A Cost-Consequences analysis of the effect of Pregabalin in the treatment of peripheral Neuropathic Pain in routine medical practice in Primary Care settings

Neuropathic pain (NeP), defined as a pain initiated or caused by a primary injury or malfunction of the nervous system, is a common symptom of a group of a variety of conditions, including diabetic neuropathy, trigeminal neuralgia, or postherpetic neuralgia [1, 2]. Prevalence of NeP has been estimated to range between 5-7.5%, and produces up to 25% of pain clinics visits [3, 4]. Due to its severity, chronic evolution, and associated comorbidities, NeP has an important individual and social impact, mainly due to the degree of disability when compared to patients with chronic pain of non-neuropathic origin [5]. NeP is associated with depression, anxiety disorders, and impairment of sleep quality. All this translates into a loss of quality of life affecting the family of patients, and the social and working environment [6‐9]. Many patients with NeP are not properly diagnosed, do not receive the appropriate therapy, or are prescribed doses of appropriate drug lower than recommended [10, 11]. All of this influences the burden of disease [12‐14], and causing important healthcare and indirect costs [11, 15‐17].

The results of a systematic review suggested that anticonvulsive drugs, such as gabapentin or pregabalin, might be considered first-line treatments for peripheral NeP [18]. Pregabalin (PGB) is an alpha₂-delta ligand of voltage gated calcium channels that displays analgesic, anxiolytic, and anticonvulsive properties [19]. In randomized, placebo-controlled clinical trials, PGB demonstrated its efficacy for pain relief in patients with diabetic neuropathy and peripheral postherpetic neuralgia, significantly improving mood symptoms, sleep, and quality of life [20‐23]. However, the use of drugs in clinical trials markedly differs from that of the routine clinical practice in several aspects, thus limiting the generalization of results [24]. In this sense, real world, non-interventional studies may provide complementary information on the effectiveness of specific treatments in real clinical practice settings [25].

The objective of this research was to analyze the clinical and economic profile of PGB in a "Real World" setting in Spain. Observed data from the clinical practice are shown, indicating the effect of PGB on pain and its associated costs derived from the use of different health and non-health care resources in a group of patients with NeP of peripheral origin treated in routine clinical practice conditions for 12-weeks in Primary Care Settings (PCS).

To date, data have been published about economic evaluation of oral therapies for peripheral NeP disorders, including modelling the cost-effectiveness of gabapentin and PGB [33‐37]. However, data presented here are the first to evaluate the effect of PGB on cost and consequences of the treatment of NeP of peripheral origin in routine clinical practice conditions ("the Real World") and, thus, complementing the findings from previous clinical trial data. PGB, monotherapy and add-on therapy, administered at doses within the therapeutically recommended range, produced a marked reduction of pain (over 50%). Percentage of patient responders were very similar to those reported in published clinical trials of PGB in patients with diabetic neuropathy [38‐40], and post-herpetic neuralgia [21‐23, 41]. Variability in mean PGB doses observed in both PGB groups reinforces the absence, in clinical practice, of a single drug, or a single effective dose suitable for all NeP patients. This point is supported by similar variability observed in mean doses of medications used in the group not receiving PGB [42]. The fact that PGB dose recorded in this study was at the bottom of its therapeutic range could explain the different declining profile of pain observed in this observational trial when compared with the findings observed in randomized clinical trials in which a more rapid decline in the first weeks of treatment, followed by a plateau of effect, was observed [21‐23, 38‐42].

The reduction observed in baseline pain score translated into a substantial decrease of the use of both healthcare and indirect resources, resulting in a subsequent reduction in overall costs. The component of cost related to drug costs increased significantly in all groups, particularly with PGB. However, these increases were offset by significant reductions in healthcare and indirect costs, yielding a significant reduction in overall costs. Decrease in direct costs was more marked in the group of subjects not receiving PGB and in the PGB add-on group than in the PGB monotherapy group. However, indirect costs, derived from the lost-workdays equivalents across the 12 week period, were also reduced at final visit to a greater extent than direct healthcare costs: the magnitude of the reduction being significantly greater in the PGB-treated groups. As a result, mean reductions in total costs were higher in both PGB groups than in patients not receiving PGB. These reductions ranged between 62% and 76% over the non-PGB group, and should be considered of a meaningful size effect.

Interestingly, the mean utilization of all-type medical visits was significantly reduced in all study groups, although this reduction was again more marked in the PGB-treated groups compared with the non-PGB group. Over 50% of the reduction in total visits was due to decrease of the number of visits to primary care doctors. This might be of relevance, taking into account the increasingly longer waiting lists in most primary care clinics. Furthermore, use of complementary tests was reduced by over 50% for most items listed. Except for the PGB monotherapy group that by definition received one drug only, the mean number of prescribed drugs remained hardly unchanged in the two other groups throughout the study.

The magnitudes of baseline costs observed in this trial were similar to those observed in other studies conducted in our context [11, 34] or in Canada [35]. These results were within the range of values observed in our observational study, supporting the validity of "real world" health costs obtained in the present study. While some economic evaluations of clinical trial data in NeP have been published comparing diverse medical interventions in subjects with peripheral NeP, we could not find any studies investigating real world practice conditions in NeP, including those studying PGB [43].

Our study presents, however, some limitations that should be borne in mind. Among them, the observational design of the study implies potential confounding factors. One of these factors is confounding by indication, inherent to observational studies involving drugs [44]. This would explain, for instance, the significant differences observed among the three groups selected for the analysis of their baseline clinical characteristics, use of complementary tests, mean number of medical visits, particularly to primary care and specialist visits, as well as LWDE. However, these differences would be expected to bias the results against PGB since, as these patients had higher levels of baseline pain severity, significantly more LWDEs, more prescribed complementary tests, or more medical visits, yielding to higher quarterly costs in cohort receiving PGB as an add-on therapy. Then, certain risk for residual confounding could not be ruled out. In the PGB monotherapy group, this might be explained by a lower use of drugs in previous therapeutic schedules, or to a lower use of opioids before the study, compared to higher levels of previous exposure to NSAIDs and paracetamol in the other two groups. In general, subjects receiving PGB in monotherapy were exposed to lower percentages of analgesics, except tricyclic drugs, than the other two study groups. On the opposite, patients in the PGB add-on group received lower levels of exposure to antiepileptic drugs. These could be the only explanation for mentioned baseline differences, as groups were similar in distribution of type of neuropathic pain, elapsed time from diagnosis and the rest of demographic characteristics collected in the trial. It appeared that subjects receiving PGB as monotherapy could be less resistant patients. Other possible limitation is the unbalanced sample size of non-PGB group in comparison with the other two groups reflecting a possible selection preference of participants for pregabalin. However, and as mentioned, bias could go against pregabalin given the worst profile of subjects in some variables and the statistical analysis performed dealt with this unbalanced sample size of groups. Another limitation is that the study was not able to capture out-of-pocket cost, thus, a full societal perspective economic evaluation could not be performed. However, the economic impact of this limitation on overall costs is really limited due to the nature of NeP as most direct healthcare resources consumption are financed by Social Security and indirect costs represent the largest portion of total cost in these conditions. Also, it is worthy to comment on the diagnosis of NeP in the study. While patients were identified using ICD-10 classification criteria for peripheral NeP in conjunction with a diagnostic tool administered to assist general practitioners in categorizing the neuropathic component of pain, we cannot exclude the possibility of misdiagnosis to some extent. On the other hand, to calculate LWDE, the study recorded patient's self-perceived productivity, which could incorporate some degree of bias or uncertainty. The etiological diagnosis of types of NeP included here may have different long-term evolutions both in term of outcomes follow-up and health resources utilization and corresponding costs. Due this, any findings observed in this research should be limited to the trial duration of this study.

Patients in non-PGB and PGB add-on therapy groups were receiving analgesics without indication for neuropathic pain, such as paracetamol, metamizol or NSAIDs to some extent. The use of these non-appropriate therapies could explain partially the lower effectiveness and higher resources utilization observed in the results of non-PGB group; even they were treated with appropriate therapies in at least three out of four cases (near 77% of subjects in this group were treated with gabapentin, tramadol, codeine or amitriptyline, perhaps at doses in the lower end of its therapeutic range). On the opposite, all subjects included in PGB groups received an appropriate analgesic (an analgesic indicated for the treatment of neuropathic pain) by definition.

Overall, despite these limitations and the fact that a residual confounding can not be completely ruled out, the results of this analysis complement the findings observed with PGB in clinical trials, then consolidating PGB as an effective therapy for the treatment of peripheral NeP due to diabetic neuropathy, postherpetic neuralgia or trigeminal neuralgia in real world conditions of care. This effectiveness resulted in a reduction of the use of direct healthcare and indirect resources in routine medical practice, leading to lower costs both for the National Health System and society. Other learning from this trial was the observation of inadequate use, type and/or doses, of analgesics for neuropathic pain conditions in the real world in an important proportion of subjects.

To conclude, our analysis suggests that treatment with pregabalin both, in monotherapy or in combination with other medications produces a substantial reduction in pain in subjects with peripheral NeP, resulting in a substantial decrease in overall costs during the 12-week period of the study. The drug cost was largely counterbalanced by a greater cost reduction in other components of the healthcare system, and by a significant reduction in LWDE. However, randomized pragmatic clinical trials should be conducted to confirm these findings.