Efficacy and tolerability of diclofenac potassium sachets in migraine: a randomized, double-blind, cross-over study in comparison with diclofenac potassium tablets and placebo

A randomized, controlled, cross-over trial compared single doses of 50 mg diclofenac potassium sachets and tablets with placebo in 328 patients with migraine pain, treating 888 attacks. For the primary endpoint 24.7% of the patients were pain free at 2 h postdose with sachets, 18.5% for tablets and 11.7% for placebo. Treatment differences were significant for sachets vs. placebo (P<0.0001), tablets vs. placebo (P=0.0040) and for sachets vs. tablets (P=0.0035). The numbers needed to treat compared with placebo to achieve pain free at 2 h were 7.75 [95% confidence interval (CI) 5.46, 13.35] for sachets and 15.83 (95% CI 8.63, 96.20) for tablets. Sachets were also statistically superior to tablets for sustained headache response, sustained pain free and reduction in headache intensity within the first 2 h postdose measured on a visual analogue scale (P<0.05). Onset of analgesic effect was 15 min for sachets and 60 min for tablets. Fewer patients needed rescue medication, and there were marked improvements in accompanying symptoms and working ability with both sachets and tablets vs. placebo. No safety issues were identified. This study demonstrates that sachets offer patients suffering from migraine pain a more effective treatment with a faster onset of analgesia when compared with tablets.     

Pregabalin in patients with postoperative dental pain.

Pregabalin is an analogue of the inhibitory neurotransmitter gamma-aminobutyric acid. In preclinical models, it has shown activity as an analgesic agent. A randomized, double-blind, placebo-controlled, parallel-group trial was undertaken to compare pregabalin to placebo and 400 mg of ibuprofen using a dental pain model. Study medication was administered postoperatively to patients who had undergone elective surgery to remove one or two third molars, at least one of which was mandibular and fully or partially impacted in bone. The study was conducted in the UK at a single centre and evaluated pregabalin at doses of 50 and 300 mg. Primary efficacy parameters included pain relief (PR), pain intensity difference (PID), pain relief intensity difference (PRID), time to onset of analgesia, and duration of analgesia. The patient's global impression of the study medication was used as a secondary efficacy parameter. Efficacy data were evaluated for the intent-to-treat (ITT) population, defined as all randomized patients who took study medication. Results showed that there were statistically significant differences in PR, PID, and PRID between the 300-mg pregabalin group and placebo. In addition, the 300-mg pregabalin group had a significantly longer duration of analgesia than the ibuprofen group and had the highest score on the patient global impression of study medication. Adverse events were reported more frequently in the pregabalin 300-mg group.Pregabalin appears to have significant analgesic properties in the third molar extraction model. Further research is needed to confirm these findings.     

A randomised, five-parallel-group, placebo-controlled trial comparing the efficacy and tolerability of analgesic combinations including a novel single-tablet combination of ibuprofen/paracetamol for postoperative dental pain

Combination analgesia is often recommended for the relief of severe pain. This was a double-blind, 5-arm, parallel-group, placebo-controlled, randomised, single-dose study designed to compare the efficacy and tolerability of a novel single-tablet combination of ibuprofen and paracetamol with that of an ibuprofen/codeine combination, and a paracetamol/codeine combination, using the dental impaction pain model. Subjects with at least 3 impacted third molars and experiencing moderate to severe postoperative pain were randomised to receive: 1 or 2 tablets of a single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg; 2 tablets of ibuprofen 200 mg/codeine 12.8 mg; 2 tablets of paracetamol 500 mg/codeine 15 mg; or placebo. Results for the primary endpoint, the sum of the mean scores of pain relief combined with pain intensity differences over 12 hours, demonstrated that 1 and 2 tablets of the single-tablet combination of ibuprofen/paracetamol were statistically significantly more efficacious than 2 tablets of placebo (P < 0.0001) and paracetamol/codeine (P ? 0.0001); furthermore, 2 tablets offered significantly superior pain relief to ibuprofen/codeine (P = 0.0001), and 1 tablet was found noninferior to this combination. Adverse events were uncommon during this study and treatment emergent adverse events were statistically significantly less frequent in the groups taking the ibuprofen/paracetamol combination compared with codeine combinations. In conclusion, 1 or 2 tablets of a single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg provided highly effective analgesia that was comparable with, or superior to, other combination analgesics currently indicated for strong pain.     

Pregabalin does not decrease acute pain or postoperative nausea and vomiting after hysterectomy: a meta-analysis

ObjectiveHysterectomy is associated with severe postoperative pain. The relative efficacy of pregabalin compared with other treatments for post-hysterectomy pain is unclear.MethodsWe searched the PubMed, Cochrane Library, and Web of Science databases for studies that compared the use of pregabalin and placebo for reducing pain in patients undergoing hysterectomy.ResultsThis meta-analysis showed that pregabalin had limited pain-relieving effects at 2, 6, 24, and 48 hours after hysterectomy compared with placebo. Pregabalin significantly reduced postoperative nausea and vomiting. However, there was no significant difference in postoperative sedation or visual disturbances between patients treated with pregabalin and placebo.ConclusionsPregabalin is not clinically superior to placebo in terms of reducing pain intensity and morphine consumption in patients undergoing hysterectomy. However, the limitations of this meta-analysis mean that more high-quality randomized controlled trials are necessary to verify our pooled results.     

Acute pain teams and the management of postoperative pain: a systematic review and meta-analysis

BACKGROUND: The introduction of acute pain teams (APTs) in every hospital performing surgery in the UK has been recommended in order to reduce postoperative pain. However, recent evidence suggests that many APTs are under-resourced. Purchasers may be more prepared to invest in these services if they are persuaded that they result in measurable improvements in patient outcomes. AIM: A systematic review of the literature and meta-analysis were performed to determine the effectiveness of APTs in improving the quality of analgesia and other postoperative outcomes of adult patients undergoing surgery. METHODS: A broad search strategy using the terms 'pain team' and 'pain service' was adapted for a variety of databases. Key journals were hand-searched and reference lists of selected reports were reviewed. Subject experts and study authors were contacted. Studies describing the impact of the APT/acute pain service (APS) on postoperative pain relief, other postoperative outcomes or the processes of postoperative pain were included. Study quality was assessed using a multidimensional instrument. A broad qualitative overview of the included studies was conducted. Continuous outcome data for pain in the first 24 hours postoperatively (in one case worst pain at 24-48 hours) were pooled. RESULTS: Fifteen studies were included in the review. There were considerable differences in study design and quality, the nature of the APT and the outcomes measured. Of the nine studies measuring pain, it was possible to present data as Standardized Mean Differences for only four studies. Quantitative synthesis indicates a statistically significant overall estimate of effect using a fixed effects model only. LIMITATIONS: Only published studies in English were included. Study inclusion decisions and data extraction were performed by one reviewer only. CONCLUSION: There is insufficient robust research to assess the impact of APTs on postoperative outcomes of adult patients or on the processes of postoperative pain relief.     

Effectiveness of an acute pain service in surgical patients — a hospital comparison study

The implementation of an acute pain service (APS) has been advocated as the cornerstone of effective pain management. However, convincing evidence demonstrating the effectiveness of an APS in controlled studies is scarce. In this study we compared both subjective and objective variables of surgical patients in two similar hospitals, one of which had established an APS. During the study period of two years 498 patients were prospectively enrolled. Pain and other related variables (appetite, mobility, need for sleep, fatigue, and general satisfaction) were assessed pre- and postoperatively by means of 10 cm VAS scales printed on two identical questionnaires. Additional data were retrieved from the patients' records. Those patients who were cared for by an APS suffered less pain (25 mm VAS at rest), sleepiness (13 mm VAS), mobility restriction, and loss of appetite. For most measures the beneficial effects of the APS were present pre- and postoperatively. However, hospital stay was similar in both hospitals (13.7 vs 14.3 days; A vs B). Our data indicate large and patient-relevant benefits of an APS, but our study design was vulnerable to various kinds of bias.     

Clonidine for treatment of postoperative pain: a dose-finding study.

The aim of this double-blind randomized study was to evaluate the optimal intravenous dose of clonidine administrated during the peri-operative period, after lumbar hemilaminectomy for herniated disk repair. The "optimal intravenous dose" was defined as that providing minimal analgesic request, stable haemodynamic profile and a minimal sedation score during 12h after extubation. Eighty adult patients, ASA physical status I-II, undergoing lumbar hemilaminectomy for herniated disk (L(4)-L(5), L(5)-S(1)) were included in the study. All the patients were randomly assigned to one of four study groups (A, B, C, D), 20 patients each. The same standardized general anaesthesia was performed for each group. Thirty minutes before the end of surgery, group A, B and C patients received three different loading doses of intravenous clonidine (5 microg/kg, 3 microg/kg, 2 microg/kg respectively), followed by the same infusion of intravenous clonidine (0.3 microg/kg per hour). Group D patients received a bolus dose and a continuous infusion of NaCl 0.9%. In the recovery unit, postoperative pain was treated by a patient-controlled analgesia device, containing morphine. Pain relief was evaluated by the total morphine requirement during the postoperative period. Systolic blood pressure (SBP), heart rate and sedation were also noted during the first 12h postoperatively. Intravenous clonidine decreased morphine requirements in a dose-dependent manner. Group A, B, C and D patients requested 5 +/- 2, 11 +/- 3, 19 +/- 4 and 29 +/- 8 doses of morphine respectively. Clonidine also affected SBP in a dose-related manner. Group A, B and C patients had an SBP decrease respectively of 26 +/- 3%, 7 +/- 4% and 2 +/- 2% compared with basic values while, at the same time, in group D patients no SBP variation was registered. In conclusion, this study demonstrates that, when sedation and analgesic effect of clonidine is required, 3 microg/kg bolus dose followed by a continuous infusion of 0.3 microg/kg per hour has to be considered the optimal intravenous dose. The higher dose of intravenous clonidine (5 microg/kg) produced better analgesia but the degree of hypotension and sedation was more severe and longer lasting; it required ephedrine administration and careful monitoring of the patient. On the other hand, the bolus of intravenous clonidine 2 microg/kg (group C) was less effective in terms of pain relief but with similar side-effects to the 3 microg/kg dosage (group B).     

Efficacy and tolerability of oxymorphone immediate release for acute postoperative pain after abdominal surgery: a randomized, double-blind, active- and placebo-controlled, parallel-group trial

BACKGROUND: Patients are typically switched from parenteral opioids to oral opioids during the 24 to 48 hours after surgery. In June 2006, an oral immediate-release (IR) tablet formulation of oxymorphone was approved for the treatment of acute moderate to severe pain. Single doses of oxymorphone IR have been reported to provide significant pain relief after orthopedic surgery. OBJECTIVE: This study assessed the efficacy and tolerability of multiple fixed doses of oxymorphone IR in the treatment of acute postoperative pain after abdominal surgery. METHODS: This was a multicenter, randomized, double-blind, active- and placebo-controlled, parallel-group study in men and women aged >or=18 years undergoing abdominal surgery that required a >or=3-cm incision. Patients who discontinued short-acting parenteral opioids and developed moderate or severe pain (4-point categorical scale [none, mild, moderate, or severe] and pain intensity >or=50 mm on a 100-mm visual analog scale [from 0 = no pain to 100 = worst pain imaginable]) within 30 hours after abdominal surgery were randomized to receive oxymorphone IR 10 or 20 mg, oxycodone IR 15 mg, or placebo every 4 to 6 hours after the previous dose. The study included 2 efficacy assessments: a single-dose evaluation for up to 6 hours after the dose, and a multipledose evaluation for up to 48 hours after the first dose. Pain was assessed at 15-minute intervals during the hour after the first dose, hourly thereafter for the next 5 hours, and before each subsequent dose. The primary efficacy end point was the median time to study discontinuation for all causes. Assessment of tolerability was based on the proportion of study discontinuations due to treatment-emergent adverse events (AEs). RESULTS: Three hundred thirty-one patients were included in the study. Demographic characteristics were similar across all groups: 98.8% (327) of patients were women, and 80.1% (265) of the abdominal surgeries were hysterectomies. The mean (SD) age of the study population was 42.6 (9.3) years. The median time to study discontinuation for all causes was significantly longer for all active treatments compared with placebo (oxymorphone IR 10 mg, 17.9 hours; oxymorphone IR 20 mg, 20.3 hours; oxycodone IR 15 mg, 24.1 hours; placebo, 4.8 hours; P < 0.006). Oxymorphone IR 20 mg was significantly more effective than placebo over the 6-hour single-dose evaluation (P < 0.05). With multiple dosing, all active-treatment groups had significantly lower least squares mean current and average pain intensities compared with placebo (P < 0.004 and P < 0.005, respectively). The least squares means of the average pain intensity were significantly lower among patients treated with oxymorphone IR 10 mg, oxymorphone IR 20 mg, or oxycodone IR 15 mg compared with those who received placebo (39.7, 35.2, 39.8, and 50.1, respectively; P < 0.005). Discontinuations due to treatment-emergent AEs did not differ significantly between groups: 8.5% (7/82), 17.3% (14/81), 13.3% (11/83), and 12.9% (11/85) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, oxycodone IR 15-mg, and placebo groups, respectively. The proportions of patients reporting at least 1 treatment-emergent AE were 46.3% (38/82), 51.9% (42/81), and 54.2% (45/83) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, and oxycodone IR 15-mg groups, respectively, compared with 34.1% (29/85) in the placebo group (P = NS). The fixed-dose design was a study limitation, as it did not allow titration to effect and thus did not mirror clinical practice. CONCLUSION: In this predominantly female population undergoing abdominal surgery, oxymorphone IR given every 4 to 6 hours for up to 48 hours provided efficacious and tolerable analgesia for moderate to severe pain.     

Use of a prophylactic antiemetic with morphine in acute pain: randomised controlled trial

Objective

The aim of this study was to compare the incidence of nausea and vomiting in patients with acute pain treated with morphine along with prophylactic metoclopramide or placebo.

Method

A randomised controlled trial was carried out on patients requiring morphine for acute pain in the emergency department (ED) setting. Children under the age of 12, patients who had been vomiting or had already received prehospital analgesia, and those unable to give consent were excluded. All patients were given either metoclopramide (10 mg) or placebo (normal saline) followed by intravenous morphine. Pain scores (measured on a visual analogue scale) before and after morphine administration, all incidents of nausea or vomiting, the dose of morphine, and the patients'' demographic data were recorded. Fisher''s exact test was used for comparing the two groups of patients.

Results

A total of 259 patients were recruited. There were 123 patients in the metoclopramide group (age range 15–94 years; median age 53) and 136 patients in the placebo group (age range 17–93 years; median age 52.5). The overall incidence of nausea and vomiting in the whole study population was 2.7%, (1.6% in the metoclopramide group and 3.7% in the placebo group). The difference between the two groups was not statistically significant (Fisher''s exact test = 0.451; p = 0.3; z‐test statistic = 1.02; 95% CI –6% to 2%).

Conclusion

When intravenous morphine is administered for acute pain, the overall incidence of nausea and vomiting is low, regardless of whether these patients are given prophylactic metoclopramide or not.     

Paracetamol with and without codeine in acute pain: a quantitative systematic review

In order to assess the analgesia obtained from single oral doses of paracetamol alone and in combination with codeine in postoperative pain, we conducted a systematic review of randomised controlled trials. We found 31 trials of paracetamol against placebo with 2515 patients, 19 trials of paracetamol plus codeine against placebo with 1204 patients and 13 trials of paracetamol plus codeine against the same dose of paracetamol with 874 patients. Pain relief information was extracted, and converted into dichotomous information (number of patients with at least 50% pain relief). Wide variations in responses to placebo (0–72%) and active drug (3–89%) were observed. In postoperative pain states paracetamol 1000 mg alone against placebo had an number-needed-to-treat (NNT) of 3.6 (3.0–4.4) and paracetamol 600/650 mg alone an NNT of 5.0 (4.1–6.9). Paracetamol 600/650 mg plus codeine 60 mg against placebo had a better NNT of 3.1 (2.6–3.8), with no overlap of 95% confidence intervals with paracetamol 600/650 mg alone. In direct comparisons of paracetamol plus codeine with paracetamol alone the additional analgesic effect of 60 mg of codeine added to paracetamol was 12 extra patients in every 100 achieving at least 50% pain relief. In indirect comparisons of each with placebo it was 14 extra patients per 100. This was an NNT for adding codeine 60 mg of 9.1 (5.8–24). The results confirm that paracetamol is an effective analgesic, and that codeine 60 mg added to paracetamol produces worthwhile additional pain relief even in single oral doses.     

Efficacy and tolerability of sumatriptan tablets in a fast-disintegrating, rapid-release formulation for the acute treatment of migraine: results of a multicenter, randomized, placebo-controlled study

BACKGROUND: Sumatriptan tablets have been developed in a fast-disintegrating, rapid-release formulation designed to facilitate tablet disintegration and drug dispersion and to potentially mitigate the effects of gastric stasis that can accompany migraine. OBJECTIVE: This study was conducted to evaluate the efficacy and tolerability of sumatriptan 50- and 100-mg tablets in a fast-disintegrating, rapid-release formulation compared with those of placebo in patients with migraine. METHODS: This clinical trial had a randomized, double-blind, placebo-controlled, parallel-group design. Exclusion criteria included >6 migraines monthly during either of the 2 months before screening; uncontrolled hypertension; suspected or confirmed cardiovascular or cerebrovascular disease; and ophthalmic, basilar, or hemiplegic migraine. Sumatriptan 50 and 100 mg and placebo were taken on an outpatient basis during the mild-pain phase of a single migraine attack. Patients recorded details of the treated migraine on a diary card and rated pain severity immediately before dosing and 30 minutes, 45 minutes, 1 hour, and 2 hours after dosing using a 4-point scale (from 0 = none to 3 = severe). The primary efficacy end point was the proportion of patients who were pain free 2 hours after dosing. Additional efficacy end points were the proportion of patients who were pain free at 30 minutes, 45 minutes, and 1 hour after dosing; the proportion who were migraine free through 2 hours after dosing; and the proportion with a sustained pain-free response. RESULTS: Patients' mean age ranged from 39.7 to 41.5 years across the 3 groups, and the majority were women (79.7%-85.9%) and white (98.7%-100%). One hundred thirty-seven patients received sumatriptan 50 mg, 142 sumatriptan 100 mg, and 153 placebo. In the intent-to-treat population (n = 432), 51.1% of patients who received sumatriptan 50 mg and 66.2% of patients who received sumatriptan 100 mg were pain free 2 hours after dosing, compared with 19.6% of the placebo group (P < 0.001, each sumatriptan dose vs placebo). In an exploratory analysis, the 2-hour pain-free rate with sumatriptan 100 mg was significantly better than that with sumatriptan 50 mg (P = 0.007). Significantly more patients who received sumatriptan 100 mg were pain free compared with placebo at 30 minutes (P < 0.01), 45 minutes (P < 0.001), and 1 hour after dosing (P < 0.001); similar pain-free results were observed in patients who received sumatriptan 50 mg at 45 minutes (P < 0.05) and 1 hour (P = 0.01). In the per-protocol population (n = 313), pain-free efficacy 2 hours after dosing was 52.7% with sumatriptan 50 mg and 74.8% with sumatriptan 100 mg, compared with 21.0% with placebo (P < 0.001, each sumatriptan dose vs placebo). These rates were greater than those in the overall study population, approximately 12.0% of whom treated moderate or severe pain. The only drug-related adverse events reported in >/=3% of patients in any treatment group were nausea and vomiting (<1%, 5%, and 2% in the sumatriptan 50 and 100 mg and placebo groups, respectively), chest symptoms (2%, 3%, and 0%), and malaise and fatigue (1%, 3%, and <1%). No serious adverse events were reported. CONCLUSIONS: In this study, sumatriptan tablets in a fast-disintegrating, rapid-release oral formulation provided pain-free efficacy in the acute treatment of migraine. Efficacy was maximized with the 100-mg dose compared with the 50-mg dose, and by treating early when pain was mild. In the intent-to-treat population, 51.1% of patients who received sumatriptan 50 mg and 66.2% of those who received sumatriptan 100 mg were pain free 2 hours after dosing. In the per-protocol population, 3 of 4 patients taking the 100-mg tablets for mild pain within 1 hour of its onset were pain free at 2 hours. Sumatriptan tablets were generally well tolerated.     

Pregabalin in severe burn injury pain: a double-blind, randomised placebo-controlled trial

This randomised, double-blind, placebo-controlled trial assessed the efficacy and tolerability of pregabalin to alleviate the neuropathic component of moderate to severe burn pain. Patients aged 18 to 65 years admitted to a burns unit with a 5% or greater total body surface area burn injury were screened to participate in the trial. Using the Neuropathic Pain Scale (NPS), patients scoring 4 or higher on ‘hot’ pain or ‘sharp’ pain were invited to participate. Consenting patients were randomly assigned to receive pregabalin or placebo for 28 days with individual dose titration commencing at 75 mg twice daily to a maximum pregabalin dose of 300 mg twice daily. The primary outcome measure was the patients’ daily response to the sharp and hot pain of the NPS. Secondary outcome measures included the remaining elements of the NPS, daily opioid requirement, length of hospital stay, pain at 6 months, and side effects of nausea, vomiting, drowsiness and giddiness. For patients administered pregabalin, the primary outcome measures hot (P = .01) and sharp (P = .04) pain were significantly reduced compared with those in patients administered placebo. Secondary outcome measures of itch, unpleasantness, surface pain, and procedural pain were significantly lower (P < .05) in the pregabalin group. Adverse effects were uncommon, with no difference between the treatment groups. There was no significant difference between the pregabalin and placebo treatment groups with respect to opioid consumption, duration of hospital stay, or pain at 6 months. Pregabalin was efficacious and well tolerated in patients after severe burn injury and whose pain was characterised by features of acute neuropathic pain.     

Cryoneurolysis of alveolar nerves for chronic dental pain: A new technique and a case series

Background

Chronic neuropathic dental pain has a poor prognosis with a low chance of significant spontaneous improvement. Local or oral therapies may be efficient, however short in terms of duration with potential side effects. Cryoneurolysis has been described to prevent acute postoperative pain or to treat some chronic pain conditions; however, application to dental orofacial pain has not been reported so far.

Case Series

Following a positive diagnostic block on the corresponding alveolar nerve, neuroablation was performed using a cryoprobe on three patients suffering from persistent pain after a dental extraction and 1 after multiple tooth surgeries. The effect of treatment was assessed using a Pain Numeric Rating Scale (NRS) and determined by changes in medication dosage and quality of life at day 7 and 3 months. Two patients experienced more than 50% of pain relief at 3 months, 2 by 50%. One patient was able to wean off pregabalin medication, one decreased amitriptyline by 50%, and one decreased tapentadol by 50%. No direct complications were reported. All of them mentioned improvement in sleep and quality of life.

Conclusion

Cryoneurolysis on alveolar nerves is a safe and easy-to-use technique allowing prolonged neuropathic pain relief after dental surgery.     

Efficacy and safety of tramadol and morphine in patients with extremely severe postoperative pain

Tramadol is used for postoperative pain management. However, it is unknown whether tramadol has the same analgesic efficacy as morphine in patients with extremely severe pain. Respiratory depression and sedation by the applied drugs is of special interest.This prospective, randomised, double-blind study was performed as a pilot study. After standardised general anaesthesia, 20 patients with extremely severe postoperative pain — visual analogue scale ≥8 (VAS) — were allocated to intravenous pain treatment with either tramadol or morphine. The goal was to reduce pain intensity to VAS ≤1 during a four hour period. Pain intensities, vital parameters and side effects were recorded every 15 minutes. Sedation (four-point scale) and blood gases were controlled every 30 minutes. Oxygen saturation was continuously monitored by pulse oximetry. An oxygen saturation below 90% without oxygen supply was taken as respiratory depression. Statistical analysis was performed with the t-test for most of the numerical parameters. A p-value <0.05 was considered significant.Both drugs reduced pain intensities to VAS ≤1 within 135 minutes (median). Median dosages were 292.5 mg for tramadol (160–460 mg) and 27 mg for morphine (20–45.1 mg). Tramadol patients experienced significantly fewer severe side effects: two morphine patients had to be excluded from the efficacy analysis of the study: one for extreme sedation, the other because of severe respiratory depression. Minor side effects had a similar incidence.In conclusion, successful treatment of extremely severe postoperative pain was achieved with both tramadol and morphine. Drug dosages were significantly higher than usually administered. Tramadol patients experienced fewer severe side effects than morphine patients.