Comparing Regimens for Diabetic Peripheral Neuropathic Pain
Comparing Regimens for Diabetic Peripheral Neuropathic Pain
The previously published study reporting the non-inferiority of duloxetine vs. pregabalin and the combination of duloxetine plus gabapentin in patients with DPNP represents the first known head-to-head comparison of the safety and tolerability of duloxetine and pregabalin, and the first formal investigation into the use of duloxetine plus gabapentin. By design, patients presented with residual pain after having been treated with gabapentin, a treatment option that it is frequently considered first line despite not having marketing approval by the FDA for management of DPNP. With a duloxetine plus gabapentin treatment option and relaxed concomitant medication use, the trial's design attempted to mimic real life prescribing for a condition where polypharmacy is common.
The tolerability findings presented here should be assessed within the context that all patients had previously received and tolerated gabapentin, and this prior exposure could have resulted in improved tolerability findings for patients taking pregabalin as well as modified findings for patients taking duloxetine or duloxetine plus gabapentin.
Although the TEAE profile for each treatment varied, each profile was consistent with previous reports for each of the medications when administered to patients with DPNP. Nausea was more prevalent in patients treated with duloxetine and duloxetine plus gabapentin compared with those treated with pregabalin; this finding is consistent with the known adverse event profile for duloxetine in patients with DPNP. In a recent pooled analysis of placebo-controlled studies of duloxetine as treatment for various painful conditions including DPNP, the most common TEAE for all indications was nausea.
Treatment-emergent insomnia was more common in the duloxetine group than in either the duloxetine plus gabapentin or pregabalin groups; insomnia has occurred in 10% of duloxetine patients in the placebo-controlled trials across approved indications in the US. The relatively lower rates of insomnia in patients treated with pregabalin and duloxetine plus gabapentin could be associated with the sedative effects of pregabalin and gabapentin. Some practitioners postulate that the main reason why these medications work well for patients with pain, especially when taken at night, is that they improve sleep. The results of clinical trials evaluating patients with DPNP treated with pregabalin and gabapentin have demonstrated beneficial effects on sleep as well as on pain. Patients with various chronic pain conditions, including DPNP, have generally shown improvement in sleep when treated with duloxetine as monotherapy. This may be related to the analgesic effect of duloxetine, allowing the patient to sleep better at night. No between-group differences occurred at end-point in the present study on the LSEQ subscales measuring quality of sleep and ability to go to sleep. The relationship between pain and sleep is complex, and studies often rely on self-reported measures of sleep quality. Discrepancies have been noted between self-reported sleep duration or quality vs. data collected via formal sleep studies; in some cases, patients claim they never slept at all yet objective results suggest otherwise.
There were more reports of oedema in patients taking pregabalin than in either of the other two treatments. Peripheral oedema is a commonly reported adverse event associated with pregabalin and gabapentin, and it has been suggested that the lowest effective dose be administered to allow for pain relief while minimising side effects, especially in older patients with neuropathic pain.
Treatment with duloxetine was associated with weight loss while treatment with pregabalin was associated with weight gain, and this between-group difference was statistically significant. The weight gain observed with pregabalin is consistent with that seen in previous studies. Given current concerns about drug-induced weight gain in patients with type 2 diabetes, this advantage of duloxetine may be clinically relevant. The average weight loss observed among patients with DPNP taking duloxetine in this study (2.39 kg) is greater than that seen in a pooled analysis of studies of duloxetine for patients with various painful conditions, where among 869 DPNP patients treated with duloxetine, mean weight loss was 0.91 kg after 3 months of placebo-controlled treatment (p = 0.001 compared with placebo-treated patients, who reported a slight weight increase in 0.05 kg). Further, considering weight change over 28–34 weeks from open-label studies of duloxetine in the treatment of DPNP, the mean weight loss over this longer-term treatment was shown to be 0.33 kg, with a standard deviation of 0.28, suggesting a distribution of weight change that can include weight gain for some DPNP patients treated with duloxetine in the longer term. Results of a pooled analysis of data from three studies of duloxetine in patients with DPNP, each of which included a 52-week routine-care-controlled extension phase, showed that patients taking duloxetine had a weight increase in the extension phase of 0.30 kg, less than was observed in patients receiving routine care (0.51 kg) (p = 0.56).
On vital signs, patients in the duloxetine group reported a mean increase in DBP at end-point compared with patients in the duloxetine plus gabapentin group, who had a slight decrease; the difference was statistically significant. However, the mean increase in the duloxetine group (2.2 mmHg) was higher than that observed in other duloxetine clinical trials (average 0.5 mmHg). There were no statistically significant between-group differences in the occurrence of treatment-emergent vital sign abnormalities at study end-point.
There were no clinically relevant findings in laboratory evaluations or between-group differences. Although a higher fasting serum glucose elevation was shown in patients receiving duloxetine plus gabapentin compared with pregabalin, the increase was slight; and most patients had a baseline HbA1c value > 6%, suggesting that there may be minimal clinical significance to this finding. An abnormally high HbA1c value at end-point (≥ 6% if < 6% at baseline) was reported by 11% of patients in the duloxetine treatment group and by 35% of patients in each of the other two groups; while the differences were not statistically significant, the number of patients was small and the study was not powered for these comparisons.
Neurotoxicities can develop in patients with DPNP, worsening their pain. In this study, changes in patients' reports of neurotoxicity did not differ among the treatment groups; changes in the cognitive and somatomotor subscales of the PNS showed decreases (i.e. lessening of complaints) in all three groups. It should be noted that initial scores on the PNS indicated that patients, on average, were not reporting neurotoxicity at baseline. While no other clinical trials using the PNS in patients with DPNP could be located, the findings of this study are consistent with clinical observations.
In this study, females taking duloxetine reported increased sexual pleasure compared with those taking duloxetine plus gabapentin, and females taking pregabalin reported increased frequency of orgasm compared with females receiving duloxetine plus gabapentin; those taking duloxetine plus gabapentin reported a decrease in both pleasure and orgasm frequency. This finding was interesting given the importance of sexual functioning on quality of life, and may be a factor to consider when discussing medication choices with patients, but this area requires more research. In the literature, there appear to be a few clinical case reports of sexual dysfunction in patients taking gabapentin for various conditions. No clinical trials evaluating the impact of gabapentin or pregabalin on sexual pleasure or orgasm could be found. This is the first known study to examine changes in sexual pleasure and orgasm in patients with DPNP treated with duloxetine. It should be noted that average sexual dysfunction at baseline was relatively high; this could be attributable to a combination of factors, e.g. these were older patients with diabetes who were also slightly overweight. Moreover, some of the patients were on antidepressants, which can interfere with sexual function.
Study limitations included the following: this was an open-label study, and the lack of blinding may have introduced bias by both the patients and the investigators because of knowledge of their random assignment to drug. Without a gabapentin monotherapy control group, conclusions drawn from the differences observed between the duloxetine and duloxetine plus gabapentin treatment groups must be viewed with caution. The minimum gabapentin dose allowed for inclusion in the study (900 mg/day) was less than the recommended daily dose (1800 mg/day). Prior exposure to gabapentin may have affected the results by possibly improving tolerability for pregabalin or for the combination of duloxetine plus gabapentin, thus limiting the generalizability of the findings. No dose changes of pregabalin or duloxetine were allowed, and given the importance of the dose relationship with pain relief in patients with DPNP, it is not clear how a flexible dose approach would have changed the results of this study.
It should be noted that the adverse event profile for the combination treatment was similar to that of duloxetine monotherapy, with the exception of more insomnia in patients receiving duloxetine alone than those receiving duloxetine plus gabapentin. Also, the adverse event profile observed in patients receiving duloxetine plus gabapentin was not different from that previously reported for gabapentin monotherapy.
Discussion
The previously published study reporting the non-inferiority of duloxetine vs. pregabalin and the combination of duloxetine plus gabapentin in patients with DPNP represents the first known head-to-head comparison of the safety and tolerability of duloxetine and pregabalin, and the first formal investigation into the use of duloxetine plus gabapentin. By design, patients presented with residual pain after having been treated with gabapentin, a treatment option that it is frequently considered first line despite not having marketing approval by the FDA for management of DPNP. With a duloxetine plus gabapentin treatment option and relaxed concomitant medication use, the trial's design attempted to mimic real life prescribing for a condition where polypharmacy is common.
The tolerability findings presented here should be assessed within the context that all patients had previously received and tolerated gabapentin, and this prior exposure could have resulted in improved tolerability findings for patients taking pregabalin as well as modified findings for patients taking duloxetine or duloxetine plus gabapentin.
Although the TEAE profile for each treatment varied, each profile was consistent with previous reports for each of the medications when administered to patients with DPNP. Nausea was more prevalent in patients treated with duloxetine and duloxetine plus gabapentin compared with those treated with pregabalin; this finding is consistent with the known adverse event profile for duloxetine in patients with DPNP. In a recent pooled analysis of placebo-controlled studies of duloxetine as treatment for various painful conditions including DPNP, the most common TEAE for all indications was nausea.
Treatment-emergent insomnia was more common in the duloxetine group than in either the duloxetine plus gabapentin or pregabalin groups; insomnia has occurred in 10% of duloxetine patients in the placebo-controlled trials across approved indications in the US. The relatively lower rates of insomnia in patients treated with pregabalin and duloxetine plus gabapentin could be associated with the sedative effects of pregabalin and gabapentin. Some practitioners postulate that the main reason why these medications work well for patients with pain, especially when taken at night, is that they improve sleep. The results of clinical trials evaluating patients with DPNP treated with pregabalin and gabapentin have demonstrated beneficial effects on sleep as well as on pain. Patients with various chronic pain conditions, including DPNP, have generally shown improvement in sleep when treated with duloxetine as monotherapy. This may be related to the analgesic effect of duloxetine, allowing the patient to sleep better at night. No between-group differences occurred at end-point in the present study on the LSEQ subscales measuring quality of sleep and ability to go to sleep. The relationship between pain and sleep is complex, and studies often rely on self-reported measures of sleep quality. Discrepancies have been noted between self-reported sleep duration or quality vs. data collected via formal sleep studies; in some cases, patients claim they never slept at all yet objective results suggest otherwise.
There were more reports of oedema in patients taking pregabalin than in either of the other two treatments. Peripheral oedema is a commonly reported adverse event associated with pregabalin and gabapentin, and it has been suggested that the lowest effective dose be administered to allow for pain relief while minimising side effects, especially in older patients with neuropathic pain.
Treatment with duloxetine was associated with weight loss while treatment with pregabalin was associated with weight gain, and this between-group difference was statistically significant. The weight gain observed with pregabalin is consistent with that seen in previous studies. Given current concerns about drug-induced weight gain in patients with type 2 diabetes, this advantage of duloxetine may be clinically relevant. The average weight loss observed among patients with DPNP taking duloxetine in this study (2.39 kg) is greater than that seen in a pooled analysis of studies of duloxetine for patients with various painful conditions, where among 869 DPNP patients treated with duloxetine, mean weight loss was 0.91 kg after 3 months of placebo-controlled treatment (p = 0.001 compared with placebo-treated patients, who reported a slight weight increase in 0.05 kg). Further, considering weight change over 28–34 weeks from open-label studies of duloxetine in the treatment of DPNP, the mean weight loss over this longer-term treatment was shown to be 0.33 kg, with a standard deviation of 0.28, suggesting a distribution of weight change that can include weight gain for some DPNP patients treated with duloxetine in the longer term. Results of a pooled analysis of data from three studies of duloxetine in patients with DPNP, each of which included a 52-week routine-care-controlled extension phase, showed that patients taking duloxetine had a weight increase in the extension phase of 0.30 kg, less than was observed in patients receiving routine care (0.51 kg) (p = 0.56).
On vital signs, patients in the duloxetine group reported a mean increase in DBP at end-point compared with patients in the duloxetine plus gabapentin group, who had a slight decrease; the difference was statistically significant. However, the mean increase in the duloxetine group (2.2 mmHg) was higher than that observed in other duloxetine clinical trials (average 0.5 mmHg). There were no statistically significant between-group differences in the occurrence of treatment-emergent vital sign abnormalities at study end-point.
There were no clinically relevant findings in laboratory evaluations or between-group differences. Although a higher fasting serum glucose elevation was shown in patients receiving duloxetine plus gabapentin compared with pregabalin, the increase was slight; and most patients had a baseline HbA1c value > 6%, suggesting that there may be minimal clinical significance to this finding. An abnormally high HbA1c value at end-point (≥ 6% if < 6% at baseline) was reported by 11% of patients in the duloxetine treatment group and by 35% of patients in each of the other two groups; while the differences were not statistically significant, the number of patients was small and the study was not powered for these comparisons.
Neurotoxicities can develop in patients with DPNP, worsening their pain. In this study, changes in patients' reports of neurotoxicity did not differ among the treatment groups; changes in the cognitive and somatomotor subscales of the PNS showed decreases (i.e. lessening of complaints) in all three groups. It should be noted that initial scores on the PNS indicated that patients, on average, were not reporting neurotoxicity at baseline. While no other clinical trials using the PNS in patients with DPNP could be located, the findings of this study are consistent with clinical observations.
In this study, females taking duloxetine reported increased sexual pleasure compared with those taking duloxetine plus gabapentin, and females taking pregabalin reported increased frequency of orgasm compared with females receiving duloxetine plus gabapentin; those taking duloxetine plus gabapentin reported a decrease in both pleasure and orgasm frequency. This finding was interesting given the importance of sexual functioning on quality of life, and may be a factor to consider when discussing medication choices with patients, but this area requires more research. In the literature, there appear to be a few clinical case reports of sexual dysfunction in patients taking gabapentin for various conditions. No clinical trials evaluating the impact of gabapentin or pregabalin on sexual pleasure or orgasm could be found. This is the first known study to examine changes in sexual pleasure and orgasm in patients with DPNP treated with duloxetine. It should be noted that average sexual dysfunction at baseline was relatively high; this could be attributable to a combination of factors, e.g. these were older patients with diabetes who were also slightly overweight. Moreover, some of the patients were on antidepressants, which can interfere with sexual function.
Study limitations included the following: this was an open-label study, and the lack of blinding may have introduced bias by both the patients and the investigators because of knowledge of their random assignment to drug. Without a gabapentin monotherapy control group, conclusions drawn from the differences observed between the duloxetine and duloxetine plus gabapentin treatment groups must be viewed with caution. The minimum gabapentin dose allowed for inclusion in the study (900 mg/day) was less than the recommended daily dose (1800 mg/day). Prior exposure to gabapentin may have affected the results by possibly improving tolerability for pregabalin or for the combination of duloxetine plus gabapentin, thus limiting the generalizability of the findings. No dose changes of pregabalin or duloxetine were allowed, and given the importance of the dose relationship with pain relief in patients with DPNP, it is not clear how a flexible dose approach would have changed the results of this study.
It should be noted that the adverse event profile for the combination treatment was similar to that of duloxetine monotherapy, with the exception of more insomnia in patients receiving duloxetine alone than those receiving duloxetine plus gabapentin. Also, the adverse event profile observed in patients receiving duloxetine plus gabapentin was not different from that previously reported for gabapentin monotherapy.
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