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GaPP2, a multicentre randomised controlled trial of the efficacy of gabapentin for the management of chronic pelvic pain in women: study protocol.
Vincent, K, Baranowski, A, Bhattacharya, S, Birch, J, Cheong, Y, Cregg, R, Daniels, J, Hewitt, CA, Macfarlane, GJ, Middleton, L, et al
BMJ open. 2018;(1):e014924
Abstract
INTRODUCTION Chronic pelvic pain (CPP) affects more than 1 million UK women with associated healthcare costs of £158 million annually. Current evidence supporting interventions when no underlying pathology is identified is very limited and treatment is frequently inadequate. Gabapentin (a GABA analogue) is efficacious and often well tolerated in other chronic pain conditions. We have completed a successful pilot randomised controlled trial Gabapentin for Pelvic Pain 1 (GaPP1) and here describe the protocol for our definitive multicentre trial to assess the efficacy of gabapentin in the management of CPP in women Gabapentin for Pelvic Pain 2 (GaPP2). METHODS AND ANALYSIS We plan to perform a double-blind placebo-controlled randomised multicentre clinical trial, recruiting 300 women with CPP from up to 40 National Health Service hospitals within the UK. After randomisation, women will titrate their medication (gabapentin or placebo) over a 4-week period to a maximum of 2700 mg or placebo equivalent and will then maintain a stable dose for a 12-week period. Response to treatment will be monitored with validated questionnaires and coprimary outcome measures of average and worst pain scores will be employed. The primary objective is to test the hypothesis that treatment with gabapentin has the potential to provide an effective oral treatment to alleviate pain in women with CPP in the absence of any obvious pelvic pathology. ETHICS AND DISSEMINATION Ethical approval has been obtained from the Coventry and Warwick Research Ethics Committee (REC 15/WM/0036). Data will be presented at international conferences and published in peer-reviewed journals. We will make the information obtained from the study available to the public through national bodies and charities. TRIAL REGISTRATION NUMBER ISRCTN77451762; Pre-results.
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Monthly vitamin D supplementation, pain, and pattern of analgesic prescription: secondary analysis from the randomized, double-blind, placebo-controlled Vitamin D Assessment study.
Wu, Z, Camargo, CA, Malihi, Z, Bartley, J, Waayer, D, Lawes, CMM, Toop, L, Khaw, KT, Scragg, R
Pain. 2018;(6):1074-1082
Abstract
Observational studies suggest that vitamin D deficiency is associated with higher risk of pain. However, evidence on the effect of vitamin D supplementation on pain is limited and contradictory. The aim of this study was to compare the effect of monthly high-dose vitamin D supplementation on a pain impact questionnaire (PIQ-6) score and prescription of analgesics in the general population. We performed a randomized, double-blind, placebo-controlled trial of 5108 community-dwelling participants, aged 50 to 84 years, who were randomly assigned to receive monthly 100,000-IU capsules of vitamin D3 (n = 2558) or placebo (n = 2550) for a median of 3.3 years. The PIQ-6 was administered at baseline, year 1, and final follow-up. Analgesic prescription data were collected from Ministry of Health. There was no difference in mean PIQ-6 score at the end of follow-up (adjusted mean difference: 0.06; P = 0.82) between the vitamin D (n = 2041) and placebo (n = 2014) participants. The proportion of participants dispensed one or more opioids was similar in the vitamin D group (n = 559, 21.9%) compared with placebo (n = 593, 23.3%); the relative risk (RR) adjusted for age, sex, and ethnicity was 0.94 (P = 0.24). Similar results were observed for dispensing of nonsteroidal anti-inflammatory drugs (RR = 0.94; P = 0.24) and other nonopioids (RR = 0.98; P = 0.34). Focusing on vitamin D deficient participants (<50 nmol/L, 24.9%), there was a lower risk of dispensing nonsteroidal anti-inflammatory drugs in the vitamin D group compared with placebo (RR = 0.87; P = 0.009); all other subgroup analyses were not significant. Long-term monthly high-dose vitamin D supplementation did not improve mean PIQ-6 score or reduce analgesic dispensing in the general population.
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Delayed increase of thrombocyte levels after a single sub-anesthetic dose of ketamine - A randomized trial.
Colic, L, Woelfer, M, Colic, M, Leutritz, AL, Liebe, T, Fensky, L, Sen, ZD, Li, M, Hoffmann, J, Kretzschmar, MA, et al
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2018;(6):701-709
Abstract
Recently, ketamine has been investigated as a potential antidepressant option for treatment resistant depression. Unlike traditional drugs, it yields immediate effects, most likely via increased glutamatergic transmission and synaptic plasticity. However, ketamine administration in humans is systemic and its long-term impact on blood parameters has not yet been described in clinical studies. Here we investigated potential sustained effects of ketamine administration (0.5 mg/kg ketamine racemate) on hematological and biochemical values in plasma and serum in a randomized double-blinded study. 80 healthy young participants were included and whole blood samples were collected 5 days before, and 14 days after the infusion. To assess the group effect, repeated measure analyses of co-variance (rmANCOVA) were conducted for the following blood parameters: levels of sodium, potassium, calcium, hemoglobin and number of erythrocytes, lymphocytes, and thrombocytes. RmANCOVA revealed a significant time by treatment effect on thrombocyte levels (F1, 74 = 13.54, p < 0.001, eta = 0.155), driven by an increase in the ketamine group (paired t-test, t = -3.51, df = 38, p = 0.001). Specificity of thrombocyte effect was confirmed by logistic regression, and in addition, no other coagulation parameters showed significant interaction. Moreover, the relative increase in the ketamine group was stable across sexes and not predicted by age, BMI, smoking, alcohol or drug use, and contraception. Our results describe aftereffects of sub-anesthetic ketamine administration on blood coagulation parameters, which should be considered especially when targeting psychiatric populations with relevant clinical comorbidities.
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Oral Cryotherapy: Prevention of Oral Mucositis and Pain Among Patients With Colorectal Cancer Undergoing Chemotherapy.
Idayu Mat Nawi, R, Lei Chui, P, Wan Ishak, WZ, Hsien Chan, CM
Clinical journal of oncology nursing. 2018;(5):555-560
Abstract
BACKGROUND Evidence remains mixed on the benefits of oral cryotherapy in the prevention of oral mucositis and pain associated with fluorouracil-based chemotherapy. OBJECTIVES The intent of this article is to evaluate the effect of oral cryotherapy on the prevention of oral mucositis and pain among patients with colorectal cancer undergoing fluorouracil-based chemotherapy. METHODS Using an experimental study design, the authors randomly assigned 80 patients to either the intervention (n = 40) or usual care group (n = 40). Intervention group participants received oral cryotherapy in the form of ice chips held in their mouths during chemotherapy infusion. Both groups used sodium bicarbonate mouthwash postchemotherapy until the next cycle. FINDINGS In the usual care group, most participants reported grade 2 (moderate to life-threatening) or greater mucositis. Pain associated with mucositis was lower using oral cryotherapy, with the majority of participants in the intervention group reporting no pain.
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An open-label, randomized, four-treatment crossover study evaluating the effects of salt form, acetaminophen, and food on the pharmacokinetics of phenylephrine.
Gelotte, CK
Regulatory toxicology and pharmacology : RTP. 2018;:333-338
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Abstract
Phenylephrine hydrochloride (HCl) is a decongestant available in over-the-counter (OTC) medicines. Previously marketed prescription products contained phenylephrine tannate, an extended-release salt, which allowed dosing every 8-12 h. Given the regulatory history that cold medicines marketed before 1962 had limited supporting clinical data, and with widespread replacement of pseudoephedrine by phenylephrine in OTC products over the last ten years, the need for contemporary studies grew. This exploratory crossover study evaluated effects of salt form, acetaminophen, and food on phenylephrine pharmacokinetics and metabolites in healthy adults. Test treatments were 25 mg phenylephrine tannate (equivalent to 10 mg phenylephrine HCl) combined with 200 mg guaifenesin, fasted; 10 mg phenylephrine HCl combined with 650 mg acetaminophen, fasted; and 10 mg phenylephrine HCl, fed. The reference treatment was 10 mg phenylephrine HCl, fasted. Plasma phenylephrine pharmacokinetics and urine metabolites were determined. Although the tannate salt slowed phenylephrine absorption compared with the HCl salt, terminal concentrations were similar, suggesting that products containing the tannate salt should not be dosed less frequently than those containing the HCl salt. The premise that acetaminophen increases phenylephrine bioavailability by competition for presystemic sulfation was corroborated by increased phenylephrine sulfate in urine. Food delayed phenylephrine absorption, but not the total amount absorbed.
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[Conventional analgesics and non-pharmacological multidisciplinary therapeutic treatment in endometriosis: CNGOF-HAS Endometriosis Guidelines].
Wattier, JM
Gynecologie, obstetrique, fertilite & senologie. 2018;(3):248-255
Abstract
UNLABELLED A major symptom of endometriosis is pelvic pain with a wide range of intensity, rhythm, type, and expression, without clearly established relationship between pain and the disease. Endometriosis-associated pain has physical, psychological/behavioral and social consequences with a significant impact on patient quality-of-life in relation with the biopsychosocial model of chronic pain. Pain assessment in all of its dimensions, as well as assessing the consequences of pain is therefore a crucial part of therapeutic management. Conventional analgesics are commonly used although studies demonstrating their efficacy in the treatment of endometriosis-related pelvic pain are lacking. Non-steroid anti-inflammatory drugs (NSAIDs), known to be effective in dysmenorrhea unrelated to endometriosis, have not been recently re-assessed in patients with endometriosis. Following rigorous assessment, the characterization of neuropathic components of endometriosis-related pelvic pain may lead to treatment with antiepileptic of antidepressant drugs, although gabapentin and amitriptyline have yet to be specifically assessed in the setting of endometriosis-related pain. Other pharmacologically active compounds have been tested to treat endometriosis-related pain but did not demonstrate efficacy with sufficient level of evidence. Diets, dietary supplements and herbal medicine are often proposed and/or used as adjuncts without any conclusive evidence. Although the effects on endometriosis-related pain are methodologically difficult to assess, physical adjunctive therapies such as acupuncture, transcutaneous neurostimulation, osteopathy/chiropractics, physical therapy and physical activity, the long-term therapeutic relationship they establish may potentiate beneficial effects perceived by patients. However, it remains difficult to demonstrate significant effects of cognitive and/or behavioral interventions on endometriosis-related pain. CONCLUSION The complexity of managing endometriosis-related pain requires a holistic approach with sustained attention to the patient. Treatments, either pharmacologic or non-pharmacologic, including adjuvant therapies, associate a technical expertise to which a human approach must be added in order to bring value to these treatments. Multidisciplinary and/or inter disciplinary approaches are therefore essential to the care of patients suffering from endometriosis.
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Analgesic Effects of Locally Administered Ketorolac-based Analgesics After Breast Surgery: A Meta-Analysis of Randomized Controlled Trials.
Chen, JY, Feng, IJ, Loh, EW, Wang, LK, Lin, CC, Tam, KW
The Clinical journal of pain. 2018;(6):577-584
Abstract
OBJECTIVE Reducing postoperative pain following breast surgery is crucial for rapid recovery and shortening hospital stay. Ketorolac, a nonsteroidal anti-inflammatory drug, has been used as a postoperative analgesic in many surgical procedures. We conducted a systemic review and meta-analysis on the efficacy of locally administered ketorolac-based analgesics in managing pain after breast surgery. METHODS We searched the PubMed, Embase, Cochrane Library, Scopus, and ClinicalTrials.gov registry for randomized control trials (RCTs) published up to September 2016. The primary outcome was pain level assessed using a visual analog scale (VAS) at 1 and 6 hours following breast surgery. RESULTS We reviewed 4 RCTs with 255 patients. For meta-analysis, VAS at 1 and 6 hours of 3 similar RCTs were compared. At 1 hour, VAS scores were significantly lower in patients administered a ketorolac solution [weighted mean difference (WMD)=-2.04; 95% confidence interval (CI): -3.08 to -1.00] or ketorolac-bupivacaine solution (WMD=-2.30; 95% CI, -4.07 to -0.54) than in controls. At 6 hours, the ketorolac-bupivacaine solution reduced VAS scores significantly (WMD=-1.40; 95% CI, -2.48 to -0.32) compared with controls. However, at 1 hour, the ketorolac solution was significantly more effective than the bupivacaine solution was (WMD=-1.70; 95% CI, -2.81 to -0.59). DISCUSSION The effects of ketorolac-based analgesics vary as per the surgery and disease type. Locally administered ketorolac-based analgesics decreased postoperative pain in breast surgery patients, and the effect of local ketorolac was better than local bupivacaine. Therefore, ketorolac-based analgesics demonstrate considerable local infiltration during pain management after breast surgery.
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Effects of nefopam with fentanyl in intravenous patient-controlled analgesia after arthroscopic orthopedic surgery: a prospective double-blind randomized trial.
Oh, YN, Kim, KN, Jeong, MA, Kim, DW, Kim, JY, Ki, HS
Turkish journal of medical sciences. 2018;(1):142-149
Abstract
Background/aim: We performed this prospective randomized double-blind study to compare the effects of nefopam versus ketorolac in intravenous fentanyl-based patient-controlled analgesia (PCA) after shoulder arthroscopic orthopedic surgery. Materials and methods: Ninety-two patients were randomly divided into two groups to receive intravenous PCA. Patients were assigned to either the nefopam group (nefopam 120 mg and fentanyl 20 µg/kg) or the ketorolac group (ketorolac 2 mg/kg and fentanyl 20 µg/kg). Pain was assessed on a visual analogue scale (VAS) and a numeric rating scale (NRS). Additionally, patient satisfaction, adverse events, and vital signs were monitored. Results: There were no significant differences in VAS score (P = 0.48) or NRS score (P = 0.15) between the two groups. Similarly, patient satisfaction did not differ between the two groups [8.5(0.8) vs. 8.2(1.0), P = 0.14]. There were no statistically significant differences in the incidence of nausea (P = 0.72), vomiting (P = 0.46), urinary retention (P = 0.82), sweating (P = 0.49), or dizziness (P = 0.45) between the two groups. Likewise, there were no differences in heart rate [78.2(7.7) vs. 75.2(6.5), P = 0.18] or SpO2 [98.4(1.8) vs. 98.5(1.9), P = 0.83]. Conclusion: Nefopam is an appropriate alternative for co-administration with fentanyl-based PCA in patients who have difficulty using nonsteroidal antiinflammatory drugs.
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Rapid-onset hyponatremia and delirium following duloxetine treatment for postherpetic neuralgia: Case report and literature review.
Wang, D, Lai, J, Lu, S, Huang, M, Hu, S, Xu, Y
Medicine. 2018;(46):e13178
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RATIONALE Hyponatremia following duloxetine treatment has been reported in patients with major depressive disorder, fibromyalgia, diabetic neuropathy, or sciatic pain. The manifestations of duloxetine-induced hyponatremia are varying in different individuals. The overall prognosis for this type of hyponatremia is favorable if properly managed. PATIENT CONCERNS AND DIAGNOSES Herein, we reported rapid-onset hyponatremia and delirium in an older patient after 2 doses of duloxetine, which was used to control his postherpetic neuralgia. Laboratory examinations revealed a rapid decline in serum sodium level and indicated the possibility of syndrome of inappropriate antidiuretic hormone (SIADH). INTERVENTIONS Discontinuation of duloxetine, restriction of water intake, and intravenous supplement of normal saline were adopted to manage the hyponatremia. OUTCOMES Serum concentration of sodium gradually normalized following aforementioned strategies. LESSONS Special attention to the electrolyte abnormality is recommended in old patients undergoing duloxetine treatment.
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Baseline Morphine Consumption May Explain Between-Study Heterogeneity in Meta-analyses of Adjuvant Analgesics and Improve Precision and Accuracy of Effect Estimates.
Doleman, B, Sutton, AJ, Sherwin, M, Lund, JN, Williams, JP
Anesthesia and analgesia. 2018;(2):648-660
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BACKGROUND Statistical heterogeneity can increase the uncertainty of results and reduce the quality of evidence derived from systematic reviews. At present, it is uncertain what the major factors are that account for heterogeneity in meta-analyses of analgesic adjuncts. Therefore, the aim of this review was to identify whether various covariates could explain statistical heterogeneity and use this to improve accuracy when reporting the efficacy of analgesics. METHODS We searched for reviews using MEDLINE, EMBASE, CINAHL, AMED, and the Cochrane Database of Systematic Reviews. First, we identified the existence of considerable statistical heterogeneity (I > 75%). Second, we conducted meta-regression analysis for the outcome of 24-hour morphine consumption using baseline risk (control group morphine consumption) and other clinical and methodological covariates. Finally, we constructed a league table of adjuvant analgesics using a novel method of reporting effect estimates assuming a fixed consumption of 50 mg postoperative morphine. RESULTS We included 344 randomized controlled trials with 28,130 participants. Ninety-one percent of analyses showed considerable statistical heterogeneity. Baseline risk was a significant cause of between-study heterogeneity for acetaminophen, nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors, tramadol, ketamine, α2-agonists, gabapentin, pregabalin, lidocaine, magnesium, and dexamethasone (R = 21%-100%; P < .05). There was some evidence that the methodological limitations of the trials explained some of the residual heterogeneity. Type of surgery was not independently associated with analgesic efficacy. Assuming a fixed baseline risk of 50 mg (in order of efficacy), gabapentin, acetaminophen, α2-agonists, nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors, pregabalin, tramadol, magnesium, and lidocaine demonstrated moderate clinically significant reductions (>10 mg). We could not exclude a moderate clinically significant effect with ketamine. Dexamethasone demonstrated a small clinical benefit (>5 mg). CONCLUSIONS We empirically identified baseline morphine consumption as the major source of heterogeneity in meta-analyses of adjuvant analgesics across all surgical interventions. Controlling for baseline morphine consumption, clinicians can use audit data to estimate the morphine-reducing effect of adding any adjuvant for their local population, regardless which surgery they undergo. Moreover, we have utilized these findings to present a novel method of reporting and an amended method of graphically displaying effect estimates, which both reduces confounding from variable baseline risk in included trials and is able to adjust for other clinical and methodological confounding variables. We recommend use of these methods in clinical practice and future reviews of analgesics for postoperative pain.