Jakob Vormstrup Holbech

The anticonvulsant levetiracetam for the treatment of pain in polyneuropathy: A randomized, placebo-controlled, cross-over trial

Levetiracetam is an anticonvulsant which is assumed to act by modulating neurotransmitter release via binding to the vesicle protein SV2A. This could have an impact on signaling in the nociceptive system, and a pilot study indicated relief of neuropathic pain with levetiracetam.UNLABELLED Levetiracetam is an anticonvulsant which is assumed to act by modulating neurotransmitter release via binding to the vesicle protein SV2A. This could have an impact on signaling in the nociceptive system, and a pilot study indicated relief of neuropathic pain with levetiracetam. OBJECTIVES The aim of this study was to test the analgesic effect of levetiracetam in painful polyneuropathy. METHODS This was a randomized, double-blind, placebo-controlled, cross-over trial with levetiracetam 3000 mg/day versus placebo (6-week treatment periods). Patients with diagnosed polyneuropathy and symptoms for more than 6 months, age between 20 and 80 years, pain intensity of more than 4 on a 0-10-point numeric rating scale, and pain at least 4 days a week were included in the study. The primary outcome measure was pain relief at the end of each treatment period as measured on a 6-point verbal scale. RESULTS Ninety-three patients were screened for participation and 39 patients entered the study. Thirty-five patients were included in the data analysis. There were no differences in the ratings of pain relief (levetiracetam 2.29 versus placebo 2.28, p=0.979), total pain intensity (levetiracetam 5.5 versus placebo 5.3, p=0.293) or any of the other outcome measures (p=0.147-1.00). CONCLUSION This study indicates that the anticonvulsant levetiracetam has no clinically relevant effect on painful polyneuropathy.

A randomized, placebo-controlled trial of levetiracetam in central pain in multiple sclerosis

Levetiracetam is an anticonvulsant which is assumed to act by modulating neurotransmitter release via binding to the vesicle protein SV2A. This could have an impact on signalling in the pain pathway. The aim of this study was to test the analgesic effect of levetiracetam in central pain in multiple sclerosis. This was a randomized, double‐blind, placebo‐controlled, cross‐over trial with levetiracetam 3000 mg/day versus placebo (6‐week treatment periods). Patients with multiple sclerosis, symptoms and signs complying with central neuropathic pain and pain symptoms for more than 6 months, as well as pain intensity of more than 4 on a 0 to 10‐point numeric rating scale were included in the study. The primary outcome measure was pain relief at the end of each treatment period as measured on a 6‐point verbal scale. Eighty‐nine patients were screened for participation and 30 patients entered the study. Twenty‐seven patients were included in the data analysis. There were no differences in the ratings of pain relief (levetiracetam 2.4 vs. placebo 2.1, p = 0.169), total pain intensity (levetiracetam 5.3 vs. placebo 5.7, p = 0.147) or any of the other outcome measures (p = 0.086–0.715) in the total sample of patients. However, there was significant reduction of pain, increased pain relief and/or more favourable pain relief with levetiracetam than with placebo in patients with lancinating or without touch‐evoked pain (p = 0.025–0.046). This study found no effect of the anticonvulsant levetiracetam in non‐selected patients with central pain in multiple sclerosis, but an effect in subgroups with specific pain symptoms was indicated.

Pain phenotype as a predictor for drug response in painful polyneuropathy: A retrospective analysis of data from controlled clinical trials

Abstract The drugs available for treatment of neuropathic pain have somewhat disappointing efficacy with many patients left with limited or no effect. Individualized treatment based on phenotype according to presumed underlying pain mechanism(s) has been proposed to improve outcomes. We report a retrospective analysis of phenotype-specific effects of several neuropathic pain drugs, which were studied in a series of crossover, placebo-controlled, clinical trials. The data originate from 7 trials with similar design and outcome recordings, which all had a thorough baseline registration of symptoms, signs, and quantitative sensory testing. The latter was used to phenotype patients into subgroups reflecting presumed pain mechanisms. There were a total of 361 patient records distributed over treatments with 4 antidepressants and 4 anticonvulsants. Five of the drugs reduced total pain significantly compared with placebo. Only a few phenotype-specific differences in total pain reduction were found within the investigated drugs. Thus, imipramine reduced total pain 1.84 (CI: 0.02-3.67) and pregabalin 0.81 (CI: −0.67 to 2.29) in patients with than without gain of sensory function. Pregabalin showed a better effect in patients with preserved large fiber function with a mean difference in total pain reduction 1.31 (CI: 0.15-2.47). No phenotype-specific effects were found for venlafaxine, escitalopram, oxcarbazepine, valproic acid, levetiracetam, or St. Johns wort. Thus, this post hoc analysis of 8 drugs with mainly nonselective actions on neuropathic pain mechanisms found limited usefulness of sensory phenotyping in pain as the basis for individualized treatment.

Imipramine and Pregabalin Combination for Painful Polyneuropathy. A Randomized Controlled Trial

Abstract Monotherapy with first-line drugs for neuropathic pain often fails to provide sufficient pain relief or has unacceptable side effects because of the need for high doses. The aim of this trial was to test whether the combination of imipramine and pregabalin in moderate doses would relieve pain more effectively than monotherapy with either of the drugs. This was a randomized, double-blind, placebo-controlled, crossover, multicenter trial consisting of four 5-week treatment periods in patients with painful polyneuropathy. Treatment arms were imipramine 75 mg/d vs pregabalin 300 mg/d vs combination therapy vs placebo. Patients with polyneuropathy and symptoms for more than 6 months, age 20 to 85 years, pain intensity ≥4 on a 0- to 10-point numeric rating scale (NRS) and pain at least 4 days a week were included in the trial. A total of 262 patients were screened for participation, 73 patients were randomized, and 69 patients were included in the data analysis. The effect on average pain in comparison with placebo was: combination (−1.67 NRS points, P < 0.001), imipramine (−1.08 NRS points, P < 0.001), and pregabalin (−0.48 NRS points, P = 0.03). The combination therapy had significantly lower pain scores than both monotherapies: combination vs imipramine (P = 0.009), combination vs pregabalin (P < 0.001). During combination therapy, the dropout rate was higher and the patients reported a higher rate and severity of side effects. Combination of moderate doses of the tricyclic antidepressant imipramine and pregabalin could be considered as an alternative to high-dosage monotherapy. However, the trial also emphasized that balance between efficacy and safety is an issue.

Combination treatment of neuropathic pain: Danish expert recommendations based on a Delphi process

Background Current Danish treatment algorithms for pharmacological treatment of neuropathic pain (NeP) are tricyclic antidepressants (TCA), gabapentin and pregabalin as first-line treatment for the most common NeP conditions. Many patients have insufficient pain relief on monotherapy, but combination therapy had not been included in guidelines until recently. Based on clinical empiricism and scientific evidence, a Delphi consensus process provided a consolidated guidance on pharmacological combination treatment of NeP. Methods A two-round virtual internet-based Delphi process with 6 Danish pain specialists was undertaken. In the first round, questions were answered individually and anonymously, whereas in the second round, the panel openly discussed first round’s summary of outcomes. Combinations of pharmacological pain treatments, that is, pregabalin/gabapentin, TCAs, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors, opioids, other antiepileptics and cutaneous patches, were assessed based on both scientific and clinical practice experiences. The Centers for Disease Control and Prevention (CDC) grading system was used for evidence rating. Results Combination of pregabalin/gabapentin with TCA is useful in patients who do not gain sufficient pain relief or tolerate either drug in high doses, or to improve sleep disturbance. Also, combination of pregabalin/gabapentin and SNRIs is reasonably well documented and experienced by some experts to result in sufficient pain relief and fewer side effects than monotherapy. Good evidence on efficacy was found for the combination of pregabalin/gabapentin or TCAs and opioids, which was also frequently used in clinical practice. The evidence for combining TCAs and SNRIs is insufficient, although sometimes used in clinical practice despite the risk of serotonin syndrome. For localized NeP, combination therapy with cutaneous patches should be considered. There was insufficient scientific evidence for any pharmacologic combination therapies with selective serotonin reuptake inhibitors – as well as for other potential combinations. Conclusions The study revealed that combination therapy is widely used in clinical practice and supported by some scientific evidence. However, further studies are needed.

The Impact of Serum Drug Concentration on the Efficacy of Imipramine, Pregabalin and their Combination in Painful Polyneuropathy

Objective: The aim of this study was to explore the serum concentration-effect relation for first-line drugs in neuropathic pain and to determine if efficacy could be increased. Methods: Data from a randomized, placebo-controlled, cross-over trial on imipramine, pregabalin, and their combination in painful polyneuropathy were used. Treatment periods were of 4 weeks’ duration, outcome was the weekly median of daily pain rated by a 0 to 10 numeric scale, and drug concentrations were determined by high-performance liquid chromatography. Results: In 47 patients, pain was reduced −1.0 (95% confidence interval [CI], −1.5 to −0.6) by imipramine, −0.4 (95% CI, −0.9 to 0.1) by pregabalin, and −1.6 (95% CI, −2.1 to −1.1) by combination therapy. On monotherapy, there was no difference between responders and nonresponders with respect to concentrations of imipramine (mean, 161 vs. 229 nmol/L, P=0.129) and pregabalin (mean, 9.8 vs. 11.7 &mgr;mol/L, P=0.178). There was no correlation between drug concentration and pain reduction for imipramine (r=0.17, P=0.247), whereas there was a marginally, positive correlation for pregabalin (r=0.28, P=0.057). There was no interaction between treatment and concentration classes (imipramine < or ≥100 nmol/L, pregabalin < or ≥10 &mgr;mol/L) either for monotherapy or for combination therapy (P=0.161 to 0.797). Isobolographic presentations of reponders with imipramine and pregabalin concentrations during combination therapy did not indicate synergistic interaction. Discussion: There were no important relations between drug concentrations and efficacy, or indication of synergistic interaction between the drugs. It was not concluded that treatment can be improved by measurement of drug concentration of pregabalin.

Impact of etiology and duration of pain on pharmacological treatment effects in painful polyneuropathy

The pharmacological treatments for painful polyneuropathy have not changed much for more than a decade, and less than half of the patients obtain adequate pain relief with first line treatments. Therefore, patient‐specific factors which could predict drug response are searched for.