P = 0.05.All inferential tests were conducted using SPSS for Windows . The threshold significance level for all tests was set at Overall, 68 patients received a total of 96 treatments with the capsaicin 8% patch at the Clinic for Pain Therapy and Palliative Medicine at the Medical Centre for the region of Aachen, Germany, between January 13, 2010 and February 7, 2011. Of these patients, six had been diagnosed with FBSS or radiculopathy, two with facial neuropathy , six with polyneuropathy, 20 with PHN, and 34 with other types of peripheral neuropathy, which included patients with posttraumatic or surgical nerve injuries and mononeuropathies . Almost Of the 68 patients who received treatment with the capsaicin 8% patch, 22 received two treatments, five received three treatments, and one patient received four treatments. Eight-week follow-up data are available for 53 of the 68 patients, and 12-week follow-up data are available for 44 of these patients. The remaining patients had not yet reached their scheduled 8- or 12-week follow-up.P < 0.001) mean reduction in NPRS score compared with baseline. A significant reduction in pain was maintained up to 12 weeks posttreatment; those patients followed up at 12 weeks (N = 44) still exhibited a reduction from baseline pain score of 43.4% .In all patients (N = 68), the decrease in pain after treatment with the capsaicin 8% patch occurred rapidly and was evident from 7 days posttreatment . At Day P < 0.001) (P = 0.282) decrease in pain intensity for patients with all types of NP investigated. Of the 53 patients with ≥8-week follow-up, 70% (N = 37) responded to treatment with the capsaicin 8% patch , the mean reduction was 48.4%  . SimilarP < 0.001) reduction in the prescribed concomitant NP medication  taken by all patients, and those classed as responders, following treatment with the capsaicin 8% patch  discontinued all other prescribed pain medications after receiving a single treatment . Of the P = 0.017) lower than the original mean baseline levels recorded before the first treatment . The reduction in NPRS score observed after re-treatment with the capsaicin 8% patch was similar to that observed after the initial treatment  in the 16 patients who were observed for 8 weeks following re-treatment. Of these patients, 63% (N = 10) exhibited a ≥30% reduction in NPRS score from baseline to Weeks 1–8.The mean reduction in NPRS score from baseline to Weeks 1–8 was also similar following re-treatment compared with the first treatment , the median time to re-treatment after application of the first patch was 125 days (95% CI 93–157 days), and the mean was 191 days (95% CI 151–230 days).All patients completed 100% of the intended capsaicin 8% patch application time. Only four patients required analgesia for application-related discomfort during their first capsaicin patch application, a single dose of a short-acting opioid . One patient required medication with metamizol, 1.5 g, during re-treatment. All patients were provided with cooling measures to reduce treatment-related discomfort following patch removal, and patients were advised to continue to use cooling measures at home, as necessary. No other adverse events were reported.This retrospective analysis demonstrated that treatment with the capsaicin 8% patch in a real-life clinical setting significantly reduced PNP for at least 12 weeks in several conditions, including patients with FBSS/radiculopathy whose pain was neuropathic in nature, facial neuropathy , peripheral neuropathy, polyneuropathy, and PHN, which affect various sites of the body and are caused by different mechanisms. There did not appear to be any difference in response to the treatment between patients from each diagnostic subtype, although this analysis was clearly not powered to show equivalence. These data, which highlight the efficacy of the capsaicin 8% patch in several NP populations, are important because the capsaicin 8% patch has a broad license, being approved for the treatment of PNP in nondiabetic adults either alone or in combination with other medicinal products for pain. While the clinical trial program demonstrated efficacy in patients with PHN and HIV-associated distal sensory polyneuropathy (HIV-DSP), this analysis clearly demonstrates the efficacy of the capsaicin 8% patch in a much wider range of NP populations.This is the first article of which we are aware that reports an analysis of the efficacy of the capsaicin 8% patch in clinical practice. Overall, the pain reduction observed in this cohort of patients in a real-life setting was larger than that seen during the Phase III clinical trials The analgesic effect of the capsaicin 8% patch was rapid, being evident within 1 day post-application. This fast onset in patients treated in the clinic was consistent with data from the published data in PHN As previously demonstrated for patients with PHN and HIV-DSP Systemic treatments for PNP are associated with unpleasant side effects that can contribute to the burden of the disease itself Pharmacy costs are significant cost drivers of PNP treatment. A retrospective study using the MarketScan® database reported that among PHN patients in the United States, excess total costs for these patients resulted from higher costs for outpatient/professional services (54%) and pharmacy (45%) The application of the capsaicin 8% patch was generally well tolerated in this real-life setting, with a low proportion of patients (6%) requiring medication for application-related discomfort during the first capsaicin 8% patch application. Medication was not required by any patients during re-treatments, and there were no early discontinuations. Interestingly, the proportion of patients who required medication for application-related discomfort during this study was lower than in the clinical trials 15–44%; –16. ReasAs a retrospective analysis, this study is limited by a lack of randomization and placebo control, and only represents experience from a single clinic. Consequently, additional analysis of patient responses to the capsaicin 8% patch in other real-life clinical settings will be required to validate the data presented here. Additional studies across a wider variety of PNP conditions are also warranted, and patient benefits relating to the reduction in the use of concomitant medications should be explored further. Nevertheless, the data presented here support the efficacy of the capsaicin 8% patch to treat NP and suggest that response rates may even be higher when used in real-life clinical practice than they were during clinical trials. Furthermore, the data show that the capsaicin 8% patch can provide rapid and sustained reductions in pain levels in patients with a variety of PNP conditions, together with a significant reduction in the requirement for prescribed concomitant pain medications. These data indicate that the capsaicin 8% patch will be a very useful addition to the treatment options available for NP.


Comorbid conditions are highly prevalent among patients with end-stage renal disease (ESRD) and index score is a predictor of mortality in dialysis patients. The aim of this study is to perform a population-based cohort study to investigate the survival rate by age and Charlson comorbidity index (CCI) in incident dialysis patients.Using the catastrophic illness registration of the Taiwan National Health Insurance Research Database for all patients from 1 January 1998 to 31 December 2008, individuals newly diagnosed with ESRD and receiving dialysis for more than 90 days were eligible for our study. Individuals younger than 18 years or renal transplantation patients either before or after dialysis were excluded. We calculated the CCI, age-weighted CCI by Deyo-Charlson method according to ICD-9 code and categorized CCI into six groups as index scores <3, 4–6, 7–9, 10–12, 13–15, >15. Cox regression models were used to analyze the association between age, CCI and survival, and the risk markers of survival.There were 79,645 incident dialysis patients, whose mean age (± SD) was 60.96 (±13.92) years; 51.43% of patients were women and 51.2% were diabetic. In cox proportional hazard models and stratifying by age, older patients had significantly higher mortality than younger patients. The mortality risk was higher in persons with higher CCI as compared with low CCI. Mortality increased steadily with higher age or comorbidity both for unadjusted and for adjusted models. For all age groups, mortality rates increased in different CCI groups with the highest rates occurring in the oldest age groups.Age and CCI are both strong predictors of survival in Taiwan. The older age or higher comorbidity index in incident dialysis patient is associated with lower long-term survival rates. These population-based estimates may assist clinicians who make decisions when patients need long-term dialysis. During the study period, International Classification of Diseases, Ninth Revision (ICD-9) codes are used to define diseases. Personal information including family history, lifestyle, and habits such as smoking and alcohol use are not available from the NHIRD.This study is based on a longitudinal health insurance database, the National Health Insurance Research Database (NHIRD), provided by the Taiwan National Health Research Institute. Taiwan launched its compulsory social insurance program, National Health Insurance (NHI), to provide health care for all the island’s residents since 1995. The annual coverage rate of the NHI program ranged from 96.16% to 99.6% and includes contracts with 97% of hospitals and clinics, with more than 23 million Taiwanese residents enrolled since 1997. It covers all medical benefit claims of ambulant and inpatient care and is extensively applied to many epidemiological studies. The NHIRD established a registry system for “Catastrophic Illnesses”, including cancer, chronic mental illness, end-stage renal disease, congenital illness, and several autoimmune diseases. Insured persons with major diseases can apply for catastrophic illness registration cards from the Bureau of National Health Insurance (BNHI) and do not need to make co-payments when seeking health care for catastrophic illness. Both outpatient and inpatient claims of beneficiaries with a catastrophic illness certificate are collected in the catastrophic illness profile and are distributed as a package. The BNHI performs routine validations of the diagnoses by reviewing the original medical charts of all of the patients who apply for catastrophic illness registration. In this study, all cases of dialysis patients are obtained from the Registry of Catastrophic Illness Database, a subpart of the NHIRD. The issuance of catastrophic illness certificates is validated by at least 2 specialists, based on careful examination of the medical records, laboratory studies, imaging studies, and dialysis treatment. Only individuals who meet the diagnostic criteria for major diseases are issued a catastrophic illness certificate. The database included all relevant information about the “catastrophic illness certificate” status, such as diagnostic codes in the format of the From the Registry for Catastrophic Illness Patient Database, we selected all patients diagnosed ESRD defined as those who had catastrophic illness registration cards for ESRD (ICD-9-CM code 585) and started hemodialysis or peritoneal dialysis of more than 90 days of renal replacement therapy between Jan,1, 1998, and Dec, 31, 2008. The NHIRD are enrolled since 1997, so the study cohort started from 1998, as a wash-out period for one year, and we also extended the observation time until 2009 in this cohort study. We excluded individuals younger than 18 years (n = 377) or those who had renal transplantation either before or after dialysis (n = 1585). Patients receiving regular dialysis without catastrophic illness certificate were not included in this study.Under the reimbursement system, hospitals have to claim medical expenses from the NHI based on the diagnosis or treatment codes for the disease presented by their patients. We used all diagnosis codes for a full year to define the existing comorbidities, including outpatient and inpatient diagnosis codes before the date of starting dialysis, which is defined as the index date. CCI and age-weighted CCI are calculated according to all diagnosis codes for a full year before the index date on every inpatient or outpatient to define the existing comorbidities www.sas.com). All statistical tests were 2 sided. p-value <0.05 was considered statistically significant.Data is summarized using proportions, and means (±standard deviation) as appropriate. The association between CCI and mortality was assessed using Cox proportional hazards model and Kaplan–Meier estimate with log rank tests declaring survival in the follow-up period for dialysis patients for each CCI level. In the mortality analyses, the patients were followed until event (death) or censoring (lost to follow-up or end of follow-up period); which ever happened first. The variables were analyzed initially by univariate analysis, and statistically significant variables were chosen for multivariate analysis. Analyses were performed using the SAS statistical package  (data not shown). Males had higher risk of all-cause mortality compared to females significantly . For CCI scores, mortality increased steadily with higher comorbidity both for unadjusted and for adjusted models. Compared to the lowest comorbidity group (reference group), fully adjusted models of CCI 4–6, CCI 7–9, CCI 10–12, CCI 13–15, CCI >15 showed hazard ratios for mortality of 1.91 , 2.39 (95% CI 2.26–2.53), 2.42 (95% CI 2.28–2.57), 2.62 (95% CI 2.44–2.81), 2.78 (95% CI 2.53–3.05), respectively. For every increase of one point in the CCI score, the relative risk of death was 1.085  (data not shown). Mortality increased steadily with higher age or comorbidity both for unadjusted and for adjusted models. The study population in the analyses was representative of the Taiwan dialysis population and enrolled 79645 incident patients with ESRD. Patient’s clinical characteristics and comorbid conditions are listed in The present study used a nationally representative dialysis dataset to evaluate the ability of the Charlson comorbidity index to predict long-term survival in a large population of incident dialysis patients. Results suggest that the CCI is a good tool to assess comorbidity and predict survival in general dialysis population as previous studies validated p for trend hazard ratio is higher in age-weighted CCI than age or CCI only. In the elderly patient, dramatically increased hazard ratio by CCI groups are found .(DOCX)Click here for additional data file.Table S2Charlson comorbidity index (CCI) weight score.(DOCX)Click here for additional data file.Table S3Weighting for age.(DOCX)Click here for additional data file.


Trigeminal neuralgia (TN) is a clinical condition characterized by paroxysmal attacks of severe and electric shock-like pain along the distribution of one or more branches of the trigeminal nerve. Various medicinal or surgical modalities have been employed in the past with variable success. Newer methods were tried in search of permanent cure or long-lasting pain relief. The purpose of this paper is to present the review of the literature regarding the use of botulinum toxin type-A (BTX-A) in the management of trigeminal neuralgia. The English philosopher John Locke in 1677 firstly described the trigeminal neuralgia (TN). In 1756, Nicolaus Andre coined the term “tic douloureux” for the condition characterized by trigeminal neuralgia pain as well as muscle spasm. In 1773, John Fothergill gave detailed description of the trigeminal neuralgia [Trigeminal neuralgia (TN) is a painful disorder of the trigeminal nerve characterized by paroxysmal attacks of severe, electric shock-like pain typically present on one side of the face. Pain is unilateral and follows one or more of the distributions of the trigeminal nerve. Mandibular and maxillary divisions are more commonly involved than ophthalmic division. There is a slight predilection for female sex. The right side of the face is more commonly involved than the left side of the face. Trigeminal neuralgia affects approximately 1 person in 25,000 people. It is more prevalent in middle or old age group people . Various treatment modalities for trigeminal neuralgia include medicinal management, peripheral nerve injection of local anesthetic or alcohol, peripheral neurectomies, alcohol injection of trigeminal ganglion, and intracranial neurosurgical procedures . Clostridium botulinum. There are seven distinct antigenic subtypes of botulinum toxin. Botulinum toxin type-A (BTX-A) is the most commonly used form for cosmetic purposes [The botulinum toxin (BTX) is a naturally occurring neurotoxin that is produced by gram-positive anaerobic bacteria purposes . Clostridium botulinum fermentation. It is precipitated, filtered, and further processed into a vacuum-dried fine powder. A standard vial of BTX-A contains 100 units of toxin, 0.5 mg of human albumin, and 0.9 mg of sodium chloride [The BTX-A is prepared by Hall strain chloride . Botulinum toxin has a high safety profile, reflected by paucity of documented irreversible medical complications , 8. BotuBotulinum toxin is contraindicated in patients with known allergy or hypersensitivity reaction to botulinum toxin or human albumin. It is not recommended in individuals with neurological diseases such as multiple sclerosis, myasthenia gravis, and Eaton-Lambert syndrome. Botulinum toxin injections must be avoided or delayed in patients taking aminoglycosides as they interfere with neuromuscular transmission . The use of botulinum toxin during lactation and pregnancy remains controversial. There are few documentations of the safe use of botulinum toxin in pregnancy without any complications . FDA claThe main effect of botulinum toxin type-A (BTX-A) is on muscle contraction because of its binding to the presynaptic nerve terminals, thus inhibiting the release of the acetylcholine (Ach). It produces its antinociceptive effect in trigeminal neuralgia by several mechanisms. A direct analgesic action has been recognized, suggesting that BTX may act through an alternative mode of action . Most hypotheses assume that BTX-A inhibits the release of Ach as well as other neurotransmitters. Inhibition of the release of these neurotransmitters from nociceptive nerve endings can lead to pain relief. Second site for BTX-A action to produce analgesic effect could be postganglionic sympathetic nerve endings utilizing norepinephrine (NE) and adenosine triphosphate (ATP) as neurotransmitters. NE is increased in chronic pain, and ATP is involved in the stimulation of muscle nociceptors. It has been postulated that BTX-A may inhibit the release of these neurotransmitters and produce analgesic effect in cases of sympathetically maintained pain involved in complex regional pain syndrome . One fundamental feature of orofacial pain is its degree of complexity. Inflammation of the nervous system may be involved in the alteration of the peripheral as well as central component of sensory nervous system. This alteration of the sensory nervous system involves various mediators, receptors, conduction, transmission, phosphorylation process, and so forth –18. DecrLocal inflammation leads to peripheral sensitization of nociceptive neurons and thus increased pain inputs. This will lead to increased release of substance P (SP) in the spinal cord leading to central sensitization . SubstanRelease of glutamate peripherally results in inflammation, pain, and edema . GlutamaAnother mechanism, by which BTX-A leads to reduction in pain, is sensory nerve adaptation. It possibly results from decreased neuroeffector secretions from mast cells, blood vessel endothelium, and sensory nerve tissue . CholineBotulinum toxin (BTX) has been used in the past for the treatment of regional dystonias associated with pain or sensory disturbance. Botulinum toxin injections to treat spasmodic torticollis showed efficacy in relieving pain far greater than other symptoms of the syndrome , 31. TheBorodic et al. performed an open-label pilot study to evaluate the efficacy of BTX-A in the treatment of TN. A total of 11 patients suffering from trigeminal neuralgia were treated with BTX-A. Nonresponsiveness to at least 3 drugs was an important inclusion criterion for the study. Multifocal injections were given over the dermatome which is painful. Multiple sites spaced at 10 mm distance were injected to cover the painful anatomic region. Injections were given transcutaneously with depth of injection penetration ranging from 1 to 3 mm. The average dose of botulinum toxin type-A (BTX-A) used was 25–75 units (7.5 U per puncture site). They recommended that anatomic site for injection should be based on the patient's description and anatomical localization of pain on facial region. Brow and upper and lower eyelid injections should be avoided as they can lead to diplopia and ptosis due to diffusion of toxin into the orbit. Patients were evaluated at the 2nd and 6th weeks. The criteria for success were based on 50% reduction in pain intensity and frequency, reduction in the use of medication, and the patient's desire for further injection therapy based on perception of improvement with the first injection. Patients who respond favourably to the treatment are defined responders, and others were named nonresponders. They reported success in 8 patients (out of 11 patients of TN) for a period of 2–4 months. The reported complications were transient facial asymmetry during dynamic movements, slight erythema, or edema of skin at injection site. They recommended the use of lower doses initially to avoid facial weakness (criteria to limit the dose of botulinum toxin). They concluded that botulinum toxin type-A (BTX-A) is generally efficient at lower doses to alleviate facial pain. They also stated that their study was a pilot study and there is a need for a well-controlled study design to confirm these results .Türk et al. performed a randomized open-ended study to evaluate the effectiveness of botulinum toxin type-A (BTX-A) in patients with trigeminal neuralgia refractory to other treatment modalities. Eight patients were injected with 100 units of botulinum toxins in the region of zygomatic arch. Based on positive outcomes and lack of any significant adverse effects, they concluded that BTX-A can be utilized in cases of refractory trigeminal neuralgia . Piovesan et al. reported successful outcomes with the use of botulinum toxin type-A (BTX-A) in patients of trigeminal neuralgia. The botulinum toxin was injected transcutaneously among the branches of trigeminal nerve. The patients were evaluated using visual analogue scale (VAS) for pain relief on follow-up visits. Out of 13 patients enrolled in the study all patients showed improvement with peak effects reached in 20 days of therapy. Four patients remained pain free, and 9 patients reported partial pain relief with >50% reduction in medication usage. The beneficial effect lasts for approximately 60 days . Zúñiga et al. treated twelve patients of idiopathic trigeminal neuralgia which are unresponsive to the medicinal treatment. In this study, the dose of botulinum toxin type-A (BTX-A) ranged between 20 and 50 units. The botulinum toxin is injected subcutaneously in divided doses at various trigger zones along the involved branch of trigeminal nerve. For mandibular division, they recommended additional injection into the masseter muscle. Interestingly, they reported pain relief within few seconds of injection in contrast to other studies which stated that it required some time to develop peak effects. Patients were evaluated at weekly interval for 8 weeks. Visual analogue scale (VAS) was used to evaluate pain prior to injection therapy and after the botulinum toxin injections on follow-up visits. Also, frequency of paroxysmal attacks per day was compared with paroxysms after the injection therapy. The cumulative mean pain score on VAS prior to BTX-A injection was 8.83, and it reduced to 4.08 at the 8th week. Similarly, cumulative number of paroxysmal attacks per 24 hours reduced from 23.42 to 8.67 at the 8th week. The authors reported significant pain relief in 10 patients, while 2 patients did not benefit from BTX-A. The patients remain pain-free for an average period of 60 days. The only disadvantage is transient facial asymmetry due to facial muscle weakness. Although they reported beneficial results, they advocated double-blind studies with larger sample size to validate the utility of BTX-A in the treatment of trigeminal neuralgia .Wu et al. performed a randomized, double-blind, and placebo-controlled study to investigate the safety, tolerability, and efficacy of botulinum toxin type-A (BTX-A) in the management of trigeminal neuralgia. A total of 42 patients were randomly divided into experimental and placebo group . Out of 42 patients, 40 patients completed the study. The botulinum toxin was administered by either submucosal or intradermal skin injection. A total of 75 units of BTX-A were injected in divided proportions along the area of pain distribution. Similarly, placebo group received equal volume of normal saline. The outcome of the study was to evaluate the degree of pain relief based on visual analogue scale (VAS) for pain. Also, the frequency of pain attacks per day was recorded. Patients with ≥50% reduction in mean pain score at a 12-week period were considered as responders. Based on this criterion, patients who did not show 50% reduction in mean pain score were categorized as nonresponders to the treatment. On statistical evaluation, 68.18% patients in experimental group were responders as compared to 15.00% in the placebo group. The difference was found to be statistically significant. The authors concluded that botulinum toxin type-A may be a safe, novel, and efficient strategy for the treatment of trigeminal neuralgia .Few case reports in the literature reported benefits of the use of botulinum toxin type-A (BTX-A) in the management of trigeminal neuralgia , 37.Summary Author: Borodic et al. Types of study: open-label pilot study.  n = 11Number of patients in the study:  Inclusion criteria: idiopathic trigeminal neuralgia refractory to at least 3 drugs.  BTX-A dose: 25–75 U Method and site of injection: transcutaneous injection in the area of pain as described and localized by the patient, spaced at a distance of 10 mm. Depth of injection 1–3 mm. Criteria for success:  at least 50% reduction in frequency of paroxysm and intensity of pain, >50% reduction in dose of medication,patients' desire for further injection because of the appreciation of the beneficial effects of the first injection. Results: eight patients with beneficial effects were designated as responders. Beneficial effects last for a period of 2–4 months. Adverse effects: transient facial asymmetry during dynamic movements, slight erythema, or edema of skin at injection site. Author: Türk et al. Types of study: randomized open-ended study.  n = 8Number of patients in the study:  Inclusion criteria: idiopathic trigeminal neuralgia refractory to treatment.  BTX-A dose: 100 U Method and site of injection: transcutaneous injection in the area of zygomatic arch. Results: eight patients show beneficial effects. Adverse effects: mild facial asymmetry. Author: Piovesan et al. Types of study: open-label study.  n = 13Number of patients in the study:  Inclusion criteria: idiopathic trigeminal neuralgia refractory to treatment.  BTX-A dose: 25–75 U Method and site of injection: transcutaneous injection among the trigeminal nerve branches. Criteria for success:  at least 50% reduction in the dose of medication,  reduction in pain intensity as measured by VAS. Results: four patients were pain free and 9 patients have >50% reduction in the medication dose. Beneficial effects last for a period of 60 days. Adverse effects: transient facial asymmetry. Author: Zúñiga et al. Types of study: open-label study.  n = 12Number of patients in the study:  Inclusion criteria: trigeminal neuralgia refractory to medicinal treatment. BTX-A dose: 20–50 U Method and site of injection: subcutaneously in area of trigger zone. For mandibular involvement additional injections in masseter muscle.  Criteria for success:  total lack or significant reduction in pain intensity on VAS, decrease in frequency of paroxysmal attacks of pain per 24 hours. Results:  ten patients show significant reduction in pain (VAS). Beneficial effects last for a period of 60 days, cumulative mean pain score on VAS decreased from 8.83 to 4.08 at week 8, cumulative number of paroxysm per 24 hr decreased from 23.42/day to 8.67/day. Adverse effects: transient facial asymmetry. Author: Wu et al. Types of study: randomized, double-blind, and placebo-controlled study. n = 42 Number of patients in the study:  Inclusion criteria: trigeminal neuralgia. BTX-A dose: 75 U Method and site of injection: intradermal or submucosal injection in the area of pain distribution. Criteria for success: patients with >50% reduction in pain intensity on VAS, decrease in frequency of paroxysmal attacks of pain, patients' overall response to treatment. Results: patients with positive outcomes were designated as responders. In BTX-A group, 68.18% patients were responders as compared to 15.00% in placebo group. Adverse effects: transient treatment-related adverse effects.The review of the literature reported success with the use of botulinum toxin type-A (BTX-A) in the management of trigeminal neuralgia refractory to other treatment modalities. But a critical appraisal of the review is essential to establish it as one of the treatment modalities. Although the above-mentioned studies favor the use of BTX-A, few points definitely need to be discussed. In the study conducted by Borodic and Acquadro, trigeminal neuralgia patients have characteristic features of inflammatory phenomenon, that is, erythema and edema along with pain . These iNurmikko and Cruccu critically reviewed the studies related to positive outcomes of botulinum toxin type-A (BTX-A) in trigeminal neuralgia , 33, 37.Also, the studies conducted by Borodic and Acquadro , PiovesaIn a brief communication, Zakrzewska et al. critically analyzed the study conducted by Piovesan et al.  regardinTrigeminal neuralgia is a clinical entity characterized by severe pain. Various conservative medicinal, minor, and major surgical procedures were used in the past with variable success. Unfortunately, few patients failed to respond to these established treatment modalities. Various new treatment alternatives have been tried to provide permanent cure to the patient with minimal morbidity and mortality. Botulinum toxin type-A is one of the recent treatment alternatives. Limited number of case reports and open-ended studies reported favorable outcomes in this regard. But these studies lack scientific merits. Based on the review of the scientific literature, it can be concluded that the scientific literature is insufficient to definitely establish the efficacy of botulinum toxin type-A in the management of trigeminal neuralgia. Further studies with larger sample size are required in this regard.


Several medications have been proposed as the first line drugs in the treatment of migraine attack. However, the low efficacy, potential complications of medications and the intolerance of some patients for oral route due to nausea and vomiting establish a difficult situation in some migraine patients. This report describes a dramatic pain relief with 60 mg of intravenous propofol in a patient with migraine attack refractory to treatment with metoclopramide, promethazine, dexamethasone and meperidine. Pain relief in this patient besides earlier case reports suggests that subanesthetic doses of propofol may be an alternative to other treatment modalities for acute migraine. Migraine headache is a disabling clinical entity and a frequent cause of attendance to the emergency department. Several medications including intravenous non-steroidal anti-inflammatory drugs, paracetamol, triptans, Phenothiazines, new atypical antipsychotics, metoclopramide and opioids have been proposed as the first line drugs in the treatment of migraine attack -6. HowevAnecdotal evidence suggests that propofol may be effective at alleviating migraine headache. Nevertheless, the current knowledge is founded on a limited number of case reports with discriminated situations. A greater body of evidence with more varied case reports is required before suggesting the routine clinical application of this treatment or even conducting clinical trials. This report describes a dramatic pain relief with propofol in a patient with migraine attack unresponsive to metoclopramide, promethazine and meperidine.A 29-year-old woman was admitted to the emergency department for severe migraine headache accompanied by nausea and vomiting from four hours before admission. Her neurological exam was normal and the quality and pattern of headache was similar to her prior migraine attacks. She expressed the quality of her headache as a sharp, pulsating pain located in the area of the left temple and forehead. The patient had received dexamethasone 8 mg and meperidine 25 mg 2 hours before admission in a day clinic but the pain was not subsided. On admission, she received metoclopramide 20 mg diluted in 500 mL of normal saline plus meperidine 25 mg and promethazine 50 mg. About 20 minutes later the patients showed jerky movements in her hands while fully awake and still with complaint of severe headache. The jerky movements were attributed to the extrapyramidal complications of metoclopramide. One mL of Intravenous lidocaine 2% and 6 mL of propofol 1% was administered for the patient. The patient fell asleep after a few seconds for more than six hours. After waking up, the patient was completely pain free without any nausea or vomiting. She stated that her migraine attacks always had lasted more than the recent headache and she was now completely pain free and seldom had experienced a state of well-being like that. On follow-up call visit 72 hours after discharge, she was well without any headache.On history taking, our patient was on maintenance doses of topiramate and amitriptyline for her frequent migraine attacks. In spite of preventive treatments, she suffered from weekly attacks of migraine headache. Once started, her headaches were not responsive to oral medications including acetaminophen codeine and ibuprofen, and often required intravenous opioids for pain relief and ordinarily, the headaches lasted over 36 hours.The dramatic pain relief in our patient adds to the body of evidence on the therapeutic effects of propofol in migraine headache. The first and most important report of propofol administration for headache was on a mixture of 77 patients suffering from migraine or non-migrainous headache refractory to the usual methods of abortive treatment. In this report, subanesthetic doses of propofol effectively relieved the patient’s headache. 63 of 77 patients in this study reported complete abolition of their headache and only three of the treated patients reported a return of the headache on the day following treatment (Two major mechanisms have been proposed for the development of migraine: cortical spreading depression and cortical hyperexcitability or central sensitization. CSD is triggered when enhanced cortical activity coincides with other triggering factors. CSD induces the release of a variety of vasoactive and inflammatory substances which makes a condition known as sterile neurogenic inflammation . This phAnother suggested theory for the development of migraine is central sensitization. Central sensitization points to the pain response to non-painful stimuli known as allodynia or decreased pain threshold, clinically presented as hyperalgesia . PropofoThe headache in our patients was not subsided with the administration of dexamethasone, promethazine, metoclopramide and even meperidine. These drugs are routinely used in the emergency departments for the treatment of migraine attacks and several studies support their therapeutic efficacy -7. Pain


This study was performed to investigate the effect of live, spontaneous harp music on individual patients in an intensive care unit (ICU), either pre- or postoperatively. The purpose was to determine whether this intervention would serve as a relaxation or healing modality, as evidenced by the effect on patient's pain, heart rate, respiratory rate, blood pressure, oxygen saturation, and heart rate variability. Each consenting patient was randomly assigned to receive either a live 10-minute concert of spontaneous music played by an expert harpist or a 10-minute rest period. Spontaneous harp music significantly decreased patient perception of pain by 27% but did not significantly affect heart rate, respiratory rate, oxygen saturation, blood pressure, or heart rate variability. Trends emerged, although being not statistically significant, that systolic blood pressure increased while heart rate variability decreased. These findings may invoke patient engagement, as opposed to relaxation, as the underlying mechanism of the decrease in the patients' pain and of the healing benefit that arises from the relationship between healer, healing modality, and patient. Use of complimentary and alternative medicine (CAM) as an adjunct to healing has been studied in postoperative cardiac patients in a few settings. Kshettry et al.  found thMusic has been used as a CAM adjuvant for healing and symptom management. Research on this topic has increased over the last decade including four published reviews in the Cochrane database in the past 5 years. The data published to date suggest that listening to music affects multiple physiological parameters, especially those related to the autonomic nervous system (ANS). Bradt et al. reviewed the evidence for music therapy with cancer patients and concluded that music therapy may have beneficial effects on anxiety, pain, quality of life, heart rate (HR), respiration rate (RR), and blood pressure (BP) in cancer patients . AnotherOne possible mechanism by which listening to music can exert beneficial effects is through increased relaxation. White  studied Acute stress can activate the immune system and cause inflammation through the complement cascade . On the N = 17) addressed live harp music in a postoperative thoracic unit and found that live harp music decreased BP and HR and increased oxygen saturation (O2SAT) [One small study ( (O2SAT) . In addi (O2SAT)  research (O2SAT) . In thisThe purpose of this study was to investigate the effect of live, spontaneous harp music on individual patients in an intensive care unit (ICU), either pre- or postoperatively to determine whether it would serve as a relaxation modality, decreasing HR, BP and respiration rate and increasing HRV and whether, based on previous results, it would reduce self-reported pain. Each consenting patient was randomly assigned to receive either a live 10-minute concert of spontaneous music played by an expert harpist or a 10-minute rest period. The type and severity of the diseases were similar between the two groups.α values (95% confidence limits or α = 0.05). The calculated power was 0.87 and was above the sufficient statistical power of 0.8.This study used a case control design with pre- and postmeasurements on a convenience sample of all patients admitted to an academic ICU. The University of Arizona Institution Review Board approved the study design prior to its commencement. Before starting the study, a power analysis was performed to determine a statistically appropriate group size. Using previous data comparing HRV before and during self-administration of another alternative therapy, a group size of 25 was calculated. Power was estimated assuming standard All patients in the ICU who were able to consent, or who had a family member who could consent, were invited to participate, regardless of diagnosis or pre- or postoperative status. Patients who agreed was consented and the study performed. Measurements were made on patients between the hours of 10 am and 3 pm. The intervention was a 10-minute live, spontaneous harp session in the patients' rooms. The same harpist, a professional harpist and harp teacher, was used for all patients in the experimental group. She played spontaneous improvised music with the intention of helping the patients heal. For the control group, the patients were left in their rooms for 10 minutes and advised to relax during that time period. Each participant (cases and control group) was given CD of the harpist at the end of the session as a thank you and as incentive for participation in the study.Heart rate variability is a noninvasive measure of the complementary relationship between the sympathetic and parasympathetic branches of the ANS . Instrumhttp://kubios.uef.fi/. Algorithms within the software program provide interactive interpretation of waveforms for the raw interbeat interval data collected. During analysis any abnormal beats were manually removed from the data. Artifacts due to slight movements of the patients were also eliminated. In cases in which too much data are eliminated, some HRV indices cannot be properly estimated. We therefore introduced an artifact percentage threshold of 10% to our analysis [Prior to the harp or control session, a plethysmograph (pulse sensor) was clipped to the subject's ear lobe for HRV measurements. When HRV was recorded, the patients were resting, either lying in bed or sitting on a reclining chair, and they were asked not to speak during the measurement to prevent movement artifacts from confounding the data. The sensor was attached to a computer via an emWave PC (HeartMath LLC) device that output inter-beat interval (HR) data to a text file that was analyzed in greater detail using a freeware HRV program, analysis . Data fi2 SAT, RR, and HR were collected from the monitors or from the patient, directly. Patient pain report, as per the thermometer visual pain scale, ). There was no significant difference in pain for the control group pre- and postrest session. Seven of the 50 patients in the control group and 11 out of the 50 patients in the music group were asleep during the experiment and so no pain scores could be obtained from those patients. Our statistical analysis showed that there were no significant differences regarding age or gender between the two groups from whom we obtained pain scores.Statistical analysis demonstrated no significant difference between control and music groups for patient age or gender. These results are presented in 2 SAT, BP, RR, and HRV) did not show any significant differences pre and postmusic or rest period. These data are presented in Tables P = 0.002, chi square = 9.62). It is unlikely that this difference affects the HRV data because gender differences in HRV disappear after age 50 [The other physiological parameters  and RR and pain (such as opiates). In an effort to reduce the impact of this study as much as possible on nursing care in the ICU, patient medication data were not collected from the electronic medical records of the participants. That element would have added an entirely different aspect to our study, because it would have compelled nurses to stop their work and check their patient's chart with us, thus disrupting the flow of work in the ICU. For this reason the data analysis could not be adjusted to account for medications that impact HR, BP, and RR. Had patient data been stratified into cardiac and pain medications this may have led to different findings. Since pharmacological interventions were already in place to keep the patients' outcome measures as low and stable as possible this also means that the effects of the harp music on outcome measures were probably underestimated. Although it would be interesting to repeat this study on patients not taking medications that affect the ANS, this is not clinically or ethically feasible for patients in pain.While our study reveals that spontaneous live harp music significantly decreased patient perception of pain, the music did not significantly affect RR, HR, HRV, BP, or ONotably, the HRV measures in our music group trended toward a decrease after intervention, although these findings were not statistically significant. The small size of the effect was probably due to the fact that many of the outcome variables were most likely modified or dampened from the pharmacological interventions the patients were receiving. That being said, these trends are potentially an interesting finding. A larger study would likely illuminate this result, especially if the data were stratified by pharmacologic interventions.Another trend was that systolic BP increased slightly in the music group after intervention despite pharmacologic control. This finding contrasts with another result  in whichThe idea that varying tempos of music may have different effects on the ANS highlights the concept that the decreased pain experienced by some of the patients in our study may not be from relaxation, but from engagement with the music. This idea is consistent with the observed slight reduction in HRV. This response may be evidence of the impact of a healing dynamic within the healer-patient relationship. Our harpist played directly to whatever she was sensing within the patient in order to enable healing through the music and through her presence with the patient. One aspect of this study that is unique is the participation of a master harpist and composer who is able to play spontaneous compositions directed specifically towards each patient's needs. This type of playing may have captured the effect not of relaxation by the patient but of engagement in a healing relationship. Patients reported they felt better and more energized. This may be reflected in the decreased pain and also slight rise in BP. It would be interesting to complete another study with taped harp music and see how this in would be compared to the live sessions and controls.These findings, if sustained and amplified in a larger study, could lead to an interesting discussion about what other measures could be introduced into the ICU to engage patients, that is, an increase in volunteers, reading to patients or having other health related practitioners visit patients in the ICU. In fact, perhaps focusing on the patient's attention is a significant factor in pain control. It seems that the human aspect of this focus is important, as many of the patients were already watching television when they were asked to prepare for the intervention. The control patients continued to watch television, an engaged focus with no relationship. The harpist's intention was to fully engage the patient, not to make them relax. The intervention engaged the patients visually (for those awake), auditorially and socially. Perhaps engaging patients in a multisensorial way will reduce pain and decrease the use of pain medication in an ICU-like setting.There were limitations to the study. Firstly, the patients were all in the ICU, some preoperatively, some postoperatively, and some were in the ICU for the only reason of needing a monitored ICU bed when there was ICU over-flow. Therefore not all the patients had a cardiac diagnosis. This is the practical reality of how the ICU unit runs in the hospital in which this study was performed. The decision was made to include all patients as potential candidates for the music or control groups to mimic reality in the event that this intervention was to be adopted by this hospital.Another confounding variable was that other family members or acquaintances often joined the participants. In order to mimic reality as much as possible, all individuals in the music or the control group were taken as they were without asking anyone to leave the room. However, the effect of other people in the room could have altered the patient's relaxation state and healing response. Since the intervention needs to be feasible for routine usage, the presence of patient visitors remains a confounding variable that cannot be assessed. A third limitation to the study was that the 2-group design did separate out the effects of the actual music from those of the nonverbal interaction between the harp player and the patients. Inclusion of a third group of patients listening to recorded harp music would show which of these two factors is of primary importance in reducing patient pain perception.Lastly, since participation in the experiment was voluntary, patients who did not like harp music could decline. There are data indicating that the individual taste of patients affects how effective music is as an intervention . Our stuDespite the limitations, the impact of this study on the environment of the ICU is important. One of the clinical nurse specialists who oversaw the ICU wrote this comment to us. “As so many of us, I truly believe in the healing properties of music and would love nothing more than to share this with others. This harp study has been a wonderful experience for both our patients and staff,” .2 SAT were not significantly affected. Possibly each patient was affected differently on an autonomic level, with differing degrees of arousal and relaxation, because the harp piece for each individual containing a different combination of tempos that the harpist perceived was most appropriate for them. The reduction in patient's perception of pain supports the introduction of live harp music into the ICU as a non-invasive means to reduce patient pain.This study reveals that spontaneous live harp music significantly decreased patient perception of pain by 27% in a ICU setting, but on average RR, HR, HRV, and O


The primary objective of this study is to review the efficacy of duloxetine in treating chronic pain using the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations for clinical significance across chronic pain states. These include pain intensity, patient ratings of overall improvement, physical functioning, and mental functioning. This review comprised the side-by-side analyses of 12 double-blind, placebo-controlled trials of duloxetine in patients with chronic pain . Patients received duloxetine (60 to 120 mg/day) or placebo. Average pain reduction was assessed over 3 months as the primary efficacy outcome. Other measures used were physical function and Patient Global Impression of Improvement. In 10 of the 12 studies, statistically significant greater pain reduction was observed for duloxetine- compared with placebo-treated patients. The response rates based on average pain reduction, improvement of physical function, and global impression were comparable across all 4 chronic pain states. Compared with patients on placebo, significantly more patients treated with duloxetine reported a moderately important pain reduction (≥30% reduction) in 9 of the 12 studies, a minimally important improvement in physical function in 8 of the 12 studies, and a moderately important to substantial improvement in Patient Global Impression of Improvement rating in 11 of the 12 studies. The analyses reported here show that duloxetine is efficacious in treating chronic pain as demonstrated by significant improvement in pain intensity, physical functioning, and patient ratings of overall improvement. The prevalence of chronic pain in the United States and Europe has been estimated at 35.5%  and 19% Unlike acute (nociceptive) pain, chronic pain is a pathological state associated with functional and structural changes within the peripheral and central nervous systems. Among these changes, central sensitization and impairment of associated pain inhibitory circuits have been extensively researched -12. ThesThree main categories of chronic pain are typically recognized . These ivia the descending pain inhibitory pathways in the brain and spinal cord .For continuous variables, an analysis of covariance (ANCOVA) model was used including baseline value, treatment, and investigator. Type III sum-of-squares for the least-squares mean (LS Mean) was used to assess treatment difference. For the categorical variable, Fisher’s exact test was used to assess the treatment difference. For time-to-first-response analysis, the Kaplan-Meier survival estimate was calculated by treatment group at each time point (Week 1 to Week 13). Patients who did not meet response criteria were considered as right-censored observation . Treatment difference was assessed through log-rank test.The term ‘significant’ indicates statistical significance throughout the manuscript. SAS version 9 was used to perform all statistical analyses.Among OA and CLBP patients, the majority were Caucasian (86.6%), female (63.4%), had a mean age of 56 years, and a mean duration of study drug exposure of 77.7 days. For DPNP patients, the majority were Caucasian (84.4%), male (56.8%), had a mean age of 60 years, and mean duration of study drug exposure of 77.6 days; whereas, in FM patients, the majority were Caucasian (87.5%), female (94.8%), had a mean age of 50 years, and a mean duration of study drug exposure of 110.2 days. In duloxetine-treated OA and CLBP patients, the most common (≥5%) adverse events were nausea (13.9%), dry mouth (7.0%), constipation (6.9%), insomnia (6.6%), diarrhea (5.7%), dizziness (5.7%), somnolence (5.6%), and fatigue (5.0%). The most common (≥5%) adverse events among duloxetine-treated DPNP patients, were nausea (23.9%), somnolence (15.9%), dizziness (11.0%), diarrhea (9.6%), insomnia (8.9%), fatigue (8.6%), constipation (9.4%), hyperhidrosis (8.5%), dry mouth (7.5%), and decreased appetite (5.3%). Among duloxetine-treated FM patients, the most common (≥5%) adverse events were nausea (29.3%), headache (20.0%), dry mouth (18.2%), insomnia (14.5%), fatigue (13.5%), constipation (14.5%), diarrhea (11.6%), dizziness (11.0%), somnolence (9.6%), hyperhidrosis (6.8%), and decreased appetite (6.5%).1). In the 2 remaining studies, duloxetine was numerically better than placebo. The observed baseline pain severity across the studies was approximately 6. On average, duloxetine-treated patients reported pain reduction of -1.43 to -3.14, while the range for placebo-treated patients was -0.67 to -1.93.Patients taking duloxetine 60 mg to 120 mg daily, on a group mean level, demonstrated significantly greater reduction in 24-hour average pain compared with placebo in 10 of the 12 chronic pain studies (Table 2). On average, the 30% and 50% response rate for duloxetine-treated patients ranged from 37% to 69% and 26% to 53%, respectively, while the range for placebo-treated patients was 27% to 49% and 15% to 35%, respectively.On the level of individual patient response, duloxetine-treated patients reported a significantly higher response rate in 8 of the 12 chronic pain studies based on 30% response criteria and 7 of the 12 studies based on 50% response criteria (Table 3).Compared with patients on placebo, patients treated with duloxetine had a significantly greater response rate in physical function improvement in 8 of the 12 studies (Table 4).Compared with patients on placebo, patients treated with duloxetine had a significantly greater PGI-improvement response rate in 11 of the 12 studies .Duloxetine hydrochloride is a selective dual 5-HT and NE reuptake inhibitor with central analgesic properties. Preclinically, duloxetine is efficacious in models of persistent, inflammatory, and neuropathic pain -21, suggDuloxetine-treated patients demonstrated a significantly greater pain reduction compared with placebo-treated patients in 10 of the 12 studies and a numerically greater reduction in the remaining 2 studies.Patients receiving duloxetine for the treatment of chronic pain states had significantly higher response rates corresponding to clinically moderate and substantially important improvement compared with patients receiving placebo.et al. [A 30% reduction from baseline to endpoint was used as one measure of response. A previous report by Farrar et al.  estimateet al. . A subseet al.  has alsoDuloxetine-treated patients demonstrated significant improvement in physical functioning in 8 of the 12 studies. Patients receiving duloxetine showed significant physical-function improvement as assessed by the BPI-Interference, as well as disease-specific measures like WOMAC physical function subscale (OA), and RMDQ-24 (CLBP). Regardless of the measures used in these studies, patients with chronic pain had a significant improvement in overall physical functioning.There was also a significant overall improvement in duloxetine-treated patients as demonstrated by the PGI-improvement rating (a measure of the degree of change at the time of assessment).The time-to-response data demonstrated that there was a significant separation between duloxetine and placebo at 1 to 2 weeks for 9 of the 12 studies and at Day 21 for the remaining 3 studies.The limitations to this work should be noted. The results are based on 3-month long trials and the results may not be extrapolated to longer treatment durations. The results of these studies also may not generalize to all individuals with chronic pain conditions, since patients with certain comorbidities were excluded from the studies.Based on the study design for each of the individual studies, the time-to-onset of significant pain relief may not be comparable. However, in a majority of the studies, the time-to-onset of response is 1 to 2 weeks.Even though IMMPACT recommends assessing mental functioning as part of the clinical response using Beck Depression Inventory (BDI) in clinical trials, this paper did not include such analyses because BDI was only collected in 8 of the 12 studies. These studies excluded patients with clinically significant impairment in mental function, and, in addition, patients with major depressive disorder (MDD) were excluded from all studies except those in FM. As a result, the BDI total scores at baseline were very low (ranges from 4.29 to 7.33 for studies that excluded MDD) at the outset and consequently there was not much room for improvement.In summary, the analyses reported here show that duloxetine is efficacious in treating four distinctively different chronic pain conditions, as demonstrated by clinically significant improvement in pain severity, physical functioning, and patients’ ratings of overall improvement. The overall pattern and magnitude of response were comparable across the 4 chronic pain conditions, suggesting that duloxetine is an effective centrally-acting general analgesic.


Several studies have been conducted on managing migraine headaches and developing effective medications for decreasing migraine-associated pain.P = 0.01) from 8.87 ± 0.83  to 1.12 ± 0.83  before and 30 min following the injection.Intravenous propofol was prescribed (10 mg every 5 min) for eight patients with intractable migraine headaches visiting the Emergency Department. The average pain score experienced by patients was recorded using the Visual Analogue Scale at the beginning of the treatment procedure and following the injection for 30 min . The patients’ reported pain scores decreased significantly (It seems that in the treatment of intractable migraine headaches, GABAergic receptors, compared to the normal conditions, have a lower activity status.Because of the high tendency of propofol to GABAergic receptors, it probably changes this physiological condition by activating the receptors, which results in a significant pain reduction. The International Association of Headache introduced acetaminophen and NSAIDs as common treatments for mild to moderate migraines, and selective 5-HT agonists (triptans) in more severe cases . HoweverP = 0.01). Before starting treatment, all patients complained of nausea, and five had vomited. Furthermore, four patients complained of photophobia and phonophobia. In all cases, after treatment, concomitant problems such as nausea, vomiting, photophobia and phonophobia had completely resolved. One patient experienced a brief period of drowsiness for 10 min, and in another case, oxygen saturation dropped to 89%, which was appropriately managed by nasal O2. Adverse events such as decreased levels of consciousness, changes in blood pressure, tachycardia or bradycardia were not recorded in any of the patients. All patients were followed up by phone for 72 h after release from the ED. Of eight patients being followed up during this time period, six never experienced headache recurrence again and remained without symptoms. However, case 1 experienced a headache and 24 h later rated his pain as 5/10; it was relieved by NSAIDs. Case 8 experienced headache recurrence 36 h later and rated her pain as 4/10. This pain was also appropriately relieved by NSAIDS.In this study, eight patients who presented to the emergency department, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran with headaches were examined . These pIn the mentioned cases (1 and 8) there was no need for re-admission to the ED and receiving IV medications since the severity of the pain was less than at the first presentation to the ED (VAS = 10/10 and 9/10).So far, little work has been done regarding the role of propofol in the treatment of migraine headaches. Common medications used for the treatment of this kind of headache include opioids, NSAIDs, ergotamine compounds, triptans, antiemetics and other analgesics. During acute migraine attacks because of absorption disorders (even in the absence of nausea and vomiting), the intravenous route is preferred .Prescription of intravenous propofol in subanesthetic doses in these eight patients caused pain relief for refractory migraine headaches. Propofol is a medication that is often used for inducing anesthesia in the operating room -6. The eAlso, another study indicated a global decrease in metabolism of CNS . Its phaIt seems that the therapeutic effects of propofol are due to its effects on the chloride channels in the β1-subunit of GABA receptors .Drummond et al. also reported the successful treatment of two cases of resistant migraine headache with intravenous propofol .Krusz et al. reported the first study of propofol use for headaches in 2000. This study indicated that 82 percent of patients were completely pain free. In the rest of them the pain decreased between 50 to 90 percent. None of the subjects experienced any drowsiness or disorientation after propofol prescription. Only a few patients had transient lethargy and unintelligible language (4–3 min), and one other (case 8) had spontaneous finger movements. The researchers concluded that propofol can be used in the clinic or emergency department as a definitive therapy for treatment-resistant migraines without side effects. In this study, the dramatic effect of propofol on pain relief in refractory migraine headaches was mentioned to be due to the high affinity of propofol to GABA receptors, which have a low activity status in migraines. Propofol, by stimulating these receptors, overcomes this physiological process and, as a result, migraine headaches can be cured. Researchers also considered using other medications with the same mechanism (GABA stimulators) as potential medications in treating migraine headaches and other types of headaches; this requires more research and investigation [Furthermore, there are several other reports demonstrating the efficacy and good therapeutic effects of intravenous propofol in the treatment of refractory migraines .As compared with other similar studies, because of its quite large sample size the present study is of significant importance for the assessment of intravenous propofol’s efficacy in the treatment of intractable migraine headaches (case series).Also, there are studies that investigated the role of propofol in the treatment of non-migraine-type chronic headaches. For example, in a study that was conducted on patients with daily chronic headaches resistant to common treatments, more than 90% of patients showed significant improvements in their headaches, and also no symptoms have been reported. Based on the results of this study, propofol administration under reliable monitoring and in controlled conditions was suggested for daily chronic headaches .High efficiency of intravenous propofol in the treatment of acute resistant migraine headaches can pave the way for new treatments in the field of migraine headaches and also be an appropriate replacement for other common medications for the treatment of migraines. With more complementary research, it will be possible to introduce this medication as a new and quite effective medication in the treatment of acute migraine headaches because of its wonderful effect of decreasing pain, rapid onset of action, safety and few side effects. However, there are still many questions about the pathophysiology and exact mechanism of migraines, and more studies are required to explore this field.It seems that in refractory migraine headaches, GABAergic receptors are in a lower activity status . BecauseEvery aspect of the present study was explained to the patients, and we obtained their written consent for participation in the study.VAS, Visual Analogue Pain Scale; NSAIDs, Nonsteroidal anti-inflammatory drugs.The authors declare that they have no competing interests.HS, AAT, AT and RG collected clinical data, reviewed the literature on the topic and drafted the manuscript. KM and MS analyzed and interpreted the patient data. All of the authors were involved in patient management or the writing of the manuscript. All authors read and approved the final manuscript.HS is Associate professor of Anesthesiology and Critical Care, Fellowship in Trauma Critical Care and CPR at the Department of Emergency Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. He is also editorial board member of Emergency medicine journal (EGM) and Pakistan Journal of Biological Sciences (PJBS). AAT is Assistant professor of Neurology at the Department of Neurology, Tabriz University of Medical Sciences, Tabriz, Iran. AT and RG are Assistant professor of Internal medicine and Emergency Medicine at the Department of Emergency Medicine, Tabriz University of Medical Sciences, Tabriz, Iran, respectively. KM is an Anesthesiologist in the Nikookari Hospital, Tabriz University of Medical Sciences, Tabriz, Iran. MS is member of Gastroenterology Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran.


Low-contact-stress (LCS) mobile-bearing total knee arthroplasty (TKA)  provides excellent functional results and wear rates in long-term follow-up analyses. Radiological analysis shows radiolucent lines (RLL) appearing immediately or two years after primary implantation, indicative of poor seat. Investigations proved RLL to be more frequent in uncemented TKA, resulting in a consensus to cement the tibial plateau, but their association with clinical findings and patients discomfort and knee pain is still unknown.553 patients with 566 low-contact-stress (LCS) total knee prostheses were screened for continuous moderate knee pain. We compared tibial stress shielding classified by Ewald in patients suffering from pain with a matched, pain-free control group on blinded X-rays. We hypothesized a positive correlation between pain and radiolucency and higher frequency of such radiolucent lines in the most medial and most lateral zones of the tibial plateau.Twenty-eight patients suffered from knee pain in total. Radiolucencies were detected in 27 of these cases and in six out of 28 matched controls without knee pain. We could demonstrate a significant correlation of knee pain and radiolucencies, which appeared significantly more frequently in the outermost zones of the tibial plateau.Our findings suggest that radiolucent lines, representing poor implant seat, about the tibial plateau are associated with knee pain in LCS patients. Radiolucencies are observed more often in noncemented LCS, and cementing the tibial plateau might improve implant seat and reduce both radiolucent lines and associated knee pain. Low-contact-stress (LCS) mobile-bearing total knee arthroplasty (TKA)  provides excellent functional results and wear rates in long-term follow-up analysis -4. The LEarlier studies demonstrated RLL to be more frequent in uncemented TKA, resulting in a consensus to cement the tibial plateau ,17, yet Therefore, this multicenter study screened 553 patients with 566 low-contact-stress total knee prostheses for continual moderate knee pain determined by the Knee Society Score . SelecteThe primary purpose of this study was to test for a correlation between knee pain and tibial radiolucent lines. The secondary purpose was to describe the distribution of radiolucencies around the tibial plateau.The study hypothesis was, that knee pain correlates with tibial radiolucent lines and that these radiolucent lines appear most frequently in the most lateral and most medial zones of the tibial plateau than in more central areas.Due to the retrospective nature of this study using anonymous data, after contacting the ethics committee it was stated, that ethical approval was not necessary at both universities.This study was designed as an age and sex matched case control study. A sample of 553 anonymous patients with 566 LCS implants was reviewed. The indication for knee replacement was based on subjective pain level, a continual need for analgesic and anti-inflammatory drugs, and objective functional limitations such as reduced walking distance and decreased range of motion. Osteoarthritis of the knee joint was verified by use of anterior-posterior and lateral X-rays. All procedures were done between January 1981 to June 2003 at two different institutions by five different surgeons.From this sample we excluded patients with septic tibial loosening, low-grade infections, or aseptic tibial loosening (n = 13) evaluated by detailed laboratory screening  or scintigraphy or any kind of femoral loosening (n = 24) as the cause . In addition, we excluded all patients with aseptic tibial or femoral loosening, which was verified using scintigraphy (n = 43). Furthermore we excluded patients with polyethylene wear, a postoperative antero-posterior long-leg standing X-ray axis of more than 5 degrees of varus or valgus, any soft tissue impingement, patellar complications, infections, reflex sympathetic dystrophy, flexion contracture, inadequate flexion,  signs of notching, overhang, overstuffing or undercutting and clinical instability (n = 67). From the remainder we included patients with at least "moderate" knee pain on the KSS were as cases, and an equal number of age- and sex-matched, pain-free patients as controls.Anonymized clinical and radiological data for all patients were obtained from a database of digitalized patient records. All patients included in this database gave informed consent to participate in the follow-up and were aware, that anonymized, aggregate data will be used for research. Therefore after contacting the ethics committee it was stated, that approval by the ethic committee was not necessary due to the retrospective nature using anonymous data.Procedures were done in general or epidural anaesthesia with a medial parapatellar or transquadricipital approach in a consecutive series at each institute. Five orthopaedic surgeons operated on the patients in total. All surgeries were performed by or under direct supervision of the head of the division of arthroplasty of both institutes. First the tibial osteotomies were performed, according to the LCS guidelines from DePuy with a posterior slope of 5° using an extramedullary system. The femoral cut was performed with an intramedullary guide system providing 3° of external rotation using the posterior condyles as reference points. Patella resurfacing was not done. This technique was applied using totally cemented  and only tibial cemented prosthesis according to the patient age and bone quality. Tibial and femoral cementation was performed with standardized methods according to the manufacturer' s instructions using Refobacin Bone Cement R (RBC)  and Palacos R + G (PRG) . Constituents were stored at room temperature (23°C) before preparation. The samples were mixed for 30 seconds after the addition of all the powder to monomer, under a vacuum of 200 millibar using the Easymix cement injector . No fractionation of the tibial plateau and the femoral shield was performed in any case. All knees were closed in layers with two drains in place, which were removed after 48 hours. which was not proven to restore the long-leg standing axis more appropriately . No singPostoperatively, patients were allowed full weight bearing and continuous passive motion was used as of the second postoperative day. All patients were discharge between 10 and 14 days postoperatively and referred to an outpatient rehabilitation program until their six week follow-up.All patients in both clinics had standardized pain management protocols: Neodolpasse i.v. (combining 75 mg diclophenac and 30 mg orphenadine) was given twice a day and Pantoloc p.o. (pantoprazol 40 mg) once a day for at least ten days. Patients with allergies or kidney disorders were given Novalgin i.v. (metamizol 1 g) three times a day in combination with Pantoloc p.o. (pantoprazol 40 mg) once. In case of further pain, an injection of Dipidolor i.m. (piritramide 7.5 mg) was given every 4 hours.At 2 to 10 year follow-up the patients were clinically evaluated using the WOMAC score and Knee Society Score . In caseP-value of less than 0.05 was considered to be significant.Independent t-tests were used to compare demographic parameters across groups. The observer agreement of the radiological evaluation was evaluated using the Cohen's kappa coefficient. The correlation between the pain  and radiolucent lines was evaluated using Pearson's coefficient. We evaluated post hoc power according to the method by Hoening and Heisey  All calcThe patients' mean age (including 533 patients) at time of surgery was 68.3 years (range: 39 to 89). The mean age at mean clinical follow-up of 7.3 years range: 2 to 10) was 75.6 years (range: 44 to 95). Demographic data is presented in table  to 10 waAt follow-up (range 5 to 10 years) the mean active range of motion (ROM) of all 566 prostheses was 102.4 degrees (range: 5 to 145). The mean WOMAC score   in the most medial/ lateral zones of the medial "zone 1" (31.6%) and lateral plateau "zone 4" (26.6%) than in less medial/lateral zones or the stem zone "zone 2 to 7"   of the tibial plateau.Parsch et al.  showed 6According to Aebli et al.  radiolucIn addition, the size of the tibial anchoring pad is larger than the femoral, making it more difficult to achieve adequate press-fit to avoid tibial stress shielding as another cause for patients discomfort after implantation of a LCS TKA .In order to guarantee adequate measurements and detection of tibial radiolucent lines, the authors performed an inter- and intraobserver correlation analysis of two observers resulting in a "good" agreement. However, according to Vyskocil et al.  radiolucThis study could demonstrate a significant correlation in patients with continual moderate knee pain with radiolucent lines, which predominantly appear in the most medial and most lateral zones of the tibial stem, but we lack further radiological information of the occurrence of possible radiolucencies in the remaining 510 pain-free patients or patients reporting only very discrete knee pain. Furthermore, we only evaluated standard anterior-posterior radiographs without data of fluoroscopically-assisted radiographs. Next, surgeries were not performed by one single surgeon but by five different surgeons in total, which could have possibly leaded to further bias of the data. However, implantation of total knee arthroplasty is a procedure only open to experienced surgeons in both clinics and mostly performed under supervision of the head of the division of arthroplasty. In addition, patients of this study had relatively long hospitalization time (average of 2 weeks), which is typical for the authors' countries but might differ from other European or US countries. Furthermore, we did not correlate the initial time when pain was reported with the first appearance of radiolucent lines but those two parameters (pain and RLL) at follow-up in general.It should be noted, that with the sample size of 56, the magnitude of differences in affected tibial zones with radiolucencies was large enough that post hoc power analysis revealed over 80%. Last, we are able to present the radiological and clinical data from all patients who suffered from continual moderate knee pain matching our inclusion criteria.We could demonstrate a significant correlation of continual moderate knee pain and the appearance of tibial radiolucent lines and that these radiolucent lines appeared significantly more frequently in most medial and most lateral zones. We believe that in case of no further specified pain after implantation of the LCS prosthesis, radiolucencies, which do not imply implant loosening, should still be suspected as the possible cause of pain. Surgeons should try to avoid the appearance of radiolucencies by implanting cemented tibial plateaus using perfect cuts and avoiding uncemented TKA systems.There exist no financial or non-financial competing interests in case of any author of this manuscript. No benefits or funds were received in support for the study.PS: preparation of the manuscript, data collection, study design; AL: revision of the manuscript, statistical advice; PW & JF: revision of the manuscript, statistical analysis, data analysis; GG & NK: revision of the manuscript; operating surgeons; KP: data collection, study design; VJ: revision of the manuscript, operating surgeon; BW: study design, revision of the manuscript. All authors read and approved the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/12/142/prepub