Beyond Hot and Spicy: TRPV Channels and their Pharmacological Modulation.

Transient receptor potential vanilloid (TRPV) channels are part of the TRP channel superfamily and named after the first identified member TRPV1, that is sensitive to the vanillylamide capsaicin. Their overall structure is similar to the structure of voltage gated potassium channels (Kv) built up as homotetramers from subunits with six transmembrane helices (S1-S6). Six TRPV channel subtypes (TRPV1-6) are known, that can be subdivided into the thermoTRPV (TRPV1-4) and the Ca2+-selective TRPV channels (TRPV5, TRPV6). Contrary to Kv channels, TRPV channels are not primary voltage gated. All six channels have distinct properties and react to several endogenous ligands as well as different gating stimuli such as heat, pH, mechanical stress, or osmotic changes. Their physiological functions are highly diverse and subtype as well as tissue specific. In many tissues they serve as sensors for different pain stimuli (heat, pressure, pH) and contribute to the homeostasis of electrolytes, the maintenance of barrier functions and the development of macrophages. Due to their fundamental role in manifold physiological and pathophysiological processes, TRPV channels are promising targets for drug development. However, drugs targeting specific TRPV channels, that are suitable for drug therapy, are rare. Moreover, selective and potent compounds for further research at TRPV channels are often lacking. In this review different aspects of the structure, the different gating stimuli, the expression pattern, the physiological and pathophysiological roles as well as the modulating mechanisms of synthetic, natural and endogenous ligands are summarized.

Multimodal Analgesic Plan for Children Undergoing Chimeric 14.18 Immunotherapy.

Immunotherapy with the chimeric 14.18 anti-GD2 antibody (ch14.18) is associated with severe neuropathic pain. Different analgesic modalities have been employed, but pain management remains challenging and side effects such as desaturation, bradycardia, and hypotension have been reported. We retrospectively analyzed the efficacy of a multimodal regimen based on gabapentin, ketamine, and morphine in controlling pain during ch14.18 chemotherapy. In our cohort, the pain was low, desaturation and hypotension were infrequent, and no episode of bradycardia was reported. Morphine consumption was similar to other studies. Our results suggest that this regimen may be a valid analgesic option in children undergoing ch14.18 infusion.

The Therapeutic Potential of Cannabis in Counteracting Oxidative Stress and Inflammation.

Significant growth of interest in cannabis (Cannabis sativa L.), especially its natural anti-inflammatory and antioxidative properties, has been observed recently. This narrative review aimed to present the state of the art of research concerning the anti-inflammatory activity of all classes of cannabinoids published in the last five years. Multimodal properties of cannabinoids include their involvement in immunological processes, anti-inflammatory, and antioxidative effects. Cannabinoids and non-cannabinoid compounds of cannabis proved their anti-inflammatory effects in numerous animal models. The research in humans is missing, and the results are unconvincing. Although preclinical evidence suggests cannabinoids are of value in treating chronic inflammatory diseases, the clinical evidence is scarce, and further well-designed clinical trials are essential to determine the prospects for using cannabinoids in inflammatory conditions.

Identification of herbal categories active in pain disorder subtypes by machine learning help reveal novel molecular mechanisms of algesia.

Chronic pain is highly prevalent and poorly controlled, of which the accurate underlying mechanisms need be further elucidated. Herbal drugs have been widely used for controlling various pain disorders. The systematic integration of pain herbal data resources might be promising to help investigate the molecular mechanisms of pain phenotypes. Here, we integrated large-scale bibliographic literatures and well-established data sources to obtain high-quality pain relevant herbal data (i.e. 426 pain related herbs with their targets). We used machine learning method to identify three distinct herb categories with their specific indications of symptoms, targets and enriched pathways, which were characterized by the efficacy of treatment to the chronic cough related neuropathic pain, the reproduction and autoimmune related pain, and the cancer pain, respectively. We further detected the novel pathophysiological mechanisms of the pain subtypes by network medicine approach to evaluate the interactions between herb targets and the pain disease modules. This work increased the understanding of the underlying molecular mechanisms of pain subtypes that herbal drugs are participating and with the ultimate aim of developing novel personalized drugs for pain disorders.

Pharmacological treatments of neuropathic pain: The latest recommendations.

We provide an up-to-date review of the pharmacological treatment of neuropathic pain with emphasis on the latest evidence-based recommendations for its pharmacological treatment. Drugs proposed as first line include tricyclic antidepressants (particularly amitriptyline), serotonin-norepinephrine reuptake inhibitors (particularly duloxetine), pregabalin and gabapentin. Second line treatments include lidocaine plasters and capsaicin high concentration patches for peripheral neuropathic pain only, and tramadol. Third line treatments include strong opioids and botulinum toxin A (for peripheral neuropathic pain). Perspectives include the development of new compounds and a more personalized therapeutic approach, which is made possible by recent progress in the assessment and understanding of neuropathic pain.

Analgesic Use in Dutch Patients With Osteoarthritis: Frequent But Low Doses.

OBJECTIVE: The aim of this study was to examine which analgesics are used by patients with osteoarthritis (OA)-related pain and how the analgesics are used in the preceding month. In addition, their beliefs about (pain) medication and the rationale of those declining to use analgesics were explored. METHODS: An online cross-sectional survey was sent to 1521 patients participating in the panel of the Dutch Arthritis Foundation. Descriptive analyses and logistic regression were used to analyze data. RESULTS: Of the 842 participants (56%) with OA that responded, 70% had generalized OA, 26% had concomitant fibromyalgia, and 34% had another musculoskeletal morbidity. Of all participants, 71% used analgesics, and 34% used more than 1 type. Analgesics were used for more than 14 days in the preceding month by most participants, with paracetamol being used most frequently (51%). Doses used were predominantly lower than the daily defined dose: 58.2% for paracetamol, 31.2% for nonsteroidal anti-inflammatory drugs/cyclooxygenase-2 inhibitors, and 75.7% for weak opioids. Compared with participants with concomitant fibromyalgia or other musculoskeletal morbidities, participants with OA alone significantly more frequently declined to use analgesics (p < 0.01) and significantly less frequently used 2 or 3 types of analgesics (p < 0.05). CONCLUSIONS: In this population with generalized OA and musculoskeletal comorbidities, medication use was high, and more than 1 type of analgesic was frequently used. Patients with concomitant fibromyalgia or other musculoskeletal morbidities more frequently used 2 or 3 types of analgesics; however, this use was often intermittent and in low doses. Medication use on a daily basis and at higher doses may lead to improved analgesic effect.

Toward an effective peripheral visceral analgesic: responding to the national opioid crisis.

This minireiew summarizes recent new developments in visceral analgesics. This promising field is important, as a new approach to address abdominal pain with peripheral visceral analgesics is considered a key approach to addressing the current opioid crisis. Some of the novel compounds address peripheral pain mechanisms through modulation of opioid receptors via biased ligands, nociceptin/orphanin FQ opioid peptide (NOP) receptor, or dual action on NOP and µ-opioid receptor, buprenorphine and morphiceptin analogs. Other compounds target nonopioid mechanisms, including cannabinoid (CB2), N-methyl-d-aspartate, calcitonin gene-related peptide, estrogen, and adenosine A2B receptors and transient receptor potential (TRP) channels (TRPV1, TRPV4, and TRPM8). Although current evidence is based predominantly on animal models of visceral pain, early human studies also support the evidence from the basic and animal research. This augurs well for the development of nonaddictive, visceral analgesics for treatment of chronic abdominal pain, an unmet clinical need.

Novel Multi-Modal Analgesia Protocol Significantly Decreases Opioid Requirements in Inflatable Penile Prosthesis Patients.

BACKGROUND: Inflatable penile prosthesis (IPP) surgery is associated with significant perioperative pain that may reduce patient satisfaction. Though various pain management strategies have been proposed, most implanters manage postoperative patients with only prescription opioids. No protocol to date has been implemented and reported for pain management in IPP patients throughout the entire recovery process following surgery. AIM: Develop a multimodal analgesic (MMA) regimen consisting of perioperative administration of acetaminophen, meloxicam, and gabapentin with intraoperative local anesthetic injections, and compare post-operative pain control to a matched cohort of patients managed with an opioid-based (OB) regimen. METHODS: We retrospectively analyzed our prospectively maintained IPP database from November 2015-January 2018. The MMA protocol was instituted for all patients beginning June 2017, and these patients were matched in a 1:2 ratio to a cohort of eligible IPP patients managed through an OB protocol. Only patients receiving a 3-piece IPP were included; those with a history of narcotic dependence, neuropathy, or chronic non-steroidal anti-inflammatory drug use were excluded. Postoperative pain scores (visual analog scale) and opioid usage (total morphine equivalents [TME] in milligrams) were compared temporally in the post-anesthesia care unit, postoperative day (POD) 0, POD 1, and following discharge. OUTCOMES: The primary outcomes of the study are postoperative pain scores and narcotic usage. RESULTS: 57 patients were eligible for analysis: 19 (33%) and 38 (66%) in the MMA and OB groups, respectively. Groups were similar in demographics. MMA patients had significantly lower visual analog scale scores in post-anesthesia care unit, POD 0, or POD 1 (mean 0.84 vs 2.97, P = .01; 2.62 vs 4.73, P = .003; and 2.26 vs 4.0, P = .01, respectively) and used fewer narcotics on POD 0 (mean 4.08 vs 13.8 mg TME, P < .001) and POD 1 (mean 5.05 vs 25.1 mg TME, P < .001). MMA patients were discharged home with fewer narcotics (mean 12.7 vs 51.3 tabs, P < .001), and despite this, the MMA group needed less narcotic medication refills (11% vs 49%, P = .007). Neither group experienced a medication-related postoperative adverse event. CLINICAL IMPLICATIONS: Multimodal pain management allows for effective pain control with minimal side effects, enhancing recovery. STRENGTHS & LIMITATIONS: This is the first report to assess use of a multi-modal pain regimen on IPP recipients with demonstration of tangible benefit throughout the recovery process. Limitations include a single-surgeon and retrospective study design. CONCLUSION: In our rigorous assessment of IPP patients, implementation of a novel MMA protocol achieved equivalent and effective pain control, while resulting in substantially fewer narcotics throughout the entire post-operative period following IPP implantation. Tong CMC, Lucas J, Shah A, et al. Novel Multi-Modal Analgesia Protocol Significantly Decreases Opioid Requirements in Inflatable Penile Prosthesis Patients. J Sex Med 2018;15:1187-1194.

Analgesia for patients undergoing shockwave lithotripsy for urinary stones - a systematic review and meta-analysis.

BACKGROUND: Shock wave lithotripsy (SWL) is the first line treatment modality for a significant proportion of patients with upper urinary tracts stones. Simple analgesics, opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are all suitable agents but the relative efficacy and tolerability of these agents is uncertain. OBJECTIVES: To determine the efficacy of the different types of analgesics used for the control of pain during SWL for urinary stones. MATERIALS AND METHODS: We searched the Cochrane Renal Group's Specialised Register, MEDLINE, EMBASE and also hand-searched reference lists of relevant articles (Figure-1). Randomised controlled trials (RCT's) comparing the use of any opioid, simple analgesic or NSAID during SWL were included. These were compared with themselves, each-other or placebo. We included any route or form of administration (bolus, PCA). We excluded agents that were used for their sedative qualities. Data were extracted and assessed for quality independently by three reviewers. Meta-analyses have been performed where possible. When not possible, descriptive analyses of variables were performed. Dichotomous outcomes are reported as relative risk (RR) and measurements on continuous scales are reported as weighted mean differences (WMD) with 95% confidence intervals. RESULTS: Overall, we included 9 RCTs (539 participants from 6 countries). Trial agents included 7 types of NSAIDs, 1 simple analgesic and 4 types of opioids. There were no significant differences in clinical efficacy or tolerability between a simple analgesic (paracetamol) and an NSAID (lornoxicam). When comparing the same simple analgesic with an opioid (tramadol), both agents provided safe and effective analgesia for the purpose of SWL with no significant differences. There were no significant differences in pain scores between NSAIDs or opioids in three studies. Adequate analgesia could be achieved more often for opioids than for NSAIDs (RR 0.358; 95% CI 043 to 0.77, P=0.0002) but consumed doses of rescue analgesia were similar between NSAIDs and opioids in two studies (P=0.58, >0.05). In terms of tolerability, there is no difference in post-operative nausea and vomiting (PONV) between the groups (RR 0.72, 95% CI 0.24 to 2.17, P=0.55). One study compared outcomes between two types of NSAIDs (diclofenac versus dexketoprofen). There were no significant differences in any of our pre-defined outcomes measures. CONCLUSION: Simple analgesics, NSAIDs and opioids can all reduce the pain associated with shock wave lithotripsy to a level where the procedure is tolerated. Whilst there are no compelling differences in safety or efficacy of simple analgesics and NSAIDs, analgesia is described as adequate more often for opioids than NSAIDs.

A machine-learned computational functional genomics-based approach to drug classification.

OBJECTIVE: The public accessibility of "big data" about the molecular targets of drugs and the biological functions of genes allows novel data science-based approaches to pharmacology that link drugs directly with their effects on pathophysiologic processes. This provides a phenotypic path to drug discovery and repurposing. This paper compares the performance of a functional genomics-based criterion to the traditional drug target-based classification. METHODS: Knowledge discovery in the DrugBank and Gene Ontology databases allowed the construction of a "drug target versus biological process" matrix as a combination of "drug versus genes" and "genes versus biological processes" matrices. As a canonical example, such matrices were constructed for classical analgesic drugs. These matrices were projected onto a toroid grid of 50 × 82 artificial neurons using a self-organizing map (SOM). The distance, respectively, cluster structure of the high-dimensional feature space of the matrices was visualized on top of this SOM using a U-matrix. RESULTS: The cluster structure emerging on the U-matrix provided a correct classification of the analgesics into two main classes of opioid and non-opioid analgesics. The classification was flawless with both the functional genomics and the traditional target-based criterion. The functional genomics approach inherently included the drugs' modulatory effects on biological processes. The main pharmacological actions known from pharmacological science were captures, e.g., actions on lipid signaling for non-opioid analgesics that comprised many NSAIDs and actions on neuronal signal transmission for opioid analgesics. CONCLUSIONS: Using machine-learned techniques for computational drug classification in a comparative assessment, a functional genomics-based criterion was found to be similarly suitable for drug classification as the traditional target-based criterion. This supports a utility of functional genomics-based approaches to computational system pharmacology for drug discovery and repurposing.

[Human Single Drug Exposures to Non-opioid Analgesics Reported to the Poisons Information Centre Erfurt from 2003 to 2012]. / Humane nichtopioide Analgetika-Monoexpositionen im Einzugsbereich des Giftnotrufes Erfurt von 2003-2012.

AIM OF THE STUDY: Because of their frequency, non-opioid analgesics (NOA) single drug exposures registered by Poisons Information Centre (PIC) Erfurt have been studied over a decade. METHODS: A retrospective analysis of frequencies, circumstances of exposure, symptom severity, and age groups in NOA single drug exposures received by the PIC Erfurt from the beginning of 2003 to the end of 2012 was undertaken. RESULTS: Of all 4749 NOA single drug exposures, the 10 most frequent were caused by paracetamol (n=1 686), ibuprofen (n=1 439), acetylsalicylic acid (n=456), dipyrone (n=274), diclofenac (n=267), flupirtine (n=138), naproxen (n=41), etoricoxib (n=36), indomethacin (n=24), and dexketoprofen (n=19). Paracetamol single drug exposures increased from 158 in 2003 to 216 in 2007 and fell afterwards to 133 in 2012. Ibuprofen single drug exposures continously rose from 57 in 2003 to 258 in 2012. Adults were more often involved in NOA (53.8%) and all single drug exposures (54.1%) than children (45.9% and 45.6%, respectively). Suicidal attempts were more frequent in NOA (43.1%) than in all single drug exposures (34.2%), whereas accidental exposures or exposures in abuse were less often (33.4 and 0.2%, 46.0 and 0.9% respectively). NOA single drug exposures resulted mostly in none to minor symptoms (77.0%) and rarely in moderate (2.1%) or severe symptoms (1.0%). One adult was found dead after probable ingestion of 32 g of acetylsalicylic acid in suicidal intention. CONCLUSIONS: Because many NOA are over-the-counter drugs, it is difficult to obtain data on their use. PIC data could provide information on the NOA use in the population.

[Care of patients with cancer pain in general practices in Germany]. / Versorgung von Patienten mit Tumorschmerzen in hausärztlichen Praxen in Deutschland.

BACKGROUND: In line with the increased life expectancy of people in Germany, the probability of falling ill with a malignant disease is continuously increasing. About 480,000 people in Germany contract cancer every year. One of the most important symptoms of a malignant disease is pain. Between 40 and 100% of patients with advanced cancer suffer from pain. The aim of this investigation is to show how German general practitioners care for these patients using analgetics. MATERIALS AND METHODS: The data were extracted from the CONTENT database (CONTinuous morbidity registration Epidemiologic NeTwork) of the Department of General Practice and Health Services Research at the University Hospital in Heidelberg. This database has data from more than 200,000 patients and more than 3 million physician/patient contacts. The prescriptions were classified using the ATC code. RESULTS: Patients experiencing pain from cancer received all kinds of analgetic drugs. The data comprises 9752 prescriptions for 1362 patients. There were 4975 (51.1 %) prescriptions for Class 1 analgesics, 929 (9.5 %) for Class 2 analgetics and 1918 (19.7 %) prescriptions for Class 3 analgetics. Coanalgetics were prescribed 1930 (19.7 %) times. 1,167 patients (85.7 %) were treated in the correct manner according to the guidelines of the World Health Organisation and 195 (14.3 %) were not. CONCLUSIONS: Most GPs in Germany follow the principles of WHO structured pain therapy. However, further improvement of the results may be achieved through intensive training of colleagues.

Parenterally administered moderate sedation and paracervical block versus general anesthesia for hysteroscopic polypectomy: a pilot study comparing postoperative outcomes.

STUDY OBJECTIVE: To compare parenterally administered moderate sedation and paracervical block versus general anesthesia during day-case operative hysteroscopy for polypectomy in terms of patients' postoperative pain perception, operating time, and postoperative drug administration. DESIGN: A pilot study (Canadian Task Force classification I). SETTING: A university hospital. PATIENTS: Women undergoing hysteroscopic polypectomy procedures (N = 56). INTERVENTIONS: Hysteroscopic polypectomy with general anesthesia or moderate parenteral sedation and paracervical block. MEASUREMENTS AND MAIN RESULTS: The patients were divided into 2 groups: 26 underwent general anesthesia (group 1), and 30 were submitted to moderate parenteral sedation and a paracervical block (group 2). General anesthesia was induced with the laryngeal mask airway with propofol (1% 1-2.5 mg/kg) and fentanyl (1-2 µg/kg) and maintained with an infusion of propofol (2% 3-5 mg/kg/h). After the procedure, patients in the general anesthesia group received postoperative analgesic medication with paracetamol (20 mg/kg) and ketorolac (0.6 mg/kg) or tramadol (2-3 mg/kg). The group receiving moderate parenterally sedation and a paracervical block received a paracervical block with mepivacaine (1% 10 mL) and lidocaine (2% 10 mL) and received fentanyl (1 µg/kg) and propofol (1% 1-3 mg/kg/h) maintaining spontaneous breathing. A blind observer recorded the operative time and the discomfort of patients using a 4-step scale (0-3). The postoperative pain assessment was performed 3 hours after the procedure with a self-administered validated tool, the Brief Pain Inventory. We found that women receiving moderate parenteral sedation and a paracervical block perceived significantly less pain in daily activity (p < .001), walking (p < .001), daily work (p < .001), relations with others (p = .007), sleep (p < .001), and pain contrasting enjoyment of life (p < .001). The total amount of time spent in the operating room in group 2 was significantly lower than in group 1 (p < .014). CONCLUSION: Moderate sedation plus a paracervical block for operative hysteroscopy is associated with reduced pain perception and a shorter operative time.

Postoperative analgesia in patients older than 75 years undergoing intervention for per-trochanteric hip fracture: a single centre retrospective cohort study.

The aim of this study was to compare the efficacy of four analgesia techniques on postoperative pain after per-trochanteric femur fracture. A retrospective cohort study was conducted on 131 consecutive patients older than 75 years enrolled in an 18-month period and who underwent per-trochanteric fracture repair under spinal analgesia. Patients received postoperative analgesia from: G1 (n = 36), intravenous analgesia on demand only; G2 (n = 28) administration of acetaminophen at fixed hours; G3 (n = 50) continuous morphine infusion; G4 (n = 17), preoperative echo-graphic guided femoral nerve block. Continuous opioid infusion failed to prevent the onset of pain at the end of the effects of subarachnoid anesthesia (rescue dose of analgesic in 48 % of patients in G3 vs. 22 % in G2 in the first day; p < 0.05). The greater effectiveness was achieved by preventing the onset of pain with drugs administered at time intervals (rescue dose of analgesic in 48 % of patients in G3, 58 % in G1 and 48 % in G4 vs. 22 % in G2 in the first day and rescue dose of analgesic in 32 % of patients in G3, 67 % in G1 and 76 % in G4 vs. 18 % in G2 in the second day; p < 0.05). Our study does not confirm the effectiveness of a single shot femoral nerve block on postoperative pain in per-trochanteric femur fracture (PAIN VAS score > 3 at t1 in 23 % of patients in G1 and 19 % in G4 vs. 10 % in G2 and G3; p < 0.05).

Postoperative pain management in the surgical wards of a tertiary care hospital in Peshawar.

OBJECTIVE: To assess levels of postoperative pain with reference to internationally validated protocols. METHODS: The hospital-based survey of postoperative patients was conducted from February 2012 to April 2012 in the surgical wards of Rehman Medical Institute, Peshawar. A questionnaire was devised incorporating internationally validated World Health Organisation pain scoring system to assess the level of pain control. The severity of postoperative pain was further evaluated by correlating it with various variables. RESULTS: Of the 210 patients interviewed, 80(38%) were males with a mean age of 44.16±20.37 and 130(62%) were females with a mean age of 36.47±14.39. Overall, 84(40%) patients experienced mild pain, 82(39%) experienced moderate pain and 33(16%) experienced severe pain, while only 11(5%) experienced no pain when assessed within the first 24 hours following surgery. The same patients when interviewed within the 48 hours following surgery showed 117(56%) were in mild pain, 72(34%) in moderate to severe pain and 21(10%) had no pain. CONCLUSIONS: The achievement of absolute no pain for all patients in the post-operative phase is next to impossible, but it should remain the ultimate target.

Rational pain management in complex regional pain syndrome 1 (CRPS 1)--a network meta-analysis.

OBJECTIVE: Guidelines for complex regional pain syndrome (CRPS) 1 advocate several substance classes to reduce pain and support physical rehabilitation, but guidance about which agent should be prioritized when designing a therapeutic regimen is not provided. Using a network meta-analytic approach, we examined the efficacy of all agent classes investigated in randomized clinical trials of CRPS 1 and provide a rank order of various substances stratified by length of illness duration. DESIGN: In this study a network meta-analysis was conducted. PATIENTS: The participants of this study were patients with CRPS 1. METHOD: Searches in electronic, previous systematic reviews, conference abstracts, book chapters, and the reference lists of relevant articles were performed. Eligible studies were randomized controlled trials comparing at least one analgesic agent with placebo or with another analgesic and reporting efficacy in reducing pain. Summary efficacy stratified by symptom duration and length of follow-up was computed across all substance classes. Two authors independently extracted data. RESULTS: In total, 16 studies were included in the analysis. Bisphosphonates appear to be the treatment of choice in early stages of CRPS 1. The effects of calcitonin surpass that of bisphosphonates and other substances as a short-term medication in more chronic stages of the illness. While most medications showed some efficacy on short-term follow-up, only bisphosphonates, NMDA analogs, and vasodilators showed better long-term pain reduction than placebo. LIMITATION: For some drug classes, only a few studies were available and many studies included a small group of patients. Insufficient data were available to analyze efficacy on disability. CONCLUSION: This network meta-analysis indicates that a rational pharmacological treatment strategy of pain management should consider bisphosphonates in early CRPS 1 and a short-term course of calcitonin in later stages. While most medications showed some efficacy on short-term follow-up, only bisphosphonates, NMDA analogs and vasodilators showed better long-term pain reduction than placebo.

A systematic review of the utility of antidepressant pharmacotherapy in the treatment of vulvodynia pain.

INTRODUCTION: Antidepressants have often been recommended as a potential treatment for the management of vulvodynia. However, review of the evidence supporting this recommendation has not been systematically assessed. AIM: To evaluate the efficacy of antidepressant pharmacotherapy in the treatment of vulvodynia. MAIN OUTCOME MEASURES: An assessment of the methodological quality of published reports addressing the utility of antidepressants in the treatment of vulvodynia was undertaken. Several secondary outcomes generated in the existing literature were also examined. METHODS: A comprehensive search of the available literature was conducted. RESULTS: The search yielded 13 published reports, i.e., 2 randomized controlled trials, 1 quasi-experimental trial, 7 non-experimental studies, and 3 case reports. A number of methodological shortcomings were identified in several of the reports with respect to study design including lack of clear inclusion/exclusion criteria, small sample sizes, lack of comparison groups, insufficient blinding, among others. The vast majority of studies utilized tricyclic antidepressants (TCAs). Evidence supporting the benefits of TCAs studied to date was limited, i.e., based largely upon descriptive reports but unsubstantiated by randomized controlled trials. There were no systematic investigations into the comparative efficacy of different antidepressant classes in the treatment of vulvodynia. CONCLUSION: There is insufficient evidence to support the recommendation of antidepressant pharmacotherapy in the treatment of vulvodynia. Although some vulvodynia-afflicted patients derive symptom relief from antidepressants, additional research is required to identify those characteristics that would predict those patients for whom antidepressants are more likely to be effective.

Headache: insight, understanding, treatment and patient management.

Tension-type headache and migraine are the most frequent primary headaches. Diagnosis is based on the patient's history and a normal neurological examination. Most patients with these two headache entities treat headache episodes with over-the-counter analgesics or non-steroidal anti-inflammatory drugs (NSAIDs). There is good scientific evidence from randomised, placebo-controlled trials indicating that aspirin, ibuprofen, ketoprofen, diclofenac and naproxen are effective in tension-type and migraine headache. Paracetamol seems to be less effective. In patients with migraine who do not respond to analgesics or NSAIDs, triptans should be prescribed. Frequent primary headaches should not be treated with frequent intake of analgesics or triptans. In these cases, preventive therapy needs to be implemented.

Gastrointestinal safety of NSAIDs and over-the-counter analgesics.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used. It is well recognised that they may adversely cause damage throughout the gastrointestinal tract and aggravate pre-existing disease. Their side effects on the upper gastrointestinal tract can be assessed by various means; each study type has different clinical connotations. Short-term use (less than 14 days) demonstrates dose-dependent damage of prescribed NSAIDs; the damage is proportional to the acidity of the drugs and not seen with Cyclooxygenase-2 (COX-2) selective inhibitors that have a pKa over 7.0. There have not been any serious outcomes, such as bleeding or perforation in these studies, and Helicobacter pylori (HP) plays no role in this damage. Long-term (3 months or more) endoscopy studies in patients show ulcer rates from 15%-35% with the various NSAIDs, but serious outcomes are exceedingly rare. Epidemiological studies show an association between NSAID intake and serious events. Ibuprofen is consistently at the lower end of toxicity rankings, whereas ketorolac and azapropazone are the worst. The risk of bleeding is increased with advancing age, presence of HP, previous history of bleeding, anticoagulant use, etc. The mega-trials show that COX-2 selective agents halve the bleeding episodes, but NSAID-induced gastric bleeding is very rare usually, less than 1 in 200 subjects taking them for a year. Seventy percent of patients develop NSAID-enteropathy, which is associated with intestinal blood and protein loss and rarely strictures. Over-the-counter (OTC) use of ibuprofen and diclofenac is associated with symptomatic gastrointestinal side effects comparable with placebo. Ibuprofen is shown to be remarkably well tolerated at OTC doses in a number of studies. There are recent studies to suggest that OTC NSAIDs should be taken on a fasting stomach, not with food as commonly advocated.