The International Association for the Study of Pain describes neuropathic pain as pain resulting from injury or disease of the somatosensory system. Neuropathic pain is a chronic and distressing syndrome that is estimated to affect 7-10% of the general population.
Painful diabetic peripheral neuropathy (pDPN) is one of the most common causes of neuropathic pain with an estimated prevalence of 0.8% in the general population and up to 26% among diabetic patients.
Considering that 29 million people in the US have diabetes, the burden of pDPN is high. Furthermore, prevalence rates are likely even higher than currently reported due to the absence of a standardized approach to identifying neuropathic pain in epidemiological research.
Pregabalin is approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of neuropathic pain due to DPN. Pregabalin binds to the α2-δ subunit of the calcium channel, decreasing calcium entry into nerve terminals and attenuating the release of neurotransmitters that affect pain pathways.
Several randomized controlled trials (RCTs) have shown that pregabalin is highly effective for the treatment of chronic pain in patients with pDPN. Furthermore, a pooled analysis of seven RCTs showed that pregabalin treatment is associated with a rapid and significant dose-related onset of sustained pain relief and a reduction in pain-related sleep interference in patients with pDPN.
| Aim |
To compare the therapeutic response to pregabalin in patients with moderate or severe painful diabetic peripheral neuropathy (pDPN).
| Research design and methods |
We pooled data from 11 placebo-controlled trials to evaluate the efficacy of fixed- or flexible-dose pregabalin (150, 300, or 600 mg/day) in pDPN patients with mean baseline pain scores of ≥4 to <7 (moderate). ) or ≥7 to ≤10 (severe). Last observation carried forward imputation was used.
| Main outcome measures |
Pregabalin-mediated change in pain, pain-related sleep interference (PRSI), and patient global impression of change (PGIC) were compared versus placebo and between moderate and severe pain cohorts. Adverse events (AEs) were reported.
| Results |
At baseline, 1816 patients had moderate pain (pregabalin, n = 1189) and 1119 patients had severe pain (pregabalin, n = 720).
Pregabalin significantly reduced pain scores at the end of the study compared to placebo when patients of all pain levels were combined (all doses; p < 0.05).
In the moderate and severe pain cohorts, treatment with pregabalin (300, 600 mg/day, or flexible) significantly reduced mean pain scores at the end of the study compared to placebo (p < 0.01).
Pain reduction was greater in patients with severe baseline pain compared to moderate baseline pain (pregabalin 300, 600 mg/day, or flexible; p < 0.0001).
Pregabalin improved PRSI and PGIC in the moderate and severe cohorts compared to placebo. The greatest improvement in PRSI also occurred in the severe cohort.
Treatment-emergent adverse effects (AEs), most commonly dizziness, somnolence, and peripheral edema, occurred more frequently in patients treated with pregabalin compared to placebo.
| Discussion |
In the current post hoc analyses, we compared the therapeutic response to pregabalin in patients with moderate or severe pDPN. Pregabalin (300 mg/day, 600 mg/day and flexible dosing) Additionally, these data emphasize the importance of dose selection for a patient with severe pain at baseline.
Pain relief may contribute to improving pain-related sleep interference (PRSI) due to the relationship between pain and sleep: sleep disturbance is often a consequence of pain impairment and can itself increase pain experience.
Painful conditions, including pDPN, can be best managed by focusing on both aspects of the relationship. Although not indicated for the treatment of pain-related sleep disturbance, pregabalin has been shown to improve patient-reported assessments of sleep quality in pDPN, with improvements evident after 1 week of treatment .
Although the mechanism of action is not completely elucidated, the responses seen with pregabalin in patients with painful diabetic peripheral neuropathy (pDPN) are likely to result from α2-δ binding in a region of the nervous system that regulates both pain and sleep. .
Preclinical nerve injury studies have linked pregabalin to a reduction in presynaptic release of gamma-aminobutyric acid (GABA) in the locus coeruleus, the main noradrenergic nucleus of the brain, leading to activation of the descending noradrenergic inhibitory system.
Noradrenergic neurons projecting from the locus coeruleus also participate in the maintenance of slow wave sleep. It is suggested that nerve injury leads to deregulation of the activities of noradrenergic neurons by GABAergic interneurons and may be responsible for sleep disturbance. This may explain how the use of pregabalin to restore noradrenergic signaling can improve both pain and PRSI in patients with pDPN.
In contrast to the idea that baseline pain severity is a good predictor of how well patients respond to pregabalin for the treatment of pain relief and sleep disturbances, pain severity did not appear to make a clinically significant difference. in the general improvement of the global health status; no significant differences were observed in the percentage of PGIC responders between the moderate and severe pain cohorts.
Positive correlations between pain, sleep, and PGIC are well documented in chronic pain studies with pregabalin. Pooled data from 10 placebo-controlled clinical trials of pregabalin showed a high correlation between percent change in pain intensity and PGIC regardless of baseline pain, while higher baseline scores required greater crude reductions in pain to represent improvement. clinically important.
The complexities involved with overall measurement of effectiveness justify the need to further explore the association between baseline pain severity and PGIC, as a function of perceived response to treatment.
Conclusions
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