Mean Daily Pain Research Articles

Effects of Flow Rate Modifications on Reported Analgesia and Quality of Life in Chronic Pain Patients Treated with Continuous Intrathecal Drug Therapy

We compared the analgesia and the quality of life of a constant daily dose of intrathecal drug administered at different flow rates in patients treated for chronic pain. We postulate that the quality of the analgesia, at the same daily dose, will show an infusion rate dependent pattern with decreased pain at higher flow rates. Twenty consecutive patients on stable intrathecal treatment were included in a double-blind three-period crossover study where the same daily dose was administered at single, double, and quadruple flow rates in a randomized sequence. The mean daily pain score and the quality of life (EuroQol measure of health outcome [EQ-5D]) were measured following each flow rate change, after 1 week of stabilization. Results. Visual analog scale (VAS) scores remained unchanged with all flow rates. Compared with the lowest flow rate, the EQ-5D index decreased with double and even more with quadruple flow rate, suggesting a clinically relevant worsening of the health state with higher flow rates. Adverse events were equally distributed in all groups. Pain VAS did not significantly change with flow rate. This is consistent with preclinical data showing very limited increase in drug distribution in the cerebrospinal fluid with much larger flow rate augmentation. However, the quality of life decreased consistently as the flow rate increased. This was entirely due to a worsening of the pain and anxiety dimension of the EQ-5D questionnaire, caused presumably by a slight increase in pain rather than adverse events. We suggest that at higher flow rates increased drug dilution results in a decreased effect at the receptor site.

Efficacy and Tolerability of Pregabalin Using a Flexible, Optimized Dose Schedule in Korean Patients With Peripheral Neuropathic Pain: A 10-Week, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study

Clinical trials from various countries have reported the efficacy of pregabalin for reducing peripheral neuropathic pain. This study assessed the efficacy and tolerability of pregabalin in Korean patients with neuropathic pain. This was a Phase III, 10-week, randomized, double-blind, placebo-controlled, multicenter study. Patients aged ≥ 18 years with neuropathic pain (diabetic peripheral neuropathy, postherpetic neuralgia, or posttraumatic neuropathic pain) were enrolled and randomly assigned (2:1 ratio) to pregabalin (150-600 mg/d) or matching placebo. Randomization was performed using a proprietary telerandomization system. The primary end point was the difference in week 8 least squares (LS) mean Daily Pain Rating Scale (DPRS) score (rated once daily from 0 ["no pain"] to 10 ["worst possible pain"]) between pregabalin and placebo, calculated using the average of the last 7 available DPRS scores. Secondary efficacy measures included the following: the proportion of responders whose DPRS scores were reduced by ≥ 30% or ≥ 50% versus baseline, the Daily Sleep Interference Scale (DSIS; 11-point scale, scored daily), the Euro Quality of Life assessment (EQ-5D; 2 items scored separately), the Medical Outcomes Study (MOS) Sleep Scale (12 items each scored separately), the Hospital Anxiety and Depression Scale (HADS; 2 items scored from 0 to 21), the Patient Global Impression of Change (PGIC) and the Clinical Global Impression of Change (CGIC; each scored on a 7-point scale), and tolerability assessments. Adverse events and vital signs were monitored throughout the study with laboratory measurements, physical examinations, neurologic examinations, and 12-lead ECG tests. Data were analyzed using ANCOVA or Cochran-Mantel-Haenszel test, and P < 0.05 was considered statistically significant. The treatment groups (n = 162 pregabalin; n = 78 placebo) were well matched at baseline (pregabalin: 51.2% [83/162] female; mean [SD] age, 59.7 [10.8] years; weight, 63.6 [9.3] kg; placebo: 59.0% [46/78] female; mean age, 61.3 [12.9] years; weight, 62.0 [9.5] kg). All patients were Korean. The mean doses at end point were 480 mg/d for pregabalin and 513 mg/d for the placebo equivalent. Most patients received concomitant drug treatments during the study: 79.6% (129/162) in the pregabalin group and 92.3% (72/78) in the placebo group. The mean DPRS score at end point was significantly lower in the pregabalin group than in the placebo group (LS mean difference, -0.50; 95% CI, -1.00 to 0.00; P = 0.049). In total, 26.1% (42/161) of pregabalin-treated patients reported ≥ 50% improvement in mean DPRS scores from baseline, compared with 14.3% (11/77) for placebo (P = 0.041 between groups). The LS mean change in the DSIS from baseline to end point favored pregabalin (-0.51; 95% CI, -0.96 to -0.07; P = 0.024). Significant improvements were also recorded for overall MOS sleep interference score (difference in LS means, -0.65; P = 0.018) and HADS anxiety subscale score (-0.85; P = 0.038). Other secondary assessments (eg, EQ-5D, HADS depression subscale, PGIC, and CGIC) did not reach significance. A higher proportion of patients reported treatment-related adverse events with pregabalin (43.8% [71/162]) than with placebo (29.5% [23/78]). Dizziness (21.0% [34/162]), somnolence (13.6% [22/162]), face edema (6.2% [10/162]), peripheral edema (6.2% [10/162]), and weight gain (5.6% [9/162]) were the most commonly reported adverse events in the pregabalin group. Flexible-dose pregabalin (150-600 mg/d for 8 weeks) was associated with a significant, although modest, reduction in mean DPRS score; an improvement in anxiety and subjective sleep; and generally good tolerability compared with placebo in these Korean patients with neuropathic pain due to diabetic peripheral neuropathy, postherpetic neuralgia, or posttraumatic neuropathic pain.

Effectiveness of an Anesthetic Continuous-Infusion Device in Children With Cerebral Palsy Undergoing Orthopaedic Surgery

Effective postoperative pain management is a vital component of orthopaedic surgical care in the pediatric population. In children with cognitive impairments pain management can be difficult, making these children vulnerable to ineffectively managed postoperative pain. This prospective, randomised study evaluated the use of a local anesthetic continuous infusion device (pain pump) to manage postoperative pain in children with cerebral palsy (CP) undergoing lower extremity orthopaedic surgical procedures. Children with a diagnosis of CP who were undergoing select orthopaedic outpatient procedures were enrolled in this study. Postoperatively, patients were randomised to receive either a pain pump in addition to oral analgesics or oral analgesics only. Patient's parents were asked to record the amount of medication administered and assess pain intensity with the use of a modified visual analogue scale for 3 days postoperatively. Parents also completed an overall pain management satisfaction questionnaire at the end of the study participation period. Fifty-four patients were enrolled in this study and data were analyzed on 37 patients. The mean daily pain intensity in the pain pump group was significantly lower for the day of surgery and for 2 days postoperatively, and there was an overall significant difference between the groups (P<0.0001). The amount of analgesic medication administered was significantly lower for the first 2 postoperative days, but there was not a significant difference between the 2 groups overall (P=0.29). Parent satisfaction with both pain management techniques was high and responses were similar between the 2 groups. Children with CP present unique postoperative pain management concerns that can be effectively addressed through the use of multimodal analgesic techniques. This study found that the pain pump is an effective pain management technique that significantly reduces pain intensity in children with CP after lower extremity orthopaedic procedures. Therapeutic Level II.

Time to Onset of Neuropathic Pain Reduction: A Retrospective Analysis of Data From Nine Controlled Trials of Pregabalin for Painful Diabetic Peripheral Neuropathy and Postherpetic Neuralgia

These retrospective analyses of daily mean pain scores from nine placebo-controlled trials of pregabalin at 150, 300, or 600 mg/day (pregabalin, n = 1205; placebo, n = 772) examined time to significant reduction of pain during the first 2 weeks of treatment of painful diabetic peripheral neuropathy and postherpetic neuralgia. Time to onset of reduction in pain-defined as the first day for which patients treated with pregabalin had significant reductions (P < 0.05) in mean pain score compared with the placebo group for that day and the subsequent day-was calculated for all treatment groups demonstrating statistically significant reduction in pain at trial end point. The time to a 1-point or greater improvement in mean pain score was measured for each patient who was a responder at end point (30% or greater improvement in mean pain score). In seven of the nine trials (representing 11 of 14 pregabalin arms), significant reduction in pain was achieved at end point. The time to onset for reduction in pain was treatment Day 1 or 2 in nine of these successful treatment arms. Individual responder analysis confirmed that responders in the pregabalin groups reported a 1-point or greater pain reduction earlier than responders in placebo groups (P < 0.0001). However, this analysis is not a direct estimate of the likelihood that an individual patient would experience noticeable pain relief by the end of the second day. Overall, for patients who will respond to pregabalin, statistically significant and sustained reduction of pain associated with diabetic peripheral neuropathy and posttherapeutic neuralgia occurs early, usually by the end of 2 days of pregabalin treatment.

Lidocaine

Lidocaine

LOCF Approach to Handling Missing Data Overestimates the Pain Score Improvement of Drop-Outs

The results of Shaibani et al's 2 Shaibani A. Fares S. Selam J.L. Arslanian A. Simpson J. Sen D. Bongardt S. Lacosamide in painful diabetic neuropathy: An 18-week double-blind placebo-controlled trial. J Pain. 2009; 10: 818-828 Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar clinical trial comparing lacosamide to placebo in painful diabetic peripheral neuropathy (DPN) are potentially misleading as presented. The authors defined the primary endpoint as the “within-patient change in the mean daily pain score from baseline to the mean value over the last 4 weeks” of the maintenance period. In order to perform an intention-to-treat analysis incorporating all patients who took study medication, some method of incorporating patients with missing data must be used. The authors of this study used a last-observation-carried-forward (LOCF) method of handling missing data. This approach, which has been previously employed in chronic neuropathic-pain clinical trials 1 O'Connor A.B. The need for improved access to FDA reviews. JAMA. 2009; 302: 191-193 Crossref PubMed Scopus (48) Google Scholar and was also used in the other published phase III clinical trial of lacosamide in painful DPN, 4 Wymer J.P. Simpson J. Sen D. Bongardt S. Efficacy and safety of lacosamide in diabetic neuropathic pain: An 18-week double-blind placebo-controlled trial of fixed-dose regimens. Clin J Pain. 2009; 25: 376-385 Crossref PubMed Scopus (110) Google Scholar overestimates treatment benefit because the pain scores of patients unable to tolerate the treatment are carried forward to the endpoint. In a chronic-pain clinical trial studying an analgesic that is not known to modify the underlying disease, pain scores would be projected to return to baseline levels in patients who stop taking the analgesic; for this reason, a baseline-observation-carried-forward (BOCF) strategy of handling missing data would provide a more accurate estimation of the true pain score during the endpoint period (in this case, weeks 14–18) (See Fig 1). This is an especially important issue in this lacosamide trial, in which more than half of the patients who received 400 mg/day or 600 mg/day dropped out (145/262, 55%), the majority of them because of adverse events (88/145, 61%). Using the authors' endpoint definition and LOCF, patients unable to tolerate lacosamide for the duration of the trial are indistinguishable in the analysis from patients who successfully complete the trial with comparable pain scores. ReplyThe Journal of PainVol. 11Issue 5PreviewTo the Editor: Full-Text PDF

Pain Medicine

Pain Medicine

Randomized Placebo-Controlled Double-Blind Clinical Trial of Cannabis-Based Medicinal Product (Sativex) in Painful Diabetic Neuropathy

OBJECTIVETo assess the efficacy of Sativex, a cannabis-based medicinal extract, as adjuvant treatment in painful diabetic peripheral neuropathy (DPN).RESEARCH DESIGN AND METHODSIn this randomized controlled trial, 30 subjects with painful DPN received daily Sativex or placebo. The primary outcome measure was change in mean daily pain scores, and secondary outcome measures included quality-of-life assessments.RESULTSThere was significant improvement in pain scores in both groups, but mean change between groups was not significant. There were no significant differences in secondary outcome measures. Patients with depression had significantly greater baseline pain scores that improved regardless of intervention.CONCLUSIONSThis first-ever trial assessing the efficacy of cannabis has shown it to be no more efficacious than placebo in painful DPN. Depression was a major confounder and may have important implications for future trials on painful DPN.

Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial

Drugs for neuropathic pain have incomplete efficacy and dose-limiting side-effects when given as monotherapy. We assessed the efficacy and tolerability of combined nortriptyline and gabapentin compared with each drug given alone. In this double-blind, double-dummy, crossover trial, patients with diabetic polyneuropathy or postherpetic neuralgia, and who had a daily pain score of at least 4 (scale 0-10), were enrolled and treated at one study site in Canada between Nov 5, 2004, and Dec 13, 2007. 56 patients were randomised in a 1:1:1 ratio with a balanced Latin square design to receive one of three sequences of daily oral gabapentin, nortriptyline, and their combination. In sequence, a different drug was given to each randomised group in three treatment periods. During each 6-week treatment period, drug doses were titrated towards maximum tolerated dose. The primary outcome was mean daily pain at maximum tolerated dose. Analysis was by intention to treat. This trial is registered, number ISRCTN73178636. 45 patients completed all three treatment periods; 47 patients completed at least two treatment periods and were analysed for the primary outcome. Mean daily pain (0-10; numerical rating scale) was 5.4 (95% CI 5.0 to 5.8) at baseline, and at maximum tolerated dose, pain was 3.2 (2.5 to 3.8) for gabapentin, 2.9 (2.4 to 3.4) for nortriptyline, and 2.3 (1.8 to 2.8) for combination treatment. Pain with combination treatment was significantly lower than with gabapentin (-0.9, 95% CI -1.4 to -0.3, p=0.001) or nortriptyline alone (-0.6, 95% CI -1.1 to -0.1, p=0.02). At maximum tolerated dose, the most common adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline (p<0.0001) or combination treatment (p<0.0001). No serious adverse events were recorded for any patients during the trial. Combined gabapentin and nortriptyline seems to be more efficacious than either drug given alone for neuropathic pain, therefore we recommend use of this combination in patients who show a partial response to either drug given alone and seek additional pain relief. Future trials should compare other combinations to their respective monotherapies for treatment of such pain. Canadian Institutes of Health Research.

Gabapentin

Gabapentin

Comparable Analgesic Efficacy of Transdermal Buprenorphine in Patients Over and Under 65 Years of Age

To compare the efficacy and tolerability of transdermal buprenorphine in elderly patients and 2 younger populations, all requiring analgesic treatment for moderate-to-severe chronic pain. Three equally sized age-groups (A>/=65, n=30; B=51 to 64, n=27; C</=50 y, n=25) were examined during 28-day treatment periods to detect potential differences in responsiveness (pain intensity, rescue medication, sleep duration) to the transdermal opioid. Distribution of pain causing diagnoses was comparable between age-groups, predominantly musculoskeletal disorders (65% of all diagnoses), diseases of the nervous system (13%), injuries (8%), and cancer (5%). Mean buprenorphine patch doses were 35, 50, and 40 mug/h (groups A, B, and C) at end of study. Pain intensity significantly decreased from pretreatment [visual analog scale (VAS)=57% and numerical rating pain scale=5.9 points) until the end of the study (day 28: 34% and 3.8 points; n=55), without differences between age-groups (VAS day 28: A=34%; B=34%; C=33%). Two-third of patients (A=67%; B=67%; C=68%) completed the study at day 28; the rates and reasons for premature study termination were similar in all age-groups. Daily mean pain intensities (days 10 to 28) were even lower (P<0.005) in elderly patients (VAS A=35.8%) as compared with both younger age-groups (B=39.8%; C=39.9%). Sleep duration incidences above 6 hours improved from 34% to a plateau above 50% (A=68%; B=38%; C=57%) for patients terminating the study as planned. The need for rescue medication was lowest in elderly patients (A=107; B=136; C=253 mug/d, days 10 to 28). The opioid typical adverse event profile (predominantly dizziness and nausea) and local skin tolerability were both comparable for younger and elderly patients. This investigation showed that the treatment of chronic pain with transdermal buprenorphine in elderly patients above the age of 65 years is at least as effective, tolerable, and safe as in patients studied in 2 age-groups below that age.

Consumption of red-hot chili pepper increases symptoms in patients with acute anal fissures. A prospective, randomized, placebo-controlled, double blind, crossover trial

Red-hot chili pepper and other spices have been blamed for causing or exacerbating symptoms of anal pathologies like anal fissure and hemorrhoids. To determine if consumption of chilies increases symptoms of acute anal fissures. Individual patients were randomized to receive capsules containing chili or placebo for one week in addition to analgesics and fiber supplement. Patients were asked to note score for symptoms like pain, anal burning, and pruritus during the study period. After 1 week, cross over treatment was administered to the same group of patients with the same methodology and results were noted at the end of 2 weeks. Fifty subjects were recruited for this study. Forty three of them completed the trial (22 in the chili group and 21 in the placebo group). The daily mean pain score was significantly lower in the placebo group in the study period. Score 2.05 in chili group and 0.97 in placebo group. There was a significant burning sensation experienced by the patients in the chili group (score 1.85 for the chili group vs 0.71 for the placebo group). Patients mean recorded improvement score was significantly higher after taking placebo. Eighty one point three percent patients preferred placebo while 13.9% preferred chilies. Two patients had no preference. Consumption of chili does increase the symptoms of acute anal fissure and reduces patient compliance.

Patient‐controlled analgesia versus continuous infusion of morphine during vaso‐occlusive crisis in sickle cell disease, a randomized controlled trial

Intravenous morphine is the treatment of choice for severe pain during vaso- occlusive crisis in sickle cell disease (SCD). However, side effects of morphine may hamper effective treatment, and high plasma levels of morphine are associated with severe complications such as acute chest syndrome. Furthermore, adequate dosing remains a problem since no objective measurement of pain severity exists and analgesia should be titrated upon the patient's reported pain. Patient-controlled analgesia (PCA) may therefore be an interesting alternative since patients can titrate the level of analgesia themselves. In this randomized controlled study, the efficacy of intravenous morphine administration with PCA was compared with continuous infusion (CI) of morphine in patients with SCD during vaso-occlusive crisis. Twenty five consecutive episodes of vaso-occlusive crisis in 19 patients with SCD were included in the study. Patients in the PCA-group had a markedly and significant lower mean and cumulative morphine consumption when compared with the patients in the CI-group (0.5 mg/hr versus 2.4 mg/hr (P < 0.001) and 33 mg versus 260 mg (P = 0.018, respectively). The mean daily pain scores were comparable (4.9 versus 5.3). The lower mean and cumulative morphine consumption in the PCA-group led to significant less nausea and constipation during treatment when compared with the CI-group (area under the curve, respectively, 11 versus 18 (P = 0.045) and 30 versus 45 (P = 0.021). Furthermore, a nonsignificant reduction in the duration of hospital admission of 3 days was observed in the PCA-group. PCA results in adequate pain relief at a much lower morphine consumption and should considered to be the first choice in morphine administration to sickle cell patients admitted with vaso-occlusive crisis.

Efficacy and tolerability of once-daily OROS® hydromorphone and twice-daily extended-release oxycodone in patients with chronic, moderate to severe osteoarthritis pain: Results of a 6-week, randomized, open-label, noninferiority analysis

Objective:This study compared the efficacy and tolerability of a once-daily controlled-release formulation of hydromorphone (OROS® hydromorphone, Janssen-Cilag, Beerse, Belgium) and twice-daily extended-release (ER) oxycodone in patients with chronic, moderate to severe osteoarthritis (OA) pain. OROS hydromorphone is currently available only in Europe. Methods:Adults who met American College of Rheumatology clinical criteria for OA of the knee or hip with moderate to severe mean daily pain intensity despite chronic use of stable doses of NSAIDs or other nonsteroidal, nonopioid therapies were eligible for participation in this randomized, open-label study. The study consisted of a 14-day dose-titration and stabilization phase and a 28-day maintenance phase. OROS hydromorphone and ER oxycodone were initiated at dosages of 8 mg QD and 10 mg BID, respectively. Patients maintained diaries in which they rated their pain (from 0 = none to 3 = severe) and pain relief (from 0 = no relief to 4 = complete relief). Other assessments completed every 14 days included patient and investigator global evaluations of treatment effectiveness (scale from 1 = poor to 5 = excellent), the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, and the Medical Outcomes Study (MOS) Sleep Scale. Adverse events (whether observed by study personnel, identified in response to questioning, or spontaneously reported) and vital signs were monitored throughout the study. The primary efficacy measures were the mean pain relief score at end point and the time from initiation of treatment to the third day of moderate to complete pain relief, as reported in the patient diary. Noninferiority analyses were conducted on all primary and secondary efficacy variables. Results:One hundred thirty-eight patients (71 OROS hydromorphone, 67 ER oxycodone) received treatment (safety population), and 83 (60.1%) completed the study. Data from 124 patients were included in the efficacy analyses; the majority of these patients were white (85.5%) and female (69.4%), with a mean age of 63.6 years. The most commonly affected joint was the knee (79.8 %). At end point, the OROS hydromorphone group had a mean pain relief score of 2.3 (median, 2.0) and the ER oxycodone group had a mean pain relief score of 2.3 (median, 2.3) (95% CI, -0.30 to ∞). The mean time to the third day of moderate to complete pain relief was 6.2 days (median, 4.0) in the OROS hydromorphone group and 5.5 days (median, 5.0) in the ER oxycodone group (95% CI, -0.31 to ∞). Mean pain intensity decreased from baseline to end point by 0.6 point in the OROS hydromorphone group and by 0.4 point in the ER oxycodone group. Mean scores on the patient global evaluation improved by a respective 1.2 and 1.0 points (median, 1 in both groups). Approximately two thirds of patients in each group (67.2% and 66.7%) rated the overall effectiveness of treatment as good to excellent at end point. There were no statistically significant differences between groups in total WOMAC scores at end point, and similar improvements from baseline in the WOMAC physical function, stiffness, and pain scales were observed in both groups. Whereas MOS sleep outcomes scores improved from baseline in both groups, OROS hydromorphone was associated with a significantly greater improvement on the MOS Sleep Problems Index I compared with ER oxycodone (P < 0.045). Adverse events were comparable in both groups; the most frequently reported adverse events were nausea (35.2% and 29.9%), constipation (29.6% and 25.4%), somnolence (25.4% and 17.9%), vomiting (16.9% and 11.9%), and dizziness (14.1% and 22.4%). Adverse events led to study discontinuation in 35.2% (25/71) of patients in the OROS hydromorphone group and 32.8% (22/67) in the ER oxycodone group. Discontinuations due to adverse events during the titration phase were numerically greater in the OROS hydromorphone group (29.6% [21/71]) than in the ER oxycodone group (19.4% [13/67]). Only 1 serious adverse event (diarrhea in a patient receiving OROS hydromorphone) was considered possibly related to study drug. Conclusions:Once-daily OROS hydromorphone and twice-daily ER oxycodone provided similar pain relief in these patients with OA of the knee or hip. The tolerability profiles of the 2 agents were similar.

Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain

Although lumbar radicular pain is the most common chronic neuropathic pain syndrome, there have been few randomized studies of drug treatments. We compared the efficacy of morphine (15–90 mg), nortriptyline (25–100 mg), their combination, and a benztropine “active placebo” (0.25–1 mg) in patients with chronic sciatica. Each period consisted of 5 weeks of dose escalation, 2 weeks of maintenance at the highest tolerated doses, and 2 weeks of dose tapering. The primary outcome was the mean daily leg pain score on a 0–10 scale during the maintenance period. Secondary outcomes included a 6-point ordinal global pain relief scale, the Beck Depression Inventory (BDI), the Oswestry Back Pain Disability Index (ODI) and the SF-36. In the 28 out of 61 patients who completed the study, none of the treatments produced significant reductions in average leg pain or other leg or back pain scores. Pain reduction, relative to placebo treatment was, 14% for nortriptyline (95% CI = [−2%, 30%]), 7% for morphine (95% CI = [−8%, 22%]), and 7% for the combination treatment (95% CI = [−4%, 18%]). Mean doses were: nortriptyline alone, 84 ± 24.44 (SD) mg/day; morphine alone, 62 ± 29 mg/day; and combination, morphine, 49 ± 27 mg/day plus nortriptyline, 55 mg ± 33.18 mg/day. Over half of the study completers reported some adverse effect with morphine, nortriptyline or their combination. Within the limitations of the modest sample size and high dropout rate, these results suggest that nortriptyline, morphine and their combination may have limited effectiveness in the treatment of chronic sciatica.

Tramadol 37.5-mg/acetaminophen 325-mg combination tablets added to regular therapy for rheumatoid arthritis pain: A 1-Week, randomized, double-blind, placebo-controlled trial

Objective: This study evaluated the efficacy and tolerability of tramadol 37.5-mg/acetaminophen 325-mg combination tablets (tramadoUAPAP) as add-on therapy in subjects with rheumatoid arthritis (RA) pain that was inadequately controlled by NSAIDs and disease-modifying antirheumatic drugs alone. Methods: Subjects in this multicenter, double-blind trial were randomized in a 3:1 ratio to receive 1 tramadol/ APAP tablet TID or a matching placebo for 1 week. Stable doses of previous medications were continued during the study. The primary efficacy variable was the mean daily pain relief score over 1 week, measured on a 6-point scale (4 = complete; ' = a lot; 2 = some; 1 = a little; 0 = none; -1 = worse). Secondary outcomes included the mean daily pain intensity score, measured on a 100-mm visual analog scale (VAS) (from 0 mm = no pain to 100 mm = extreme pain); pain intensity and pain relief at day 7; subjects' and investigators' mean overall assessments of study drug, measured on a Likert scale (from 2 = very good to -2 = very poor); and subjects' assessments of 8 aspects of physical function (measured on the Health Assessment Questionnaire). Results: Of 277 subjects randomized to treatment, 267 (201 tramadol/APAP, 66 placebo) were included in the intent-to-treat population. Mean (SD) daily pain relief scores at the end of 1 week were significantly greater in the tramadol/APAP group compared with the placebo group (1.04 [0.89] vs 0.78 [0.80], respectively; P = 0.037), and mean daily pain intensity scores at the end of 1 week were significantly lower (47.23 [19.96] vs 53.81 [16.59]; P = 0.018). Physical function at the end of 1 week did not differ significantly between tramadol/APAP and placebo. Two hundred seventy-two subjects (205 tramadol/APAP, 67 placebo) were evaluable for tolerability. One hundred thirty-three of these subjects had at least 1 adverse event. The incidence of adverse events was significantly higher in the tramadol/APAP group than in the placebo group (57.6% vs 22.4%; P < 0.001). Discontinuations due to adverse events occurred in 19.0% of the tramadol/APAP group and 3.0% of the placebo group ( P = 0.001). Of 213 treatment-related adverse events in tramadol/APAP subjects, nausea (34.1%) was the most frequent, followed by dizziness (20.0%) and vomiting (15.6%). One serious adverse eventchest discomfort, nausea, and vomiting after taking study medication—occurred in a subject receiving tramadol/APAP The symptoms resolved 1 day after discontinuing tramadol/APAP Conclusions: In this study, tramadol/APAP used as add-on therapy in subjects with symptomatic RA was associated with a significant improvement in pain relief and a significant reduction in pain intensity compared with placebo, with no improvement in physical function. Use of tramadol/APAP may be considered when analgesics are needed in addition to conventional NSAIDs and disease-modifying antirheumatic drugs in subjects with RA.

A Randomized Controlled Trial of Patient Controlled Analgesia Versus Continuous Infusion of Morphine during Vaso-Occlusive Crisis in Sickle Cell Disease.

Intravenous morphine is the treatment of choice for severe pain during vaso-occlusive crisis in sickle cell disease (SCD). However, side-effects of morphine may hamper effective treatment and high plasma levels of morphine are associated with severe complications such as acute chest syndrome. Furthermore, adequate dosing remains a problem since no objective measurement of pain severity exists and analgesia should be titrated upon the patient's reported pain. Patient-controlled analgesia (PCA) may therefore be an interesting alternative since patients can titrate the level of analgesia themselves. Although PCA is currently used for the treatment of vaso-occlusive crises in SCD, no randomized controlled trials have been performed in admitted patients with a vaso-occlusive crisis so far. In the present study, we conducted a randomized controlled trial to compare the administration of morphine with PCA versus CI in sickle cell patients with vaso-occlusive crises. Patients were randomized between PCA and CI of morphine within 24 hours after hospital admission. Endpoints of the study were: the mean and cumulative morphine dose, pain intensity, incidence of side-effects (nausea, constipation, pruritus and drowsiness) and quality of life (QoL). Pain intensity was measured daily using a ten-point-scale verbal pain score. Reduction of pain intensity was measured by subtracting a pain score on a ten point visual analogue scale (VAS) before randomization from the same measurement two days after randomization. Side-effects were measured four times per day on a 11-point numerical rating scale. QoL was measured using the 36-item Short Form Healthy Survey (SF36). Twenty five consecutive episodes of vaso-occlusive crisis in 19 patients with SCD were included in the study. No difference in the mean daily pain scores were found between the two groups (4.9 versus 5.3). However, patients in the PCA-group demonstrated to have a strongly reduced mean and cumulative morphine consumption as compared to the patients in the CI-group (0.5 mg/h versus 2.4 mg/h (P<0.001) and 33 mg versus 260 mg (P=0.018) respectively). The lower mean and cumulative morphine consumption in the PCA-group led to significant less nausea and constipation during treatment as compared to the CI-group (area under the curve respectively 11 versus 18 (P= 0.045) and 30 versus 45 (P= 0.021)). Furthermore, a non-significant reduction in the duration of hospital admission of 3 days was observed in the PCA-group. Patient controlled analgesia results in adequate pain relief at a much lower morphine consumption and should considered to be first choice in morphine administration to sickle cell patients admitted with vaso-occlusive crisis. [Display omitted]

Effects of gabapentin on morphine consumption and pain in severely burned patients

Objective Nociception is the major cause of burn pain and leads to central hyperalgesia. Gabapentin ( Gp) is an antihyperalgesic drug that selectively affects central sensitization. We studied the opioid-sparing and analgesic effects of Gp in severely burned patients. Methods Ten patients (mean total burned body surface area (TBSA), 25%), received 2400 mg of oral Gp daily from after burn days 3–24 in addition to standard pain therapy. They were compared to a retrospective matching group. Outcomes were cumulative morphine consumption and mean daily pain scores. Outcomes were recorded during treatment (21 days) and 21 days after treatment. Results During treatment and post-treatment phases, patients receiving Gp had cumulative morphine consumption and a mean daily pain score significantly lower than controls. Conclusion Gp use reduced opioid consumption and lowered pain scores that seemed to extend beyond its pharmacologic action probably result from the ability of Gp to prevent central hyperalgesia induced by burns.

Natural history of pain following herpes zoster

In a longitudinal observational study of 94 patients (39M:55F, mean age 69) at elevated risk for developing post herpetic neuralgia (PHN), the natural history of pain during the first 6 months after herpes zoster (HZ) rash onset was determined. Pain severity and impact were rated using pain-VAS, SF-MPQ, and MPI. Applying a definition of PHN of average daily pain >0/100 on the pain VAS during the last 48 h, 30 subjects had PHN at 6 months. These 30 subjects reported more pain and a higher SF-MPQ score ( p < 0.01) at study inclusion than the 64 subjects whose pain completely resolved by 6 months. At 6 months, mean daily pain in the PHN group was 11/100 (95% CI 5,16) and only nine of these subjects were still taking prescription medication for HZ pain. The rate of recovery (pain severity over time) was the same in the PHN and no-pain groups. At study inclusion, the SF-MPQ and MPI scores in our PHN group were similar to historical controls with chronic severe PHN enrolled in clinical trials, but by 6 months the scores in our PHN subjects were significantly lower than historic controls. Only two subjects met the more stringent criteria for ‘clinically meaningful’ PHN at 6 months (⩾30/100 on the pain VAS). Defining PHN as average daily pain >0/100 at 6 months after rash onset appears to substantially overestimate the number of HZ patients negatively impacted by ongoing pain and disability.

Topiramate in Chronic Lumbar Radicular Pain

Chronic lumbar radicular pain is the most common neuropathic pain syndrome. This was a double-blind, randomized, 2-period crossover trial of topiramate (50 to 400 mg) and diphenhydramine (6.25 to 50 mg) as active placebo to assess the efficacy of topiramate. Each period consisted of a 4-week escalation, a 2-week maintenance at the highest tolerated dose, and a 2-week taper. Main outcome was the mean daily leg pain score on a 0 to 10 scale during the maintenance period. Global pain relief was assessed on a 6-level category scale. In the 29 of 42 patients who completed the study, topiramate reduced leg pain by a mean of 19% ( P = .065). Global pain relief scores were significantly better on topiramate ( P < .005). Mean doses were topiramate 200 mg and diphenhydramine 40 mg. We concluded that topiramate treatment might reduce chronic sciatica in some patients but causes frequent side effects and dropouts. We would not recommend topiramate unless studies of alternative regimens showed a better therapeutic ratio. Perspective The anticonvulsant topiramate might reduce chronic lumbar nerve root pain through effects such as blockade of voltage-gated sodium channels and AMPA/kainite glutamate receptors, modulation of voltage-gated calcium channels, and gamma-aminobutyric acid agonist-like effects.