Göran Leijon

5% lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an open-label, non-inferiority two-stage RCT study

ABSTRACT Objective: To compare efficacy and safety of 5% lidocaine medicated plaster with pregabalin in patients with post-herpetic neuralgia (PHN) or painful diabetic polyneuropathy (DPN). Study design and methods: This was a two-stage adaptive, randomized, open-label, multicentre, non-inferiority study. Data are reported from the initial 4-week comparative phase, in which adults with PHN or painful DPN received either topical 5% lidocaine medicated plaster applied to the most painful skin area or twice-daily pregabalin capsules titrated to effect according to the Summary of Product Characteristics. The primary endpoint was response rate at 4 weeks, defined as reduction averaged over the last three days from baseline of ≥2 points or an absolute value of ≤4 points on the 11-point Numerical Rating Scale (NRS-3). Secondary endpoints included 30% and 50% reductions in NRS-3 scores; change in allodynia severity rating; quality of life (QoL) parameters EQ-5D, CGIC, and PGIC; patient satisfaction with treatment; and evaluation of safety (laboratory parameters, vital signs, physical examinations, adverse events [AEs], drug-related AEs [DRAEs], and withdrawal due to AEs). Results: Ninety-six patients with PHN and 204 with painful DPN were analysed (full analysis set, FAS). Overall, 66.4% of patients treated with the 5% lidocaine medicated plaster and 61.5% receiving pregabalin were considered responders (corresponding numbers for the per protocol set, PPS: 65.3% vs. 62.0%). In PHN more patients responded to 5% lidocaine medicated plaster treatment than to pregabalin (PPS: 62.2% vs. 46.5%), while response was comparable for patients with painful DPN (PPS: 66.7% vs 69.1%). 30% and 50% reductions in NRS-3 scores were greater with 5% lidocaine medicated plaster than with pregabalin. Both treatments reduced allodynia severity. 5% lidocaine medicated plaster showed greater improvements in QoL based on EQ-5D in both PHN and DPN. PGIC and CGIC scores indicated greater improvement for 5% lidocaine medicated plaster treated patients with PHN. Improvements were comparable between treatments in painful DPN. Fewer patients administering 5% lidocaine medicated plaster experienced AEs (safety set, SAF: 18.7% vs. 46.4%), DRAEs (5.8% vs. 41.2%) and related discontinuations compared to patients taking pregabalin. Conclusion: 5% lidocaine medicated plaster showed better efficacy compared with pregabalin in patients with PHN. Within DPN, efficacy was comparable for both treatments. 5% lidocaine medicated plaster showed a favourable efficacy/safety profile with greater improvements in patient satisfaction and QoL compared with pregabalin for both indications, supporting its first line position in the treatment of localized neuropathic pain.

Efficacy and safety of combination therapy with 5% lidocaine medicated plaster and pregabalin in post-herpetic neuralgia and diabetic polyneuropathy

ABSTRACT Objective: Neuropathic pain is often difficult to treat due to a complex pathophysiology. This study evaluated the efficacy, tolerability and safety of combination therapy with 5% lidocaine medicated plaster and pregabalin for neuropathic pain in patients with post-herpetic neuralgia (PHN) or painful diabetic polyneuropathy (DPN). Methods: Patients completing 4-week monotherapy with 5% lidocaine medicated plaster or pregabalin were enrolled in an 8-week combination phase. Patients with adequate response to monotherapy (recalled average pain intensity of 4 or less on 11-point numeric rating scale in the previous 3 days [NRS-3 score]) continued their previous therapy, whereas those with insufficient response received combination therapy. Efficacy endpoints included change in NRS-3 from combination phase baseline, Patient and Clinical Global Impression of Change (PGIC/CGIC), and patients satisfaction with treatment. Safety evaluation included adverse events (AEs), drug-related AEs (DRAEs), and withdrawal due to AEs. Clinical trial registration: EudraCT No. 2006-003132-29. Results: Of 229 patients in the per-protocol set (PPS: 68 PHN and 161 DPN), 71 received 5% lidocaine medicated plaster monotherapy, 57 had pregabalin added to 5% lidocaine medicated plaster, 57 pregabalin monotherapy and 44 received 5% lidocaine medicated plaster in addition to continued pregabalin treatment. There were no meaningful differences in demographic data between the treatment groups. Patients continuing on monotherapy demonstrated additional decreases in NRS-3 scores. Patients receiving combination therapy achieved clinically relevant reduction in NRS-3 values in addition to improvement achieved during the 4 weeks of monotherapy. Improvement was similar between the two combination therapy groups. Considerable improvements in patients’ treatment satisfaction were reported. Incidences of AEs were in line with previous reports for the two treatments and combination therapy was generally well tolerated. Conclusions: In patients with PHN and painful DPN failing to respond to monotherapy, combination therapy with 5% lidocaine medicated plaster and pregabalin provides additional clinically relevant pain relief and is safe and well-tolerated.

Somatosensory abnormalities in atypical odontalgia : A case-control study

Abstract Somatosensory function in patients with persistent idiopathic types of orofacial pain like atypical odontalgia (AO) is not well described. This study tested the hypothesis that AO patients have significantly more somatosensory abnormalities than age‐ and sex‐matched controls. Forty‐six AO patients and 35 controls participated. Inclusion criteria for AO were pain in a region where a tooth had been endodontically or surgically treated, persistent pain >6 months, and lack of clinical and radiological findings. The examination included qualitative tests and a battery of intraoral quantitative sensory testing (QST). Most AO patients (85%) had qualitative somatosensory abnormality compared with few controls (14%). The most common qualitative abnormalities in AO patients were found with pin‐prick 67.4%, cold 47.8%, and touch 46.5% compared with 11.4%, 8.6%, and 2.9%, respectively, in the control group (P < 0.001). Between‐group differences were seen for many intraoral QST: mechanical detection threshold, mechanical pain threshold (pinprick), dynamic mechanical allodynia (brush), dynamic mechanical allodynia (vibration), wind‐up ratio, and pressure pain threshold (P < 0.01). In the trigeminal area, between‐group differences in thermal thresholds were nonsignificant while differences in cold detection at the thenar eminence were significant. Individual somatosensory profiles revealed complex patterns with hyper‐ and hyposensitivity to intraoral QST. Between‐group differences in pressure pain thresholds (P < 0.02) were observed at the thenar eminence. In conclusion, significant abnormalities in intraoral somatosensory function were observed in AO, which may reflect peripheral and central sensitization of trigeminal pathways. More generalized sensitization of the nociceptive system may also be part of AO pathophysiology.

Efficacy and safety of 5% lidocaine (lignocaine) medicated plaster in comparison with pregabalin in patients with postherpetic neuralgia and diabetic polyneuropathy: interim analysis from an open-label, two-stage adaptive, randomized, controlled trial.

AbstractBackground and objective: Postherpetic neuralgia (PHN) and diabetic polyneuropathy (DPN) are two common causes of peripheral neuropathic pain. Typical localized symptoms can include burning sensations or intermittent shooting or stabbing pains with or without allodynia. Evidence-based treatment guidelines recommend the 5% lidocaine (lignocaine) medicated plaster or pregabalin as first-line therapy for relief of peripheral neuropathic pain. This study aimed to compare 5% lidocaine medicated plaster treatment with pregabalin in patients with PHN and patients with DPN. Methods: The study was a two-stage, adaptive, randomized, controlled, open-label, multicentre trial that incorporated a drug wash-out phase of up to 2 weeks prior to the start of the comparative phase. At the end of the enrolment phase, patients who fulfilled the eligibility criteria were randomized to either 5% lidocaine medicated plaster or pregabalin treatment and entered the 4-week comparative phase. The interim analysis represents the first stage of the two-stage adaptive trial design and was planned to include data from the comparative phase for the first 150 randomized patients of the 300 total planned for the trial. Patients aged ≥18 years with PHN or DPN were recruited from 53 investigational centres in 14 European countries. For this interim analysis, 55 patients with PHN and 91 with DPN (full-analysis set [FAS]), randomly assigned to the treatment groups, were available for analysis. Topical 5% lidocaine medicated plaster treatment was administered by patients to the area of most painful skin. A maximum of three or four plasters were applied for up to 12 hours within each 24-hour period in patients with PHN or DPN, respectively. Pregabalin capsules were administered orally, twice daily. The dose was titrated to effect: all patients received 150mg/day in the first week and 300 mg/day in the second week of treatment. After 1week at 300 mg/day, the dose of pregabalin was further increased to 600 mg/day in patients with high pain intensity scores. The pre-planned primary study endpoint was the rate of treatment responders, defined as completing patients experiencing a reduction from baseline of ≥2 points or an absolute value of ≥4 points on the 11-item numerical rating scale of recalled average pain intensity over the last 3 days (NRS-3), after 4 weeks of treatment. Secondary endpoints included ≥30% and ≥50% reductions in NRS-3 scores, changes in neuropathic pain symptom inventory (NPSI) scores and allodynia severity ratings. Results: Overall, 65.3% of patients treated with the 5% lidocaine medicated plaster and 62.0% receiving pregabalin responded to treatment with respect to the primary endpoint. A higher proportion of PHN patients responded to plaster treatment compared with pregabalin (63.0% vs 37.5%), whereas in the larger DPN group treatments were comparable. Both treatments improved NPSI scores and reduced allodynia severity. Patients administering lidocaine plaster experienced fewer drug-related adverse events (3.9% vs 39.2%) and there were substantially fewer discontinuations due to drug-related adverse events (1.3% vs 20.3%). Conclusion: After 4 weeks, 5% lidocaine medicated plaster treatment was associated with similar levels of analgesia in patients with PHN or DPN but substantially fewer frequent adverse events than pregabalin.

Effect of local anesthesia on atypical odontalgia--a randomized controlled trial.

Abstract The aim of the study was to evaluate the analgesic effect of lidocaine in a double‐blind, controlled multi‐center study on patients with atypical odontalgia (AO) – a possible orofacial neuropathic pain condition. Thirty‐five consecutive AO patients (range 31–81 years) with a mean pain duration of 7.2 years (range 1–30 years) were recruited from four different orofacial pain clinics in Sweden. In a randomized cross‐over design, 1.5 ml local anesthesia (20 mg/ml lidocaine and 12.5 μg/ml adrenaline) or 1.5 ml saline (9 mg/ml NaCl solution) (placebo) was injected to block the painful area. The VAS pain scores showed an overall effect of time (ANOVA: P < 0.001) and treatment (ANOVA: P = 0.018) with a significant interaction between the factors (ANOVA: P < 0.001). Overall, VAS pain relief was significantly greater at 15–120 min following the lidocaine injections compared to the placebo injections (Tukey: P < 0.05). All patients demonstrated significant disturbances in somatosensory function on the painful side compared to the non‐painful side as revealed by quantitative sensory tests, however, only one significant inverse correlation was found between percentage pain relief and the magnitude of brush‐evoked allodynia (Spearman: P < 0.01). In conclusion, AO patients experienced significant, but not complete, pain relief from administration of local anesthetics compared with placebo. The findings indicate that the spontaneous pain in AO patients only to some extent is dependent on peripheral afferent inputs and that sensitization of higher order neurons may be involved in the pathophysiology of AO.

Vascular risk factors in INPH: A prospective case-control study (the INPH-CRasH study)

Objective: To assess the complete vascular risk factor (VRF) profile of idiopathic normal pressure hydrocephalus (INPH) using a large sample of representative patients with INPH and population-based controls to determine the extent to which vascular disease influences INPH pathophysiology. Methods: All patients with INPH who underwent shunting in Sweden in 2008–2010 were compared to age- and sex-matched population-based controls. Inclusion criteria were age 60–85 years and no dementia. The 10 most important VRFs and cerebrovascular and peripheral vascular disease were prospectively assessed using blood samples, clinical examinations, and standardized questionnaires. Assessed VRFs were hypertension, hyperlipidemia, diabetes, obesity, psychosocial factors, smoking habits, diet, alcohol intake, cardiac disease, and physical activity. Results: In total, 176 patients with INPH and 368 controls participated. Multivariable logistic regression analysis indicated that hyperlipidemia (odds ratio [OR] 2.380; 95% confidence interval [CI] 1.434–3.950), diabetes (OR 2.169; 95% CI 1.195–3.938), obesity (OR 5.428; 95% CI 2.502–11.772), and psychosocial factors (OR 5.343; 95% CI 3.219–8.868) were independently associated with INPH. Hypertension, physical inactivity, and cerebrovascular and peripheral vascular disease were also overrepresented in INPH. Moderate alcohol intake and physical activity were overrepresented among the controls. The population-attributable risk percentage was 24%. Conclusions: Our findings confirm that patients with INPH have more VRFs and lack the protective factors present in the general population. Almost 25% of cases of INPH may be explained by VRFs. This suggests that INPH may be a subtype of vascular dementia. Targeted interventions against modifiable VRFs are likely to have beneficial effects on INPH.

Incidence and outcome of surgery for adult hydrocephalus patients in Sweden

Abstract Object: To present population-based and age related incidence of surgery and clinical outcome for adult patients operated for hydrocephalus, registered in the Swedish Hydrocephalus Quality Registry (SHQR). Methods: All patients registered in SHQR during 2004–2011 were included. Data on age, gender, type of hydrocephalus and type of surgery were extracted as well as three months outcome for patients with idiopathic normal pressure hydrocephalus (iNPH). Results: The material consisted of 2360 patients, 1229 men and 1131 women, age 63.8 ± 14.4 years (mean ± standard deviation (SD)). The mean total incidence of surgery was 5.1 ± 0.9 surgeries/100,000/year; 4.7 ± 0.9 shunt surgeries and 0.4 ± 0.1 endoscopic third ventriculostomies. For iNPH, secondary communicating hydrocephalus and obstructive hydrocephalus, the incidence of surgery was 2.2 ± 0.8, 1.9 ± 0.3 and 0.8 ± 0.1/100,000/year, respectively. During 2004–2011, the incidence of surgery increased in total (p = .044), especially in age groups 70–79 years and ≥80 years (p = .012 and p = .031). After surgery, 253 of 652 iNPH patients (38.8%) improved at least one step on the modified Rankin scale (mRS). Number needed to treat was 3.0 for improving one patient from unfavourable (mRS 3–5) to favourable (mRS 0–2). The mean score of a modified iNPH scale increased from 54 ± 23 preoperatively to 63 ± 25 postoperatively (p < .0001, n = 704), and 58% improved. No significant regional differences in incidence, surgical techniques or outcome were found. Conclusions: Incidence of hydrocephalus surgery increased significantly during 2004–2011, specifically in elderly patients. Surgical treatment of iNPH markedly improved functional independence, but the improvement rate was low compared to recent single- and multicentre studies. Thus, the potential for surgical improvement is likely lower than generally reported when treating patients as part of everyday clinical care.

Postural function in idiopathic normal pressure hydrocephalus before and after shunt surgery: A controlled study using computerized dynamic posturography (EquiTest)

INTRODUCTION Postural dysfunction is one of the major features of idiopathic normal pressure hydrocephalus (iNPH). With computerized dynamic posturography (CDP) balance can be assessed objectively. The primary aim of this study was to describe the postural function in iNPH patients pre- and post-operatively in comparison with healthy individuals (HI) using CDP. SUBJECTS AND METHODS Thirty-five patients (16 M, 19 F) with a mean age of 73 (range 49-81) with iNPH, and sixteen HI (7 M, 9 F) aged 73 (62-89) were included. iNPH patients were operated on with a ventriculo-peritoneal shunt. Patients and HI were tested regarding motor function, balance and cognition. CDP, EquiTest (NeuroCom International, Clackamas, OR), was performed before and three months after shunt surgery and twice in HI, with a three-month interval. RESULTS Pre-operatively, the 35 patients had poorer balance measured with the Sensory Organizing Test (SOT) score in every condition (p=0.01 in SOT 1 and p<0.001 in SOT 2-6) compared to the HI. The greatest difference was in test conditions measuring mainly vestibular function, where loss of balance (LOB) was frequent. Twenty patients were evaluated three months after shunt surgery and 18/20 (90%) of them were considered shunt responders, with a mean improvement of motor score of 26% (range 5-67%). There was an improvement post-operatively in the weighted composite SOT score (p<0.05) but no significant change in any of the SOT conditions. LOB was not significantly reduced in any of the test conditions. CONCLUSION CDP showed that the patients had a poorer balance than the HI. The greatest difference was in SOT 5-6, indicating that the postural disturbance is of primarily central vestibular origin. There was a slight improvement of balance post-operatively.

Reduced thalamic N-acetylaspartate in idiopathic normal pressure hydrocephalus: a controlled 1H-magnetic resonance spectroscopy study of frontal deep white matter and the thalamus using absolute quantification

Introduction Patients with idiopathic normal pressure hydrocephalus (INPH) frequently have a reduction in cerebral blood flow in the subcortical frontal lobe/basal ganglia/thalamic areas. With magnetic resonance spectroscopy, the metabolism in the brain can be examined. The aim of this study was to investigate if there was a compromised metabolism in the thalamus and in the subcortical frontal areas in INPH patients. This was done by measuring total creatine, myo-inositol, total choline, N-acetylaspartate (NAA), total N-acetylaspartate (tNA), glutamate and lactate levels. A comparison was made with healthy individuals (HI). Subjects and methods 16 patients (nine males, seven females, mean age 74 years, range 49–83) diagnosed as INPH and 15 HI (nine males, six females, mean age 74 years, range 62–89) were examined. 1H magnetic resonance spectroscopy (1.5 T, point-resolved spectroscopy, echo time/relaxation time 30/3000 ms, volume of interest 2.5–3 ml) was performed in frontal deep white matter and in the thalamus. Absolute quantification with internal water as a reference was used. Results INPH patients had lower NAA (p=0.02) and lower tNA (p=0.05) concentrations in the thalamus compared with HI. NAA and tNA in the frontal deep white matter did not differ between patients and HI. The absolute metabolic concentrations of total creatine, myo-inositol total choline, tNA, lactate and Cr ratios in frontal deep white matter and in the thalamus were similar in INPH patients and HI. Conclusion Reduced thalamic NAA and tNA in INPH patients suggest a compromised metabolic neuronal function in these regions. Thus, the thalamus might have an important role in the pathogenesis of INPH.

Preoperative and postoperative 1H-MR spectroscopy changes in frontal deep white matter and the thalamus in idiopathic normal pressure hydrocephalus

Background In a previous study we found significantly decreased N-acetyl aspartate (NAA) and total N-acetyl (tNA) groups in the thalamus of patients with idiopathic normal pressure hydrocephalus (iNPH) compared with healthy individuals (HI). No significant difference between the groups could be found in the frontal deep white matter (FDWM). Objective The primary aim of this study was to investigate if these metabolites in the thalamus were normalised after shunt surgery. The secondary aim was to investigate postoperative metabolic changes in FDWM. Subjects and methods Fourteen patients with iNPH, mean age 74 years, and 15 HI, also mean age 74 years, were examined. Assessment of a motor score (MOSs) was performed before and after shunt surgery. Absolute quantitative 1H-MR spectroscopy (1.5 T, volumes of interest 2.5–3 ml) was performed on the patients in the FDWM and in the thalamus, before and 3 months after shunt surgery, and also once on the HI. The following metabolites were analysed: tNA, NAA, total creatine, total choline (tCho), myo-inositol (mIns), glutamate and lactate concentrations. MRI volumetric calculations of the lateral ventricles were also performed. Results At 3 months postoperatively, we found no significant changes of tNA or NAA in the thalamus. In contrast, in the FDWM, there was a significant increase of tCho (p=0.01) and a borderline significant decrease of mIns (p=0.06). 12/14 patients were shunt responders (motor function). Median reduction of the lateral ventricle was 16%. A weak correlation between MOS and ventricular reduction was seen. Conclusions Normalisation of thalamic tNA and NAA could not be detected postoperatively. The increased tCho and decreased mIns in the FDWM postoperatively might relate to clinical improvement.