Cerebral Biochemical Effect of Pregabalin in Patients with Painful Diabetic Neuropathy: A Randomized Controlled Trial

Diabetes mellitus (DM) is a worldwide health problem of epidemic proportions, with the prevalence estimated to rise from 171 million people in 2000 to 366 million in 2030 [1]. Depending on the diagnostic criteria and population studied, the prevalence of painful diabetic polyneuropathy (PDN) varies from 8 to 26% [2‐4]. PDN is one of the most common causes of neuropathic pain, resulting in allodynia, hyperesthesia and hyperalgesia. Patients with PDN report these symptoms mostly in the distal region of their lower extremities. Consequently, several imaging modalities, such as magnetic resonance (MR) neurography and diffusion tensor imaging, have been developed which focus on the microstructural imaging of peripheral nerves at the anatomical level of the nerve fascicles [5‐7]. Despite these recent developments in peripheral nerve analysis, there is a consensus that chronic pain and its underlying mechanisms can be examined by brain imaging modalities, such as (functional) MR imaging (MRI) and MR spectroscopy (MRS) [8]. Such structural and functional neuroimaging studies in patients suffering from DM have shown alterations in numerous brain regions [9‐11]. A recent meta-analysis of proton MRS (¹H-nuclear MR [¹H-MNR]) in DM patients indicated that several metabolite levels are altered in various regions of the brain [12]. In addition to the identification of regional metabolite alterations, ¹H-NMR analysis can possibly also be used to measure treatment response and thus evaluate treatment efficacy [13]. To date, ¹H-NMR has been used to identify changes in brain chemistry following the administration of pregabalin to patients diagnosed with fibromyalgia [14]. Treatment with pregabalin is, according to internationally accepted guidelines, also recommended as a first-line symptomatic treatment for PDN [15]. Prior research suggests that the analgesic effects of pregabalin may be mediated through a reduction of hyperexcitation in ascending pain pathways, with pregabalin reducing dysregulation in areas of the brain associated with pain perception and restoring the inhibitory descending nociceptive pathways [14, 16]. Several chronic pain studies utilizing ¹H-MRS have shown increased glutamate (Glu) levels and decreased gamma-amino-butyric-acid (GABA) levels in the thalamus, the rostral anterior cingulate cortex (rACC) and the insula [17‐19]. Building further on these insights, our main hypothesis is that the clinical effect of pregabalin as a medical treatment for neuropathic pain results in a decrease of cerebral glutaminergic (excitatory) neurotransmission and an increase of GABAminergic (inhibitory) neurotransmission.

The goals of this ¹H-NMR study are twofold. First, we investigated the neurobiological effects of pregabalin as a treatment for neuropathic pain in four regions of interest (ROIs): the right rACC, dominant dorsolateral prefrontal cortex (DLPFC) and the bilateral thalami. Second, we evaluated the dose–response relation in these ROIs.

In this randomized controlled trial (RCT) we examined neurochemical changes in several brain neurometabolites following pregabalin administration in a population of patients with PDN. Pregabalin, an anticonvulsant, is considered to be the first-line treatment in the management of PDN, despite there being a lack of clear supporting evidence [20]. Studies on pain relief based on a dose-dependent response have shown that, in general, pregabalin administered in doses of 150 mg is ineffective while doses of 300 mg up to 600 mg result in a meaningful decrease of pain in patients suffering from PDN [20‐23]. Notwithstanding increasing prescription rates, the literature on the efficacy and dose dependency of pregabalin is still conflicting [24]. Therefore, we designed this study to investigate both the efficacy of pregabalin and the effect of different doses in an objective manner. The results of many previous studies, mainly based on subjective questionnaires and pain scales, contradict each other, while only a handful of studies have examined the effect of pregabalin versus placebo [25, 26]. These two shortcomings are addressed in our study.

It is important to first clarify the efficacy and impact of the different doses of pregabalin. Tolle et al. [25] examined the effects of pregabalin in 394 patients with PDN and found a significant decrease in pain between placebo and pregabalin administered at a dose of 600 mg per day but no differences for doses of 150 mg and 300 mg per day, respectively. A pain reduction of 50% was noted in almost half of the patients treated with pregabalin, while the same reduction was also seen in one-third of placebo patients [25]. Contradictory results have also been reported, with Rosenstock et al. [26] reporting a significant superiority of 300 mg/day pregabalin versus placebo. The findings of these two studies underline the challenge of treating neuropathic pain with pregabalin, as not one dose seems to be effective for all patients. To make the matter yet more complicated, a recent RCT showed no significant pain reduction with pregabalin treatment for leg pain in patients with sciatica [27]. These results are in line with our findings, as we found no differences in metabolite concentrations between the placebo and pregabalin (intervention) groups, but did observe some differences, although small, between the different doses.

This brings us to our second point of emphasis, as all of the previous high-level RCTs describe a decrease in numerical rating scale or VAS as a successful treatment, relying on self-reporting to assess treatment effectiveness. However, some patients suffering from PDN feel no pain, while others with the exact same pathology suffer from severe pain, implying that cortical processing and individual variability in antinociceptive mechanisms play an important role in the development of pain and pain perception. Therefore, we suggest that brain imaging is an objective diagnostic tool to assess brain chemistry and treatment efficacy, providing a solution by objectifying the neural correlates of pain perception and pain modulation. Imaging modalities have already shown promise for further unraveling of the central mechanisms contributing to pain chronification [17, 28‐31], which is of utmost importance as recent publications stress the underlying central mechanisms of  PDN, which are not yet fully understood and seem to play an important role. [32, 33].

Our study failed to identify significant, consistent changes in the concentrations of brain metabolites between the placebo and intervention group. Several explanations for this may be considered. One possibility is that ¹H-MRS is not an adequate tool to investigate cerebral changes in neurobiology. However, ¹H-MRS has been proven to be a valid, non-invasive and ionizing radiation-free analytical technique, not only in chronic pain populations, but also in patients with other pathologies, such as depression and Parkinson disease [34, 35]. Furthermore, it is a widely accepted technique to assess the outlines of brain tumors when planning surgery; this approach also allows metabolites to be identified and quantified, thereby providing the necessary anatomical, physiological and chemical information [36, 37]. Various studies have thus confirmed the reliability, reproducibility and stability of ¹H-MRS [37‐40]. Thus, the validity of ¹H-MRS should not be questioned, as it has proven to be a valuable tool to evaluate disease states or treatment protocols [41]. The second and probably the most realistic explanation for our findings may be found in our hypothesis which states that the analgesic effects of pregabalin are caused by reducing hyperexcitation in ascending pain pathways, thereby reducing dysregulation in areas of the brain associated with pain perception and restoring the inhibitory nociceptive pathways [14, 16]. Several chronic pain studies utilizing ¹H-MRS have shown increased Glu levels and decreased GABA levels in the thalamus and ACC [17‐19, 42, 43], confirming this disturbed excitation–inhibition balance and supporting our hypothesis that the clinical effect of pregabalin as a medical treatment for neuropathic pain would result in a decrease of cerebral glutaminergic (excitatory) neurotransmission and an increase in GABAminergic (inhibitory) neurotransmission. Unfortunately, the results of our study could not be used to confirm our hypothesis, suggesting that pregabalin does not restore the function of the inhibitory nociceptive pathways. In our study, we found no significant differences between patients with PDN and the controls in terms of GABA level, despite the role of GABA receptors in the modulation of pain perception. This lack of significant findings may be due to low concentrations of GABA in the brain; however, spectral editing sequences like MEGA-PRESS resolve this spectral overlap [44]. Also, NAA concentration in the thalamus has been proposed as a potential tool for investigating the efficacy of various therapies [45]. In some studies, a decrease was seen in several patient populations with neuropathic pain, with reduced NAA levels found in the DLPFC (low back pain) and the thalamus (postherpetic neuralgia, failed back surgery syndrome, complex regional pain syndrome) [17, 29]. These results underline the importance of reduced NAA levels as a chemical marker for chronic pain [29]. However, this neurometabolite did not show significant alterations over time or with dose. The same can be said for mINS and Glc, all of which have been shown to have some relationship with chronic pain but not to undergo significant alterations in concentration due to pregabalin treatment [17, 30].

The results of this study suggest that there is no objective, predictive value of ¹H-MRS to identify pain reduction by pregabalin, with equal concentrations of metabolites in the different brain regions in the placebo and pregabalin groups. However, comparison of the different doses of pregabalin did reveal that higher doses induced reductions in the concentrations of mINS in the rACC and DLPFC as well as decreased concentrations of GABA in the rACC. These findings can be explained by published findings which show that higher concentrations of MI and GABA are associated with higher pain intensity ratings [46, 47].

This placebo-controlled trial is the first of its kind to investigate the effect of pregabalin on brain metabolite concentration in a population suffering from PDN. Although ¹H-MRS analysis showed that pregabalin does not cause significant changes in the metabolic profile of the brain, some interesting conclusion can be drawn. Although no differences were found in metabolite concentrations between the placebo and intervention group, some differences were found regarding the different doses.